US20120058078A1

US20120058078A1 - Assay for the detection of factors that modulate the expression of ingap

Info

Publication number: US20120058078A1
Application number: US13/195,596
Authority: US
Inventors: David A. Taylor-Fishwick; Aaron I. Vinik
Original assignee: GMP Endotherapeutics Inc
Current assignee: GMP Endotherapeutics Inc
Priority date: 2002-01-11
Filing date: 2011-08-01
Publication date: 2012-03-08
Also published as: WO2003060096A2; WO2003060096A3; US7355024B2; PL371485A1; MXPA04006708A; CN1615150A; JP2005514930A; KR20040072700A; AU2003202273A1; NO20043330L; IL162493A0; MA27241A1; EP1463517A2; KR100766759B1; EP1463517A4; KR20070043057A; US20030207301A1; BR0306784A; US20090156458A1; CA2470359A1

Abstract

A reporter construct contains mammalian INGAP 5′-regulatory region or a fragment thereof, a minimal promoter element from mammalian INGAP or a heterologous promoter, and a reporter gene. The reporter construct can be used to screen for agents which alone or in combination up-regulate or down-regulate reporter gene expression. Alternatively, the reporter construct can be used to screen for agents that bind to the hamster INGAP 5′-regulatory region or a fragment thereof.

Description

This application is a continuation of U.S. patent application Ser. No. 12/062,740, filed on which is a continuation of U.S. patent application Ser. No. 10/339,767 filed on Jan. 9, 2003, now U.S. Pat. No. 7,355,024, which claims priority to provisional applications: 60/388,315 filed on Jun. 14, 2002, provisional application 60/361,073 filed on Mar. 1, 2002 and provisional application 60/346,898 filed on Jan. 11, 2002, the contents of which are incorporated by reference.

REFERENCE TO SEQ ID

The Sequence listing in “1247090060.tx” created on Aug. 1, 2011, being 108 KB in size, is incorporated by reference.

FIELD OF THE INVENTION

The invention relates to the field of assays for the detection of factors that modulate gene expression. Specifically, the invention relates to reporter constructs and methods for identifying agents that modulate the expression of the INGAP gene.

BACKGROUND OF THE INVENTION

Islet neogenesis gene associated protein (INGAP protein) has been identified as a pancreatic acinar cell protein that can induce islet cell neogenesis from progenitor cells resident in the pancreas in a manner that recapitulates islet development during normal embryogenesis. INGAP is unique in its ability to stimulate growth and differentiation of islets of Langerhans from precursor cells associated with pancreas. These islets evolve a mature insulin secretory profile capable of responding to perturbations in blood glucose in a physiologic manner. This potential anti-diabetic therapeutic has been shown to demonstrate homology across several species and to exert a biological response.
Pancreatic islet cell mass is lost in type 1 diabetes mellitus, a disease in which a progressive autoimmune reaction results in the selective destruction of insulin-producing β-cells. In type 2 diabetes mellitus, so-called adult-onset disease, but also increasingly a condition in young overweight people, the β-cell mass may be reduced by as much as 60% of normal. The number of functioning β-cells in the pancreas is of critical significance for the development, course, and outcome of diabetes. In type I diabetes, there is a reduction of β-cell mass to less than 2% of normal. Even in the face of severe insulin resistance as occurs in type II diabetes, the development of diabetes only occurs if there is inadequate compensatory increase in β-cell mass. Thus, the development of either of the major forms of diabetes can be regarded as a failure of adaptive β-cell growth and a subsequent deficiency in insulin secretion. Stimulating the growth of islets and β-cells from precursor cells, known as islet neogenesis, is an attractive approach to the amelioration of diabetes. There is need in the art for methods to identify agents that can modulate the expression of INGAP, whether in animals or in cultured cells.

BRIEF SUMMARY OF THE INVENTION

It is an object of the invention to provide a reporter construct containing the 5′-regulatory region from mammalian INGAP gene.
It is another object of the invention to provide methods for identifying agents which modulate INGAP expression.
It is another object of the invention to provide a nucleic acid or fragment of INGAP 5′-regulatory region.
It is another object of the invention to provide methods for increasing INGAP expression.
It is another object of the invention to provide a kit for modulating INGAP expression.
These and other objects of the invention are provided by one or more of the embodiments described below.
In one aspect of the invention a reporter construct is provided. The reporter construct comprises a regulatory region nucleotide sequence and a nucleotide sequence encoding a detectable product. In one aspect of the invention, the reporter construct is provided in a vector. The regulatory region nucleotide sequence is linked to the nucleotide sequence encoding a detectable product. The regulatory region nucleotide sequence may comprise one or more fragments of 5′ regulatory region of the INGAP genomic sequence, SEQ ID NO: 23, or it may comprise the entire length of the 5′ regulatory region. In one embodiment of the reporter construct, a promoter element is interposed between the regulatory region nucleotide sequence and the nucleotide sequence encoding a detectable product. The promoter element may be selected from the promoter elements present in the INGAP regulatory sequence. Alternatively, the promoter element present in the vector comprising the reporter construct may be used. The detectable product encoded by the said nucleotide sequence encoding a detectable product could be either a nucleic acid or a protein. The detectable product need not be the INGAP gene nucleic acid or protein.
In another embodiment of the invention, a method identifying agents that modulate INGAP expression is provided. The method comprises contacting a cell with a test agent, wherein the cell comprises a reporter construct of the present invention. Expression of the detectable nucleic acid or protein product in the cell is determined. A test agent is identified as a modulator of INGAP expression if the test agent modulates expression of the detectable product in the cell.
In another embodiment of the invention, an isolated nucleic acid comprising the genomic sequence of the hamster INGAP gene (SEQ ID NO: 2), or a fragment thereof is provided.
According to another embodiment of the invention, an in vitro method for identifying agents that modulate INGAP expression is provided. The method comprises contacting a test agent with a reporter construct of the present invention in a cell-free system that allows for transcription and translation of a nucleotide sequence. Expression of the detectable product is determined. The substance is identified as a modulator of INGAP expression if the test substance modulates expression of the detectable product.
According to another embodiment of the invention, an in vitro method for identifying an agent that modulate INGAP expression is provided. The method comprises contacting a test agent with a nucleic acid of the invention. Binding of the test agent to the nucleic acid is determined. The test agent is identified as a modulator of INGAP expression if the test agent binds to the nucleic acid.
According to another embodiment of the invention a method for increasing INGAP expression is provided. An effective amount of a factor that stimulates INGAP expression directly or indirectly, for example cytokines, chemokines, growth factors, or pharmacological agents, is administered to a mammal in need of increased INGAP expression.
According to another embodiment of the invention a kit for modulating INGAP expression is provided. The kit comprises a modulator of INGAP expression and instructions for using the modulator of INGAP expression to modulate INGAP expression.
According to another embodiment of the invention a method for modulating INGAP expression in a mammal to treat a disease state related to reduced islet cell function is provided. The method comprises the step of administering to the mammal an effective amount of a modulator of INGAP expression whereby the level of INGAP expression in the mammal is modified.
All documents cited are, in relevant part, incorporated herein by reference; the citation of any document is not to be construed as an admission that it is prior art with respect to the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the annotation of the hamster INGAP gene structure. The boundaries of introns 1-5 are listed in Table 1.

FIG. 2 shows an overview of the 5′-regulatory region of the hamster INGAP gene (nucleotides 1-3137 of SEQ ID NO: 2) showing many well known and well-characterized transcription factor binding sites. The minimal promoter element contains the regions noted with an underline (CAAT-box, TATA-box, and GC-box).

FIG. 3 shows a schematic of many well known and well-characterized transcription factor-binding sites for nucleotides 1-3123 of the 5′-regulatory region (SEQ ID NO: 1) of the hamster INGAP gene. Table 3 further describes these transcription factor-binding sites.

FIG. 4 shows the predicted transcription start sites within the 5′-regulatory region (SEQ ID NO: 1) of the hamster INGAP gene (SEQ ID NO: 2). The predicted start site is indicated by a boldface nucleotide. The start and end nucleotide numbers are indicated for the promoter sequence. The numbers refer to nucleotide numbers of the hamster INGAP gene (SEQ ID NO: 2)

FIG. 5 shows the adapter primer structure and sequence used in gene walking. Adapter primer 1 (AP1) and adapter primer 2 (AP2) are shown.

FIGS. 6 and 7 show the strategy for reconstructing the hamster INGAP gene. The hamster INGAP gene was reconstructed using the technique of gene walking. Shown are the fragments and the gene specific primers (GSP1 and GSP2) used in PCR amplification for gene walking. Fragments were joined together using unique restriction enzyme sites within each fragment. The nucleotide sequences of the individual primers are listed in Table 2.

FIG. 8 shows the fragments of INGAP 5′-regulatory region, which were cloned into pβGal-basic upstream of a β-galactosidase reporter gene. The labels on the left refer to the nucleotide fragments of SEQ ID NO: 23 which were cloned upstream of pβGal-basic.

FIG. 9A shows reporter activity in human embryonic kidney cells (293T) transfected with a reporter construct that contains various fragments of the 5′-regulatory region (SEQ ID NO: 23) of hamster INGAP DNA cloned upstream of a β-galactosidase reporter gene (pβGal-basic), or in a reporter construct which contains no INGAP DNA. The cells are stimulated with phorbol myristate acetate. Promoter activity is assessed by determining the level of β-galactosidase present in the cell using a β-galactosidase luminescent assay.

FIG. 9B shows reporter activity in human embryonic kidney cells (293T) transfected with a reporter construct that contains nucleotides 2030 to 3137 of the 5′-regulatory region (SEQ ID NO: 23) of hamster INGAP cloned upstream of a β-galactosidase reporter gene, or in a reporter construct which contains no INGAP DNA. The cells are stimulated with leukemia inhibitory factor. Promoter activity is assessed by determining the level of β-galactosidase present in the cell using a β-galactosidase luminescent assay.

FIG. 10 shows the reporter activity in human embryonic kidney cells (293T) transfected with a reporter construct that contains different fragments (see FIG. 8) of the 5′-regulatory region of hamster INGAP cloned upstream of a β-galactosidase reporter gene. The cells are stimulated with phorbol myristate acetate. Concentrations of PMA used are 6 ng/ml, 17 ng/ml, 50 ng/ml, 100 ng/ml, or 300 ng/ml. Promoter activity is assessed by determining the level of β-galactosidase present in the cell using a β-galactosidase luminescent assay.

FIG. 11 shows reporter activity in human embryonic kidney cells (293T) transfected with a reporter construct that contains different fragments (see FIG. 8) of the 5′-regulatory region of hamster INGAP cloned upstream of a β-galactosidase reporter gene. The cells are stimulated with human leukemia inhibitory factor (hLIF). Concentrations of hLIF used are 1 ng/ml, 10 ng/ml, or 30 ng/ml. Promoter activity was assessed by determining the level of β-galactosidase present in the cell using a β-galactosidase luminescent assay.

FIG. 12 shows RNA analysis for INGAP gene upregulation in rat amphicrine pancreatic cells, AR42J, treated with cytokine IL-6 or untreated. Total RNA is probed by Northern analysis for INGAP gene.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

It must be noted that as used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise.
The term “promoter” is used to define the region of a gene at which initiation and rate of transcription are controlled. It contains the site at which RNA polymerase binds and also sites for the binding of regulatory proteins, e.g. transcription factors, repressors, etc. In order to differentiate between the transcription initiation site and other sites that modulate rate of transcription, promoter region is generally subdivided into “minimal promoter element” and “regulatory region”. The term “minimal promoter element” or sometimes simply referred to as “promoter” therefore may include TATA box, GC-rich sequence and CAAT box; while “regulatory region” is usually a long stretch of nucleotide sequence where transcription factors and other factors bind. Most eukaryotic genes have long regulatory regions where many different transcription factors bind. The expression or the lack of expression of a given gene in a given cell type, tissue, organ, or an organism is governed by the interactions that take place on its regulatory region.
The term “transcription factor” is used to describe the proteins that bind short stretches of DNA in the regulatory regions of a gene. Transcription factors may interact with each other as well as RNA polymerase. Thus, transcription factors may bind hormones or second messengers, DNA, RNA, other transcription factors, or other proteins. They may activate or inhibit transcription of a given gene. Transcription factors are also sometimes referred to as “enhancers” or “repressors”. Transcription factor binding sites can be used to identify agents that bind to the 5′-regulatory region of the gene and modulate the gene's expression.
The term “reporter” is used to describe a coding sequence attached to a heterologous promoter or enhancer elements and whose product, either nucleic acid or protein, is easily detected and is quantifiable. Some common reporter genes include β-galactosidase (lacZ), chloramphenicol acetyltransferase (cat), β-glucuronidase (GUS), and green fluorescent protein (GFP).
A “reporter construct” is a piece of nucleic acid that includes a promoter element and a reporter gene housed in a suitable vector plasmid DNA. Regulatory region nucleotide sequences may be cloned 5′ of the promoter element to determine if they contain transcription factor binding sites. The reporter construct-containing vector is introduced into a cell that contains many transcription factors. Activation of the reporter gene by transcription factors may be monitored by detection and quantification of the product of the reporter gene.
The term “agent” is used here to essentially describe any means to modulate INGAP expression. Agent may be a chemical compound, a biological agent, or a physical force, a mechanical contraption, or any combinations thereof.

INGAP Promoter and Regulatory Region

It is a discovery of the present inventors that INGAP gene is regulated by a 5′-regulatory region that is susceptible to modulation by many known transcription factors, including PMA and LIF.
It is a further discovery of the present invention that the 5′-regulatory region nucleotide sequence of the INGAP gene may be used in screening assays to identify agents capable of modulating the INGAP gene expression. These modulating agents have potential as therapeutic agents for treating pathological conditions including, but not limited to, diabetes mellitus, both type 1 and type 2, endocrine and non-endocrine hypoplasia, hypertrophy, adenoma, neoplasia, and nesidioblastosis.
Mammalian INGAP, like most genes, has a 5′-regulatory region followed by introns and exons. The sequence of a mammalian (Hamster sp.) INGAP gene is provided as SEQ ID NO: 2. FIG. 1 details the relative location of the 5′-regulatory region, the introns and the exons of the hamster INGAP gene. The boundaries of introns 1-5 and the location of the TATA-box and the poly-A signal are listed in Table 1.

	TABLE 1

		Position In INGAP
	Description	Gene (SEQ ID NO: 2)

	TATA-Box	3094
	INTRON 1	3150-3426
	INTRON 2	3508-4442
	INTRON 3	4562-4735
	INTRON 4	4874-5459
	INTRON 5	5587-5843
	Poly-A Signal	6098-6103

The nucleotide sequence of the 5′-regulatory region including the promoter elements of mammalian INGAP, is shown partially in SEQ ID NO: 1, and completely in SEQ ID NO: 2 and 23 (nucleotides 1-3137 of SEQ ID NO: 2). Nucleotides 1-3120 of SEQ ID NO: 1 are identical to nucleotides 1-3120 of SEQ ID NO: 2 and SEQ ID NO: 23. An overview of the 5′-regulatory region is shown in FIG. 2. Representative transcription enhancer/repressor binding sites are shown also in FIG. 2. Predicted transcription enhancer/repressor binding sites for nucleotides 1-3123 of the 5′-regulatory region are shown in FIG. 3. Table 3 at the end of the specification details these transcription factors and their binding sites, and their locations in the regulatory region. Potential transcription factor binding analysis was done using MatInspector Professional™, which is a bioinformatics software that utilizes a library of matrix descriptions for transcription factor binding sites to locate matches in sequences of unlimited length (Quandt, K., Frech, K., Karas, H., Wingender, E., Werner, T. (1995) Nucleic Acids Res. 23, 4878-4884).
Table 3 lists predicted binding proteins (Further Information) based upon their classification into functionally similar matrix families (Family/matrix). The DNA sequence predicted to bind the protein (Sequence), whether sense or antisense DNA (Str) and location of the sequence in SEQ ID NO: 2, (Position) are listed. Further the similarity to the consecutive highest conserved nucleotides of a matrix (Core sim.) and similarity to all nucleotides in that matrix (Matrix sim.) along with the optimized value (Opt) defined in a way that a minimum number of matches is found in non-regulatory test sequences are also listed. Details to the algorithms used in MatInspector Professional™ is referenced:
OPT: This matrix similarity is the optimized value defined in a way that a minimum number of matches are found in non-regulatory test sequences (i.e. with this matrix similarity the number of false positive matches is minimized). This matrix similarity is used when the user checks “Optimized” as the matrix similarity threshold for MatInspector Professional™.
Family: Each matrix belongs to a so-called matrix family, where functionally similar matrices are grouped together, eliminating redundant matches by MatInspector Professional™ professional (if the family option was selected). E.g. the matrix family V$NFKB includes 5 similar matrices for NFkappaB (V$NFKAPPAB.01, V$NFKAPPAB 0.02, V$NFKAPPAB 0.03, V$NFKAPPAB50.01, V$NFKAPPAB65.01) as well as 1 matrix for the NFkappaB related factor c-Rel (V$CREL.01).
Matrix: The MatInspector Professional™ matrices have an identifier that indicates one of the following seven groups: vertebrates (V$), insects (I$), plants (P$), fungi (F$), nematodes (N$), bacteria (B$), and other functional elements (O$); followed by an acronym for the factor the matrix refers to, and a consecutive number discriminating between different matrices for the same factor. Thus, V$OCT1.02 indicates the second matrix for vertebral Oct-1 factor.
Core Sim: The “core sequence” of a matrix is defined as the (usually 4) consecutive highest conserved positions of the matrix. The core similarity is calculated as described here. The maximum core similarity of 1.0 is only reached when the highest conserved bases of a matrix match exactly in the sequence. More important than the core similarity is the matrix similarity which takes into account all bases over the whole matrix length.
Matrix Sim: The matrix similarity is calculated as described here. A perfect match to the matrix gets a score of 1.00 (each sequence position corresponds to the highest conserved nucleotide at that position in the matrix), a “good” match to the matrix usually has a similarity of >0.80. Mismatches in highly conserved positions of the matrix decrease the matrix similarity more than mismatches in less conserved regions.
Another aspect of the invention provides for a reporter construct. Reporter constructs contain a 5′ regulatory region nucleotide sequence fragment of SEQ ID NO: 23 (e.g., an enhancer and/or repressor binding site containing region), a promoter element (which may or may not be from INGAP regulatory region nucleotide sequence, SEQ ID NO: 23), and a reporter gene. The 5′-regulatory region nucleotide sequence is positioned upstream of the reporter gene. In order to determine the identity of various transcription factors that bind the 5′ regulatory region nucleotide sequence and to elucidate their binding locations within the 5′ regulatory nucleotide sequence of the INGAP gene, the region may be mapped using deletion analysis. One or more fragments of the regulatory region nucleotide sequence may be initially analyzed for their responses to various transcription factor activators. Once, a region of interest is determined, further fine mapping may be carried out where DNA from different locations within the regulatory region could be combined to make a more robust, and responsive reporter construct. DNA sequences, such as INGAP 5′-regulatory region DNA or a fragment thereof, can be manipulated by methods well known in the art. Examples of such techniques include, but are not limited to, polymerase chain reaction (PCR), restriction enzyme endonuclease digestion, ligation, and gene walking. Cloning fragments of DNA, such as 5′-regulatory regions is well known in the art.
Another approach to quantify the expression levels of a gene is to measure transcription of the gene. PCR-ELISA may be used to capture transcripts onto a solid phase using biotin or digoxigenin-labelled primers, oligonucleotide probes (oligoprobes) or directly after incorporation of the digoxigenin into the transcripts (Watzinger, F. and Lion, T. (2001) Nucleic Acids Res., 29, e52). Once captured, the transcripts can be detected using an enzyme-labeled avidin or anti-digoxigenin reporter molecule similar to a standard ELISA format. Another approach is to employ real-time PCR to detect the transcript of the reporter gene (Mackay, I. M. and Nitsche, A., Nucleic Acids Res. 2002 Mar. 15; 30 (6), 1292-305). In real-time PCR fluorogenic nucleotides are used and progress of the transcript is monitored in real-time as the polymerase transcribes the reporter gene.
The promoter element in the reporter construct may or may not be from the same gene as the 5′-regulatory region. As an example, the enhancer/repressor region from the INGAP 5′-regulatory region, or a fragment of the enhancer/repressor region from the INGAP 5′-regulatory region, may be cloned upstream of a heterologous minimal promoter element, e.g., the minimal CMV promoter (Boshart et al., 1985) and the promoters for TK (Nordeen, 1988), IL-2, and MMTV.
Transcription of a gene begins around the minimal promoter. FIG. 4 shows the predicted transcription start sites for mammalian INGAP gene (SEQ ID NO: 2). SEQ ID NO: 2 was analyzed using “Neural Network Promoter Prediction” program designed by Martin Reese to identify eukaryotic promoter recognition elements such as TATA-box, GC-box, CAAT-box, and the transcription start site. These promoter elements are present in various combinations separated by various distances in sequence. The program is available on the Internet and is located at http://www.fruitfly.org/seq_tools/promoter.html.
The reporter construct can be used to identify agents that modulate, either alone or in combination, the expression of INGAP. Some such agents may modulate expression of INGAP by binding to the regulatory region directly while others may regulate expression of transcription factors that bind to the INGAP regulatory region.
The reporter construct can be transfected into a host cell in vitro, or in vivo through the pancreatic duct, either transiently or stably, and a test agent introduced to the assay system. Examples of test agents include, but are not limited to organic and inorganic chemical agents, carbohydrates, proteins, oligonucleotides, cholecystokinin, mechanically induced pressure, and agents which cause a pancreatic duct obstruction. Expression of the reporter gene product can be determined by an assay appropriate for the reporter gene employed. Examples of such assays include, but are not limited to a luminescent assay for β-galactosidase or luciferase, an enzymatic assay for chloramphenicol acetyl transferase, and fluorescence detection for fluorescent proteins. Such assays are well known in the art, and a skilled artisan will be able to select an appropriate assay for the chosen reporter. A test agent is identified as a modulator of INGAP expression if the test agent modulates expression of the reporter gene product. Preferably the level of increase or decrease is at least 50%, 100%, 200%, 500%, or 1000%, but any statistically significant change can be an indicator of modulatory activity. A skilled artisan may also determine reporter gene product expression in untreated cells, and in treated and untreated cells transfected with a promoter-less reporter gene only. Such determinations can be used to determine background levels of expression.
Test agents can also be obtained by fractionating pancreatic secretion fluids. A pancreatic duct obstruction can be used as an exemplary method of harvesting pancreatic secretion fluids. The pancreatic secretion fluids can be fractionated by methods well known in the art. Examples include high-pressure liquid chromatography (HPLC), size exclusion chromatography, hydrophobic interacting columns, and density gradient centrifugation. Individual fractions can be tested for agents that modulate reporter gene expression using a method described herein. The individual fractions can be further fractionated to identify agents that modulate reporter gene expression. The identified test agents can be used to modulate the expression of INGAP.
A host cell can be any cell suitable for transfection and maintenance in a suitable assay system. Examples of suitable cells include, but are not limited to, mammalian cells, human cells, mouse cells, rat cells, monkey cells, dog cells, bovine cells, and porcine cells. Preferably the cells used will be human cells. The cells could be either transformed cells line or primary cells. Whole organ explants may also be used where the regulation may be monitored over many different cell types. Many methods exist in the art for transfecting or infecting cells with reporter construct DNA. Such methods include, but are not limited to, lipofection, electroporation, calcium phosphate precipitation, DEAE dextran, gene guns, and modified viral techniques (e.g., recombinant adenovirus or recombinant retrovirus). The skilled artisan can readily choose a method suitable for use with a given cell type and assay system.
The reporter construct can also be introduced in vivo directly into cells of the pancreas. Examples of methods to introduce the reporter construct into pancreatic cells in vivo include pancreatic duct retrograde perfusion and in vivo electroporation (Mir, 2001). The reporter construct encodes a reporter gene product that is readily measured in vivo. A test agent can be administered systemically or locally, and expression of the reporter gene in vivo can be determined by an assay appropriate for the particular reporter employed. Examples of such include a fluorescence assay for green fluorescent protein.
Methods for identifying agents that modulate INGAP expression can also be accomplished in vitro. The reporter construct can be contacted with a test agent in vitro under conditions sufficient for transcription and/or translation of the reporter gene. Components such as rabbit reticulocyte lysates or wheat germ extracts can be utilized for such a method. Subsequently, the expression level of the reporter gene can be determined as described above utilizing an appropriate assay for a given reporter gene. A test agent is identified as a modulator of INGAP expression if the test agent modulates expression of the reporter gene. Threshold levels of change can be set by the practitioner as discussed above.
A test agent can alternatively be contacted with an isolated and purified INGAP 5′-regulatory DNA molecule and one can determine if the test agent binds to the DNA molecule. Test agents can be a chemical agent, a protein, or a nucleic acid. Appropriate INGAP 5′-regulatory DNA molecules would include nucleotides 1-6586 of SEQ ID NO: 2, the 5′-regulatory region DNA (SEQ ID NO: 1, or SEQ ID NO: 23), or any fragment of the 5′-regulatory region, preferably a fragment which contains one or more enhancer/repressor binding sites. Methods to determine binding of the test agent to the fragment of DNA are well known in the art, e.g., electrophoretic mobility shift assay (EMSA). See for example Sambrook et al., MOLECULAR CLONING: A LABORATORY MANUAL, 2d ed., 1989, at pages 9.50-9.51. Fragments of the 5′-regulatory region can be obtained by methods well known in the art using the disclosed sequence (SEQ ID NO: 2). Examples of such methods include, PCR, restriction enzyme digestion, and chemical synthesis. Any fragment of DNA within the 5′-regulatory region (SEQ ID NO: 1, or 23) can be used. The exact location that an agent binds can be determined for example by utilizing smaller fragments to map precisely the binding site for the test agent. Test agents that bind in the assay can be further tested in other assays that require modulatory activity.
An agent that causes an increase or decrease in reporter gene expression can be used as a modulator of INGAP expression. The modulator can be administered to a mammal in need of such modulation. Examples of mammals that may need INGAP expression modulation are those with reduced pancreatic function, in particular reduced islet cell function. Such mammals include those who have diabetes mellitus, impaired glucose tolerance, impaired fasting glucose, hyperglycemia, obesity, and pancreatic insufficiency.
An agent that is identified as a modulator of INGAP expression can be supplied in a kit to treat diseases associated with reduced islet cell function. The kit would comprise in single or divided containers, in single or divided doses a modulator of INGAP expression. Written instructions may be included for using the modulator of INGAP expression. The instructions may simply refer a reader to another location such as a website or other information source.
Agents that cause an increase in reporter gene expression can be used to increase INGAP expression to treat a disease state related to reduced islet cell function. Agents that cause a decrease in reporter gene expression can be used to decrease INGAP expression to treat a disease state related to hyperactivity of islet cells or a disease where reduced INGAP expression is desirable. Examples of such agents include, but are not limited to, PMA, LIF, interleukin-6, Oncostatin M, and ciliary neurotropic factor. Agents can be administered by any number of routes including, but not limited to, oral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, intraventricular, transdermal, subcutaneous, intraperitoneal, intranasal, parenteral, topical, sublingual, rectal, or pancreatic duct retrograde perfusion. Agents for oral administration can be formulated using pharmaceutically acceptable carriers well known in the art in dosages suitable for oral administration. Such carriers enable the pharmaceutical compositions to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for ingestion by the mammal.
Agents for intravenous, intramuscular, intra-arterial, transdermal, and subcutaneous injections can be formulated using pharmaceutically acceptable carriers well known in the art in dosages suitable for injection into the mammal. Agents for intranasal, topical, and rectal administration can be formulated using pharmaceutically acceptable carriers well known in the art in dosages suitable for surface administration to the mammal. Mammals in need of an increase in INGAP expression include for example, mammals with diabetes mellitus, impaired glucose tolerance, impaired fasting glucose, hyperglycemia, obesity, and pancreatic insufficiency. Mammals in need of a decrease in INGAP expression include for example, mammals with hypoglycemia.
The following examples are offered by way of illustration and do not limit the invention disclosed herein.

EXAMPLES

Example 1

Hamster INGAP Genomic Sequence and Structure

The hamster INGAP genomic sequence and structure was determined by gene walking (Clontech) and DNA sequencing. Gene walking is a method for walking upstream toward a promoter or downstream in genomic DNA from a known sequence, such as cDNA. This method utilizes four uncloned, adapter-ligated genomic fragment libraries. The manufacturer's recommended protocol is followed with one notable exception; hamster genomic DNA was used to create the uncloned, adapter-ligated genomic fragment libraries.
To create uncloned, adapter ligated genomic fragment libraries, genomic DNA was purified from hamster cells. Four separate aliquots were thoroughly digested with PvuII, StuI, DraI, or EcoRV. Following digestion, inactivation of the restriction enzymes, and dephosphorylation, each separate pool of DNA fragments was ligated to an adapter AP1 SEQ ID NO: 489 or AP2 SEQ ID NO: 490, see FIG. 5. The adapter was phosphorylated to provide the requisite phosphate group for a ligation reaction.
Also note that the 3-prime side of the short adapter contains an amine group to prevent the adapters from forming concatamers.
Two gene specific primers (GSP1 and GSP2) were designed for each region of known sequence (i.e., the exons of the INGAP gene). See FIG. 6 for fragment location and GSP1 and GSP2 location. The gene specific primers were designed as reverse PCR primers for all fragments except fragments 1_2 and 14_5. The gene specific primers for fragments 1_2 and 14_5 were designed as forward primers. Adapter primer 1 (AP1) and adapter primer 2 (AP2) (FIG. 5) were forward PCR primers for all fragments except fragments 1_2 and 14_5, which were reverse PCR primers. The outer gene specific primer (GSP1) was used with adapter primer 1 in a PCR reaction. To increase specificity, a second, nested PCR was set up using the inner gene specific primer (GSP2) and adapter primer 2. A small aliquot of the first reaction served as template for the second reaction. Gene specific PCR primers utilized for gene walking are listed in Table 2 and the strategy used to build the INGAP genomic sequence is shown in FIGS. 6 and 7. The arrowheads in FIG. 6 represent the adapter primers (AP1 and AP2), while the circles represent the gene specific primers (GSP1 and GSP2).

TABLE 2

NAME (LOCATION)	SEQUENCE

INGEN 21_3 (1464, 1482)	5′-ACAAGCAATCTAGAGATGG-3′ (SEQ ID NO: 3)

INGEN 19_3 (1401, 1423)	5′-GTTCAGCTATGTTCATAGCAGGG-3′ (SEQ ID NO: 4)

INGEN 16_3 (1855, 1876)	5′-GTCTGTATGACTGTGTGGGAAG-3′ (SEQ ID NO: 5)

INGEN 15_3 (1929, 1948)	5′-GCACTTGAACTCAATGGCTC-3′ (SEQ ID NO: 6)

INGEN 14_3 (2147, 2168)	5′-GAACCACCTGACATGGGTGATG-3′ (SEQ ID NO: 7)

INGEN 13_3 (2177, 2200)	5′-GGGCATCGTATCATCTGGTTACAG-3′ (SEQ ID NO: 8)

INGEN 8_3 (2544, 2565)	5′-GGTTCAAAAAAGCTGCTTCAAC-3′ (SEQ ID NO: 9)

INGEN 7_3 (2666, 2689)	5′-GGAATAGCTGCAATTTATGCCCAT-3′ (SEQ ID NO: 10)

INGEN 4_3 (2833, 2858)	5′-CTTAGGAACATTCAGGCAGCCTCCTG-3′ (SEQ ID NO: 11)

INGEN 3_3 (2866, 2891)	5′-GTTGCCCTCTGCCACGTGTCAAGTTC-3′ (SEQ ID NO: 12)

INGEN 2_3 (3444, 3470)	5′-CATCCAAGACATCCTACAGAGGGTCAT-3′ (SEQ ID NO: 13)

INGEN 1_3 (3475, 3501)	5′-CCCAAGAAAGGAACATCAGGCAGGAAA-3′ (SEQ ID NO: 14)

INGEN 2_2 (3330, 3350)	5′-CCAAATGAGTGCTTCCCTGAA-3′ (SEQ ID NO: 15)

INGEN 1_2 (3241, 3266)	5′-GCAGCACTCTGAAACTCAGTAGAGTT-3′ (SEQ ID NO: 16)

INGEN 14_5 (5544, 5563)	5′-GCTGCTGACCGTGGTTATTG-3′ (SEQ ID NO: 17)

INGEN 13_5 (5463, 5485)	5′-ACACTACCCAACGGAAGTGGATG-3′ (SEQ ID NO: 18)

INGAP1_1L (3475, 3492)	5′-TTTCCTGCCTGATGTTCC-3′ (SEQ ID NO: 19)

INGAP1_1R (5957, 5976)	5′-TCATACTTGCTTCCTTGTCC-3′ (SEQ ID NO: 20)

INGAP2_1L (4470, 4488)	5′-CTTCACGTATAACCTGTCC-3′ (SEQ ID NO: 21)

INGAP2_1R (5905, 5923)	5′-ATTAGAACTGCCCTAGACC-3′ (SEQ ID NO: 22)

The PCR fragments were sequenced to determine the nucleotide sequence of the INGAP 5′-regulatory region, the introns, the intron/exon junctions, and the 3-prime polyadenylation regions. The nucleotide sequence of hamster INGAP genomic DNA is shown in SEQ ID NO: 2.

Example 2

Cloning Hamster INGAP 5′-Regulatory Region Fragment into a Reporter Construct

To construct the INGAP 5′-regulatory region, individual PCR fragments were joined together at unique restriction sites located within two adjoining fragments. FIGS. 6 and 7 detail the strategy used to piece the INGAP 5′-regulatory region together. Fragments 8_3 and 2_3 were joined at a unique SphI site; 14_3 and 8_3 were joined at a unique BbsI site; 16_3 and 14_3 were joined at a unique PstI site. The nucleotide sequence of hamster INGAP 5′-regulatory region DNA is shown in SEQ ID NO: 1 and 23 in the sequence listing.
The hamster INGAP 5′-regulatory region or a fragment of the 5′-regulatory region was cloned into a reporter plasmid, pβGal-Basic (Clontech). The 5′-regulatory region or fragments were cloned utilizing the unique XmaI site from the gene walking adapter primer and a unique BgIII site located at the 3-prime side of the regulatory region. FIG. 8 details the fragments cloned into pβGal-Basic. The sizes of the fragments are indicated to the right of the fragments and are expressed as the number of nucleotides of the fragment.

Example 3

Assay System to Screen for Factors that Modulate the Expression of INGAP

Promoter analysis of INGAP identified a number of potential promoter-proximal regulatory sites including the consensus transcription factor binding sites; cAMP response element (CRE), AP-1 and STAT. Promoter-fragment reporter-gene constructs were transiently transfected into 293T cells and co-transfection of secretory alkaline phosphatase was used to normalize for transfection efficiency.
Reporter constructs containing INGAP 5′-regulatory region fragments 2_3 sP (SEQ ID NO: 37), 2_3 dP (SEQ ID NO: 38), 2_3 pP (SEQ ID NO: 36), 14_3P (SEQ ID NO: 34), 16_3P (SEQ ID NO: 31), or 19_3P (SEQ ID NO: 23) were transfected into human cells. The pβGal-Basic plasmid without the hamster INGAP DNA was also transfected into human cells as a control to measure the level of endogenous reporter activity. Two days following transfection, the cells were treated with PMA for 24 hours or were untreated. To determine the level of promoter activity, the amount of β-galactosidase gene product was determined using a luminescent assay for β-galactosidase. FIG. 9A shows that construct 14_3P activated the INGAP expression the most, followed by 2_3 pP, and 16_3P.
Reporter construct containing INGAP 5′-regulatory region DNA nucleotides 2030 to 3120 was transfected into human cells. The pβGal-Basic plasmid without the hamster INGAP DNA was also transfected into human cells as a control to measure the level of endogenous reporter activity. Two days following transfection, the cells were treated with LIF for 24 hours or were untreated. To determine the level of promoter activity, the amount of β-galactosidase gene product was determined using a luminescent assay for β-galactosidase. FIG. 9B shows the results. LIF was determined to increase the activity of the 5′-regulatory region of mammalian INGAP. Forskolin (an activator of cAMP/CREB/CRE) did not modulate gene expression (data not shown).
It is important to note that when present in human cells, the hamster INGAP 5′-regulatory region is transactivated by the human transcription factors. Thus, linked to a reporter gene, the 5′-regulatory region of hamster INGAP creates a sensitive assay system to screen for factors that modulate the expression of INGAP.

Example 4

Determination of Approximate Location of PMA and LIF-Mediated Transcription Factor Binding in the 5′-Regulatory Region

To map the approximate location of PMA-initiated or LIF-initiated transcription factor binding different fragments of the hamster INGAP 5′-regulatory region were cloned into pβGal-Basic. See FIG. 8. The fragments cloned into the reporter construct were 2_3 sP (SEQ ID NO: 37), 2_3 dP (SEQ ID NO: 38), 2_3 pP (SEQ ID NO: 36), 14_3P (SEQ ID NO: 34), 16_3P (SEQ ID NO: 31), or 19_3P (SEQ ID NO: 23). The reporter constructs were transfected into human cells. Two days following transfection, the cells were treated with different concentrations of PMA or LIF for 24 hours. The concentrations of PMA used were 6 ng/ml, 17 ng/ml, 50 ng/ml, 100 ng/ml, or 300 ng/ml. The concentrations of LIF used were 1 ng/ml, 10 ng/ml, or 30 ng/ml. To determine the level of promoter activity, the amount of β-galactosidase gene product was determined using a luminescent assay for β-galactosidase. FIGS. 10 and 11 show the results for PMA and LIF treatment, respectively. Both PMA and LIF activated the cell reporter constructs. The exact location of the DNA contact sites can be narrowed further by cloning smaller fragments of the hamster INGAP 5′-regulatory region and by site directed mutations or deletions.

Example 5

RNA Analysis of INGAP Gene Upregulation

To determine if INGAP RNA levels increase after stimulation with a cytokine that signals through STAT, rat amphocrine pancreatic cells, AR42J were treated with IL-6 (1000 U/ml) for 24 hours. Total RNA was extracted from the treated and untreated cells using techniques well known in the art, e.g., using TRIZOL® reagent.
Equal amounts of total RNA (10 μg) were loaded in 2.5% formaldehyde gel and electrophoresed for 4 hours at 70V with a constant circulation of the buffer using a circulating pump. The gel was photographed and washed with water twice at room temperature and soaked in 20×SSC. The gel was transferred to a nylon membrane (Amersham) in 20×SSC overnight following a standard procedure. The membrane was washed with 20×SSC to remove any agar that might have attached to the membrane and baked for 4 hours at 80° C.
One hundred nanograms of hamster INGAP cDNA was labeled using Random Prime Labeling kit (Roche-BMB) and alpha-P³²dCTP (ICN). Approximately 20 million counts were used for hybridization in 20 ml hybridization buffer following the standard procedure at 42° C. for overnight. The blot was washed as follows: 2-times at room temperature with 2×SSC for 10 minutes each; 2-times at 42° C. with 2×SSC for 10 minutes each; 2-times at 55° C. with 1×SSC for 10 minutes each. The membrane was exposed to the film (XOMAT-Kodak) and kept at −80° C. overnight before developing.
Treatment with IL-6 caused an increase in INGAP gene expression (FIG. 12). These data demonstrate that extracellular factors that elevate AP-1-binding transcription factors and STAT-binding transcription factors are involved in the regulation of INGAP gene expression. These studies suggest that it is feasible to enhance INGAP expression as a means of inducing islet neogenesis.
While particular embodiments of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.

TABLE 3

SEQ
ID	Further	Position

NO:	Family/matrix	Information	Opt.	from-to	anchor

SEQ	V$LEFF/LEF1.01	TCF/LEF-1,	0.86	12-28	20
ID		involved in the
NO:		Wnt signal
41		transduction
		pathway

SEQ	V$MITF/MIT.01	MIT	0.81	22-40	31
ID		(microphthalmia
NO:		transcription
42		factor) and TFE3

SEQ	V$OCT1/OCT1.05	octamer-binding	0.90	27-41	34
ID		factor 1
NO:
43

SEQ	V$TCFF/TCF11.01	TCF11/KCR-	1.00	32-38	35
ID		F1/Nrf1
NO:		homodimers
44

SEQ	V$MYOF/MYOGNF1.01	Myogenin/	0.71	25-53	39
ID		nuclear factor 1
NO:		or related factors
45

SEQ	V$ZBPF/ZBP89.01	Zinc finger	0.93	36-48	42
ID		transcription
NO:		factor ZBP-89
46

SEQ	V$SP1F/GC.01	GC box elements	0.88	38-52	45
ID
NO:
47

SEQ	V$PERO/PPARA.01	PPAR/RXR	0.70	44-64	54
ID		heterodimers
NO:
48

SEQ	V$PAX5/PAX9.01	zebrafish PAX9	0.78	43-71	57
ID		binding sites
NO:
49

SEQ	V$TBPF/ATATA.01	Avian C-type LTR	0.81	68-84	76
ID		TATA box
NO:
50

SEQ	V$HMTB/MTBF.01	muscle-specific	0.90	76-84	80
ID		Mt binding site
NO:
51

SEQ	V$OCT1/OCT1.06	octamer-binding	0.80	74-88	81
ID		factor 1
NO:
52

NO:		(en-1)
65

SEQ	V$BARB/BARBIE.01	barbiturate-	0.88	230-244	237
ID		inducible element
NO:
66

SEQ	V$TBPF/TATA.01	cellular and viral	0.90	230-246	238
ID		TATA box
NO:		elements
67

SEQ	V$BARB/BARBIE.01	barbiturate-	0.88	252-266	259
ID		inducible element
NO:
68

SEQ	V$MYT1/MYT1.01	MyT1 zinc finger	0.75	272-284	278
ID		transcription
NO:		factor involved in
69		primary
		neurogenesis

SEQ	V$SMAD/SMAD4.01	Smad4	0.94	304-312	308
ID		transcription
NO:		factor involved in
70		TGF-beta
		signaling

SEQ	V$HOXF/CRX.01	Cone-rod	0.94	312-328	320
ID		homeobox-
NO:		containing
71		transcription
		factor/otx-like
		homeobox gene

SEQ	V$ECAT/NFY.01	nuclear factor Y	0.90	337-351	344
ID		(Y-box binding
NO:		factor)
72

SEQ	V$HOXF/PTX1.01	Pituitary	0.79	337-353	345
ID		Homeobox 1
NO:		(Ptx1)
73

SEQ	V$FKHD/FREAC2.01	Fork head	0.84	362-378	370
ID		RElated
NO:		ACtivator-2
74

SEQ	V$MINI/MUSCLE_INI.02	Muscle Initiator	0.86	401-419	410
ID		Sequence
NO:
75

SEQ	V$MOKF/MOK2.01	Ribonucleoprotein	0.74	409-429	419
ID		associated zinc
NO:		finger protein
76		MOK-2 (mouse)

SEQ	V$ZFIA/ZID.01	zinc finger with	0.85	414-426	420
ID		interaction
NO:		domain
77

SEQ	V$CART/XVENT2.01	Xenopus	0.82	418-434	426
ID		homeodomain
NO:		factor Xvent-2;
78		early BMP
		signaling
		response

SEQ	V$OCT1/OCT1.04	octamer-binding	0.80	421-435	428
ID		factor 1
NO:
79

SEQ	V$HOMS/S8.01	Binding site for	0.97	426-434	430
ID		S8 type
NO:		homeodomains
80

SEQ	V$NKXH/NKX25.02	homeo domain	0.88	424-436	430
ID		factor Nkx-
NO:		2.5/Csx, tinman
81		homolog low
		affinity sites

SEQ	V$CREB/CREBP1.01	cAMP-responsive	0.80	425-445	435
ID		element binding
NO:		protein 1
82

SEQ	V$COMP/COMP1.01	COMP1,	0.76	434-454	444
ID		cooperates with
NO:		myogenic
83		proteins in
		multicomponent
		complex

SEQ	V$HOXF/HOX1-3.01	Hox-1.3,	0.83	444-460	452
ID		vertebrate
NO:		homeobox
84		protein

SEQ	V$ETSF/GABP.01	GABP: GA	0.85	454-470	462
ID		binding protein
NO:
85

SEQ	V$LEFF/LEF1.01	TCF/LEF-1,	0.86	463-479	471
ID		involved in the
NO:		Wnt signal
86		transduction
		pathway

SEQ	V$STAT/STAT6.01	STAT6: signal	0.84	464-482	473
ID		transducer and
NO:		activator of
87		transcription 6

SEQ	V$GATA/GATA1.03	GATA-binding	0.95	490-502	496
ID		factor 1
NO:
88

SEQ	V$SRFF/SRF.01	serum response	0.66	487-505	496
ID		factor
NO:
89

SEQ	V$EVI1/EVI1.04	Ecotropic viral	0.77	493-509	501
ID		integration site 1
NO:		encoded factor
90

SEQ	V$AP4R/TH1E47.01	Thing1/E47	0.93	509-525	517
ID		heterodimer, TH1
NO:		bHLH member
91		specific
		expression in a
		variety of
		embryonic
		tissues

SEQ	V$AP4R/TAL1BETAITF2.01	Tal-1beta/ITF-2	0.85	512-528	520
ID		heterodimer
NO:
92

SEQ	V$NEUR/NEUROD1.01	DNA binding site	0.83	514-526	520
ID		for NEUROD1
NO:		(BETA-2/E47
93		dimer)

SEQ	V$MEF2/MEF2.05	MEF2	0.96	518-540	529
ID
NO:
94

SEQ	V$EVI1/EVI1.04	Ecotropic viral	0.77	523-539	531
ID		integration site 1
NO:		encoded factor
95

SEQ	V$MEF2/AMEF2.01	myocyte	0.80	521-543	532
ID		enhancer factor
NO:
96

SEQ	V$TBPF/MTATA.01	Muscle TATA box	0.84	524-540	532
ID
NO:
97

SEQ	V$HOXF/HOX1-3.01	Hox-1.3,	0.83	543-559	551
ID		vertebrate
NO:		homeobox
98		protein

SEQ	V$PDX1/ISL1.01	Pancreatic and	0.82	543-563	553
ID		intestinal lim-
NO:		homeodomain
99		factor

SEQ	V$OCT1/OCT1.05	octamer-binding	0.90	556-570	563
ID		factor 1
NO:
100

SEQ	V$CIZF/NMP4.01	NMP4 (nuclear	0.97	562-572	567
ID		matrix protein 4)/
NO:		CIZ (Cas-
101		interacting zinc
		finger protein)

SEQ	V$EVI1/EVI1.01	Ecotropic viral	0.72	569-585	577
ID		integration site 1
NO:		encoded factor
102

SEQ	V$AP1F/AP1.01	AP1 binding site	0.95	582-602	592
ID
NO:
103

SEQ	V$PIT1/PIT1.01	Pit1, GHF-1	0.86	589-599	594
ID		pituitary specific
NO:		pou domain
104		transcription
		factor

SEQ	V$AP1F/AP1.01	AP1 binding site	0.95	586-606	596
ID
NO:
105

SEQ	V$VMYB/VMYB.01	v-Myb	0.90	593-603	598
ID
NO:
106

SEQ	V$CIZF/NMP4.01	NMP4 (nuclear	0.97	595-605	600
ID		matrix protein 4)/
NO:		CIZ (Cas-
107		interacting zinc
		finger protein)

SEQ	V$GREF/PRE.01	Progesterone	0.84	604-622	613
ID		receptor binding
NO:		site
108

SEQ	V$GKLF/GKLF.01	Gut-enriched	0.91	632-646	639
ID		Krueppel-like
NO:		factor
109

SEQ	V$CIZF/NMP4.01	NMP4 (nuclear	0.97	637-647	642
ID		matrix protein 4)/
NO:		CIZ (Cas-
110		interacting zinc
		finger protein)

SEQ	V$NFAT/NFAT.01	Nuclear factor of	0.97	640-650	645
ID		activated T-cells
NO:
111

SEQ	V$MAZF/MAZ.01	Myc associated	0.90	649-661	655
ID		zinc finger
NO:		protein (MAZ)
112

SEQ	V$EGRF/WT1.01	Wilms Tumor	0.88	658-672	665
ID		Suppressor
NO:
113

SEQ	V$ZBPF/ZBP89.01	Zinc finger	0.93	663-675	669
ID		transcription
NO:		factor ZBP-89
114

SEQ	V$IRFF/IRF2.01	interferon	0.80	702-716	709
ID		regulatory factor 2
NO:
115

SEQ	V$BRNF/BRN2.01	POU factor Brn-2	0.91	746-762	754
ID		(N-Oct 3)
NO:
116

SEQ	V$ETSF/PU1.01	Pu.1 (Pu120) Ets-	0.86	746-762	754
ID		like transcription
NO:		factor identified
117		in lymphoid B-
		cells

SEQ	V$EVI1/EVI1.04	Ecotropic viral	0.77	750-766	758
ID		integration site 1
NO:		encoded factor
118

SEQ	V$EVI1/EVI1.05	Ecotropic viral	0.80	755-771	763
ID		integration site 1
NO:		encoded factor
119

SEQ	V$ZBPF/ZBP89.01	Zinc finger	0.93	764-776	770
ID		transcription
NO:		factor ZBP-89
120

SEQ	V$FAST/FAST1.01	FAST-1 SMAD	0.81	769-783	776
ID		interacting
NO:		protein
121

SEQ	V$TBPF/TATA.02	Mammalian C-	0.89	771-787	779
ID		type LTR TATA
NO:		box
122

SEQ	V$PAX5/PAX9.01	zebrafish PAX9	0.78	781-809	795
ID		binding sites
NO:
123

SEQ	V$OCT1/OCT.01	Octamer binding	0.79	793-807	800
ID		site (OCT1/OCT2
NO:		consensus)
124

SEQ	V$OCTP/OCT1P.01	octamer-binding	0.86	798-810	804
ID		factor 1, POU-
NO:		specific domain
125

SEQ	V$SRFF/SRF.01	serum response	0.66	797-815	806
ID		factor
NO:
126

SEQ	V$EVI1/EVI1.05	Ecotropic viral	0.80	802-818	810
ID		integration site 1
NO:		encoded factor
127

SEQ	V$CLOX/CDP.01	cut-like	0.75	803-819	811
ID		homeodomain
NO:		protein
128

SEQ	V$EVI1/EVI1.02	Ecotropic viral	0.83	807-823	815
ID		integration site 1
NO:		encoded factor
129

SEQ	V$ECAT/NFY.02	nuclear factor Y	0.91	810-824	817
ID		(Y-box binding
NO:		factor)
130

SEQ	V$HAML/AML3.01	Runt-related	0.84	811-825	818
ID		transcription
NO:		factor 2/CBFA1
131		(core-binding
		factor, runt
		domain, alpha
		subunit 1)

SEQ	V$PCAT/CAAT.01	cellular and viral	0.90	813-823	818
ID		CCAAT box
NO:
132

SEQ	V$GATA/GATA.01	GATA binding site	0.95	818-830	824
ID		(consensus)
NO:
133

SEQ	V$HNF1/HNF1.02	Hepatic nuclear	0.76	818-834	826
ID		factor 1
NO:
134

SEQ	V$HOXT/MEIS1_HOXA9.01	Homeobox	0.79	823-835	829
ID		protein MEIS1
NO:		binding site
135

SEQ	V$ECAT/NFY.01	nuclear factor Y	0.90	837-851	844
ID		(Y-box binding
NO:		factor)
136

SEQ	V$FKHD/FREAC2.01	Fork head	0.84	844-860	852
ID		RElated
NO:		ACtivator-2
137

SEQ	V$EVI1/EVI1.06	Ecotropic viral	0.83	846-862	854
ID		integration site 1
NO:		encoded factor
138

SEQ	V$GATA/GATA1.01	GATA-binding	0.96	853-865	859
ID		factor 1
NO:
139

SEQ	V$PCAT/ACAAT.01	Avian C-type LTR	0.86	856-866	861
ID		CCAAT box
NO:
140

SEQ	V$XBBF/RFX1.01	X-box binding	0.89	909-927	918
ID		protein RFX1
NO:
141

SEQ	V$EBOX/MYCMAX.02	c-Myc/Max	0.92	912-928	920
ID		heterodimer
NO:
142

SEQ	V$MITF/MIT.01	MIT	0.81	911-929	920
ID		(microphthalmia
NO:		transcription
143		factor) and TFE3

SEQ	V$ETSF/PU1.01	Pu.1 (Pu120) Ets-	0.86	927-943	935
ID		like transcription
NO:		factor identified
144		in lymphoid B-
		cells

SEQ	V$OCT1/OCT1.06	octamer-binding	0.80	932-946	939
ID		factor 1
NO:
145

SEQ	V$TALE/TGIF.01	TG-interacting	1.00	936-942	939
ID		factor belonging
NO:		to TALE class of
146		homeodomain
		factors

SEQ	V$MITF/MIT.01	MIT	0.81	935-953	944
ID		(microphthalmia
NO:		transcription
147		factor) and TFE3

SEQ	V$OCT1/OCT1.04	octamer-binding	0.80	941-955	948
ID		factor 1
NO:
148

SEQ	V$GATA/GATA.01	GATA binding site	0.95	962-974	968
ID		(consensus)
NO:
149

SEQ	V$SRFF/SRF.01	serum response	0.66	968-986	977
ID		factor
NO:
150

SEQ	V$CDXF/CDX2.01	Cdx-2	0.84	970-988	979
ID		mammalian
NO:		caudal related
151		intestinal transcr.
		factor

SEQ	V$FKHD/XFD2.01	Xenopus fork	0.89	972-988	980
ID		head domain
NO:		factor 2
152

SEQ	V$MEF2/MEF2.01	myogenic	0.74	970-992	981
ID		enhancer factor 2
NO:
153

SEQ	V$TBPF/TATA.01	cellular and viral	0.90	973-989	981
ID		TATA box
NO:		elements
154

SEQ	V$CART/CART1.01	Cart-1 (cartilage	0.84	978-994	986
ID		homeoprotein 1)
NO:
155

SEQ	V$CART/CART1.01	Cart-1 (cartilage	0.84	985-1001	993
ID		homeoprotein 1)
NO:
156

SEQ	V$SATB/SATB1.01	Special AT-rich	0.93	985-1001	993
ID		sequence-binding
NO:		protein 1,
157		predominantly
		expressed in
		thymocytes,
		binds to matrix
		attachment
		regions (MARs)

SEQ	V$BRNF/BRN3.01	POU transcription	0.78	987-1003	995
ID		factor Brn-3
NO:
158

SEQ	V$CLOX/CDP.01	cut-like	0.75	987-1003	995
ID		homeodomain
NO:		protein
159

SEQ	V$HOMS/S8.01	Binding site for	0.97	992-1000	996
ID		S8 type
NO:		homeodomains
160

SEQ	V$NKXH/DLX1.01	DLX-1, -2, and -5	0.91	990-1002	996
ID		binding sites
NO:
161

SEQ	V$HOXF/HOX1-3.01	Hox-1.3,	0.83	989-1005	997
ID		vertebrate
NO:		homeobox
162		protein

SEQ	V$PDX1/PDX1.01	Pdx1 (IDX1/IPF1)	0.74	988-1008	998
ID		pancreatic and
NO:		intestinal
163		homeodomain TF

SEQ	V$FKHD/XFD3.01	Xenopus fork	0.82	998-1014	1006
ID		head domain
NO:		factor 3
164

SEQ	V$HNF1/HNF1.01	hepatic nuclear	0.78	1000-1016	1008
ID		factor 1
NO:
165

SEQ	V$HNF1/HNF1.01	hepatic nuclear	0.78	1002-1018	1010
ID		factor 1
NO:
166

SEQ	V$PAX4/PAX4.01	Pax-4 paired	0.97	1005-1015	1010
ID		domain protein,
NO:		together with
167		PAX-6 involved in
		pancreatic
		development

SEQ	V$HOMS/S8.01	Binding site for	0.97	1007-1015	1011
ID		S8 type
NO:		homeodomains
168

SEQ	V$HOXF/HOX1-3.01	Hox-1.3,	0.83	1003-1019	1011
ID		vertebrate
NO:		homeobox
169		protein

SEQ	V$NKXH/DLX1.01	DLX-1, -2, and -5	0.91	1005-1017	1011
ID		binding sites
NO:
170

SEQ	V$RBIT/BRIGHT.01	Bright, B cell	0.92	1005-1017	1011
ID		regulator of IgH
NO:		transcription
171

SEQ	V$TBPF/ATATA.01	Avian C-type LTR	0.81	1005-1021	1013
ID		TATA box
NO:
172

SEQ	V$CREB/CREBP1.01	cAMP-responsive	0.80	1004-1024	1014
ID		element binding
NO:		protein 1
173

SEQ	V$RORA/RORA2.01	RAR-related	0.82	1007-1023	1015
ID		orphan receptor
NO:		alpha2
174

SEQ	V$PCAT/CAAT.01	cellular and viral	0.90	1022-1032	1027
ID		CCAAT box
NO:
175

SEQ	V$NKXH/NKX25.02	homeo domain	0.88	1022-1034	1028
ID		factor Nkx-
NO:		2.5/Csx, tinman
176		homolog low
		affinity sites

SEQ	V$CREB/HLF.01	hepatic leukemia	0.84	1022-1042	1032
ID		factor
NO:
177

SEQ	V$HOXF/HOX1-3.01	Hox-1.3,	0.83	1056-1072	1064
ID		vertebrate
NO:		homeobox
178		protein

SEQ	V$HOMS/S8.01	Binding site for	0.97	1061-1069	1065
ID		S8 type
NO:		homeodomains
179

SEQ	V$NKXH/DLX1.01	DLX-1, -2, and -5	0.91	1059-1071	1065
ID		binding sites
NO:
180

SEQ	V$RBIT/BRIGHT.01	Bright, B cell	0.92	1059-1071	1065
ID		regulator of IgH
NO:		transcription
181

SEQ	V$BRNF/BRN2.01	POU factor Brn-2	0.91	1058-1074	1066
ID		(N-Oct 3)
NO:
182

SEQ	V$OCT1/OCT1.06	octamer-binding	0.80	1060-1074	1067
ID		factor 1
NO:
183

SEQ	V$HOXF/HOX1-3.01	Hox-1.3,	0.83	1061-1077	1069
ID		vertebrate
NO:		homeobox
184		protein

SEQ	V$OCT1/OCT1.06	octamer-binding	0.80	1079-1093	1086
ID		factor 1
NO:
185

SEQ	V$FAST/FAST1.01	FAST-1 SMAD	0.81	1080-1094	1087
ID		interacting
NO:		protein
186

SEQ	V$RREB/RREB1.01	Ras-responsive	0.79	1081-1095	1088
ID		element binding
NO:		protein 1
187

SEQ	V$E2FF/E2F.02	E2F, involved in	0.84	1085-1099	1092
ID		cell cycle
NO:		regulation,
188		interacts with Rb
		p107 protein

SEQ	V$CREB/TAXCREB.01	Tax/CREB	0.81	1091-1111	1101
ID		complex
NO:
189

SEQ	V$AP1F/VMAF.01	v-Maf	0.82	1092-1112	1102
ID
NO:
190

SEQ	V$MYT1/MYT1.01	MyT1 zinc finger	0.75	1123-1135	1129
ID		transcription
NO:		factor involved in
191		primary
		neurogenesis

SEQ	V$CLOX/CLOX.01	Clox	0.81	1136-1152	1144
ID
NO:
192

SEQ	V$HNF4/HNF4.01	Hepatic nuclear	0.82	1156-1172	1164
ID		factor 4
NO:
193

SEQ	V$LEFF/LEF1.01	TCF/LEF-1,	0.86	1157-1173	1165
ID		involved in the
NO:		Wnt signal
194		transduction
		pathway

SEQ	V$PERO/PPARA.01	PPAR/RXR	0.70	1157-1177	1167
ID		heterodimers
NO:
195

SEQ	V$CLOX/CLOX.01	Clox	0.81	1173-1189	1181
ID
NO:
196

SEQ	V$HNF6/HNF6.01	Liver enriched	0.82	1175-1189	1182
ID		Cut -
NO:		Homeodomain
197		transcription
		factor HNF6
		(ONECUT)

SEQ	V$SRFF/SRF.02	serum response	0.83	1177-1195	1186
ID		factor
NO:
198

SEQ	V$CLOX/CDPCR3.01	cut-like	0.75	1180-1196	1188
ID		homeodomain
NO:		protein
199

SEQ	V$PIT1/PIT1.01	Pit1, GHF-1	0.86	1186-1196	1191
ID		pituitary specific
NO:		pou domain
200		transcription
		factor

SEQ	V$HMTB/MTBF.01	muscle-specific	0.90	1196-1204	1200
ID		Mt binding site
NO:
201

SEQ	V$FKHD/HFH8.01	HNF-3/Fkh	0.92	1200-1216	1208
ID		Homolog-8
NO:
202

SEQ	V$E4FF/E4F.01	GLI-Krueppel-	0.82	1223-1235	1229
ID		related
NO:		transcription
203		factor, regulator
		of adenovirus E4
		promoter

SEQ	V$CREB/HLF.01	hepatic leukemia	0.84	1221-1241	1231
ID		factor
NO:
204

SEQ	V$VBPF/VBP.01	PAR-type chicken	0.86	1226-1236	1231
ID		vitellogenin
NO:		promoter-binding
205		protein

SEQ	V$OCT1/OCT.01	Octamer binding	0.79	1259-1273	1266
ID		site (OCT1/OCT2
NO:		consensus)
206

SEQ	V$STAT/STAT6.01	STAT6: signal	0.84	1261-1279	1270
ID		transducer and
NO:		activator of
207		transcription 6

SEQ	V$CDXF/CDX2.01	Cdx-2	0.84	1270-1288	1279
ID		mammalian
NO:		caudal related
208		intestinal transcr.
		factor

SEQ	V$SORY/SOX9.01	SOX (SRY-related	0.90	1280-1296	1288
ID		HMG box)
NO:
209

SEQ	V$FKHD/HFH2.01	HNF-3/Fkh	0.93	1285-1301	1293
ID		Homolog	2
NO:
210

SEQ	V$CDXF/CDX2.01	Cdx-2	0.84	1286-1304	1295
ID		mammalian
NO:		caudal related
211		intestinal transcr.
		factor

SEQ	V$OCTB/TST1.01	POU-factor Tst-	0.87	1288-1302	1295
ID		1/Oct-6
NO:
212

SEQ	V$PDX1/ISL1.01	Pancreatic and	0.82	1298-1318	1308
ID		intestinal lim-
NO:		homeodomain
213		factor

SEQ	V$SORY/SOX9.01	SOX (SRY-related	0.90	1308-1324	1316
ID		HMG box)
NO:
214

SEQ	V$CREB/HLF.01	hepatic leukemia	0.84	1310-1330	1320
ID		factor
NO:
215

SEQ	V$VBPF/VBP.01	PAR-type chicken	0.86	1315-1325	1320
ID		vitellogenin
NO:		promoter-binding
216		protein

SEQ	V$CEBP/CEBPB.01	CCAAT/enhancer	0.94	1313-1331	1322
ID		binding protein
NO:		beta
217

SEQ	V$PDX1/ISL1.01	Pancreatic and	0.82	1313-1333	1323
ID		intestinal lim-
NO:		homeodomain
218		factor

SEQ	V$HAML/AML1.01	runt-factor AML-1	1.00	1323-1337	1330
ID
NO:
219

SEQ	V$GREF/ARE.01	Androgene	0.80	1323-1341	1332
ID		receptor binding
NO:		site
220

SEQ	V$TEAF/TEF1.01	TEF-1 related	0.84	1343-1355	1349
ID		muscle factor
NO:
221

SEQ	V$CMYB/CMYB.01	c-Myb, important	0.99	1352-1360	1356
ID		in hematopoesis,
NO:		cellular
222		equivalent to
		avian
		myoblastosis
		virus oncogene v-
		myb

SEQ	V$AP4R/TH1E47.01	Thing1/E47	0.93	1378-1394	1386
ID		heterodimer, TH1
NO:		bHLH member
223		specific
		expression in a
		variety of
		embryonic
		tissues

SEQ	V$CP2F/CP2.01	CP2	0.90	1384-1394	1389
ID
NO:
224

SEQ	V$CHOP/CHOP.01	heterodimers of	0.90	1386-1398	1392
ID		CHOP and
NO:		C/EBPalpha
225

SEQ	V$CEBP/CEBP.02	C/EBP binding	0.85	1385-1403	1394
ID		site
NO:
226

SEQ	V$MEF2/HMEF2.01	myocyte	0.76	1384-1406	1395
ID		enhancer factor
NO:
227

SEQ	V$OCT1/OCT1.03	octamer-binding	0.85	1388-1402	1395
ID		factor 1
NO:
228

SEQ	V$HMTB/MTBF.01	muscle-specific	0.90	1394-1402	1398
ID		Mt binding site
NO:
229

SEQ	V$CLOX/CDPCR3.01	cut-like	0.75	1422-1438	1430
ID		homeodomain
NO:		protein
230

SEQ	V$OCT1/OCT1.05	octamer-binding	0.90	1423-1437	1430
ID		factor 1
NO:
231

SEQ	V$HOXF/HOX1-3.01	Hox-1.3,	0.83	1423-1439	1431
ID		vertebrate
NO:		homeobox
232		protein

SEQ	V$PDX1/PDX1.01	Pdx1 (IDX1/IPF1)	0.74	1423-1443	1433
ID		pancreatic and
NO:		intestinal
233		homeodomain TF

SEQ	V$SORY/SOX5.01	Sox-5	0.87	1426-1442	1434
ID
NO:
234

SEQ	V$OCT1/OCT1.05	octamer-binding	0.90	1444-1458	1451
ID		factor 1
NO:
235

SEQ	V$CREB/E4BP4.01	E4BP4, bZIP	0.80	1443-1463	1453
ID		domain,
NO:		transcriptional
236		repressor

SEQ	V$VBPF/VBP.01	PAR-type chicken	0.86	1449-1459	1454
ID		vitellogenin
NO:		promoter-binding
237		protein

SEQ	V$TBPF/MTATA.01	Muscle TATA box	0.84	1455-1471	1463
ID
NO:
238

SEQ	V$PBXF/PBX1.01	homeo domain	0.78	1469-1481	1475
ID		factor Pbx-1
NO:
239

SEQ	V$COMP/COMP1.01	COMP1,	0.76	1467-1487	1477
ID		cooperates with
NO:		myogenic
240		proteins in
		multicomponent
		complex

SEQ	V$SORY/S0X5.01	Sox-5	0.87	1478-1494	1486
ID
NO:
241

SEQ	V$FKHD/FREAC2.01	Fork head	0.84	1485-1501	1493
ID		RElated
NO:		ACtivator-2
242

SEQ	V$PDX1/ISL1.01	Pancreatic and	0.82	1495-1515	1505
ID		intestinal lim-
NO:		homeodomain
243		factor

SEQ	V$HOXF/HOX1-3.01	Hox-1.3,	0.83	1499-1515	1507
ID		vertebrate
NO:		homeobox
244		protein

SEQ	V$PDX1/PDX1.01	Pdx1 (IDX1/IPF1)	0.74	1498-1518	1508
ID		pancreatic and
NO:		intestinal
245		homeodomain TF

SEQ	V$CART/XVENT2.01	Xenopus	0.82	1502-1518	1510
ID		homeodomain
NO:		factor Xvent-2;
246		early BMP
		signaling
		response

SEQ	V$CDXF/CDX2.01	Cdx-2	0.84	1507-1525	1516
ID		mammalian
NO:		caudal related
247		intestinal transcr.
		factor

SEQ	V$MEF2/MEF2.05	MEF2	0.96	1505-1527	1516
ID
NO:
248

SEQ	V$HNF1/HNF1.01	hepatic nuclear	0.78	1510-1526	1518
ID		factor 1
NO:
249

SEQ	V$OCT1/OCT1.06	octamer-binding	0.80	1511-1525	1518
ID		factor 1
NO:
250

SEQ	V$TBPF/TATA.02	Mammalian C-	0.89	1510-1526	1518
ID		type LTR TATA
NO:		box
251

SEQ	V$NKXH/MSX.01	Homeodomain	0.97	1514-1526	1520
ID		proteins MSX-1
NO:		and MSX-2
252

SEQ	V$RBIT/BRIGHT.01	Bright, B cell	0.92	1515-1527	1521
ID		regulator of IgH
NO:		transcription
253

SEQ	V$MEF2/AMEF2.01	myocyte	0.80	1514-1536	1525
ID		enhancer factor
NO:
254

SEQ	V$EVI1/EVI1.02	Ecotropic viral	0.83	1526-1542	1534
ID		integration site 1
NO:		encoded factor
255

SEQ	V$GATA/GATA1.02	GATA-binding	0.99	1528-1540	1534
ID		factor 1
NO:
256

SEQ	V$GATA/GATA3.02	GATA-binding	0.91	1537-1549	1543
ID		factor 3
NO:
257

SEQ	V$GATA/GATA3.02	GATA-binding	0.91	1559-1571	1565
ID		factor 3
NO:
258

SEQ	V$OCT1/OCT1.02	octamer-binding	0.82	1561-1575	1568
ID		factor 1
NO:
259

SEQ	V$CEBP/CEBPB.01	CCAAT/enhancer	0.94	1567-1585	1576
ID		binding protein
NO:		beta
260

SEQ	V$PLZF/PLZF.01	Promyelocytic	0.86	1574-1588	1581
ID		leukemia zink
NO:		finger (TF with
261		nine Krueppel-
		like zink fingers)

SEQ	V$PAX3/PAX3.01	Pax-3 paired	0.76	1587-1599	1593
ID		domain protein,
NO:		expressed in
262		embryogenesis,
		mutations
		correlate to
		Waardenburg
		Syndrome

SEQ	V$CREB/ATF.01	activating	0.90	1588-1608	1598
ID		transcription
NO:		factor
263

SEQ	V$AP4R/TH1E47.01	Thing1/E47	0.93	1614-1630	1622
ID		heterodimer, TH1
NO:		bHLH member
264		specific
		expression in a
		variety of
		embryonic
		tissues

SEQ	V$NKXH/MSX.01	Homeodomain	0.97	1619-1631	1625
ID		proteins MSX-1
NO:		and MSX-2
265

SEQ	V$RBIT/BRIGHT.01	Bright, B cell	0.92	1620-1632	1626
ID		regulator of IgH
NO:		transcription
266

SEQ	V$OCTB/TST1.01	POU-factor Tst-	0.87	1620-1634	1627
ID		1/Oct-6
NO:
267

SEQ	V$NKXH/DLX3.01	Distal-less 3	0.91	1628-1640	1634
ID		homeodomain
NO:		transcription
268		factor

SEQ	V$GREF/PRE.01	Progesterone	0.84	1628-1646	1637
ID		receptor binding
NO:		site
269

SEQ	V$TBPF/TATA.01	cellular and viral	0.90	1636-1652	1644
ID		TATA box
NO:		elements
270

SEQ	V$FKHD/XFD2.01	Xenopus fork	0.89	1637-1653	1645
ID		head domain
NO:		factor 2
271

SEQ	V$TBPF/TATA.01	cellular and viral	0.90	1638-1654	1646
ID		TATA box
NO:		elements
272

SEQ	V$CREB/E4BP4.01	E4BP4, bZIP	0.80	1638-1658	1648
ID		domain,
NO:		transcriptional
273		repressor

SEQ	V$PDX1/ISL1.01	Pancreatic and	0.82	1644-1664	1654
ID		intestinal lim-
NO:		homeodomain
274		factor

SEQ	V$COMP/COMP1.01	COMP1,	0.76	1648-1668	1658
ID		cooperates with
NO:		myogenic
275		proteins in
		multicomponent
		complex

SEQ	V$TBPF/TATA.02	Mammalian C-	0.89	1658-1674	1666
ID		type LTR TATA
NO:		box
276

SEQ	V$IRFF/ISRE.01	interferon-	0.81	1662-1676	1669
ID		stimulated
NO:		response element
277

SEQ	V$XBBF/RFX1.01	X-box binding	0.89	1660-1678	1669
ID		protein RFX1
NO:
278

SEQ	V$MYT1/MYT1.02	MyT1 zinc finger	0.88	1667-1679	1673
ID		transcription
NO:		factor involved in
279		primary
		neurogenesis

SEQ	V$OCT1/OCT1.06	octamer-binding	0.80	1683-1697	1690
ID		factor 1
NO:
280

SEQ	V$AP1F/TCF11MAFG.01	TCF11/MafG	0.81	1681-1701	1691
ID		heterodimers,
NO:		binding to
281		subclass of AP1
		sites

SEQ	V$NKXH/MSX2.01	Muscle segment	0.95	1687-1699	1693
ID		homeo box 2,
NO:		homologue of
282		Drosophila (HOX
		8)

SEQ	V$FAST/FAST1.01	FAST-1 SMAD	0.81	1687-1701	1694
ID		interacting
NO:		protein
283

SEQ	V$PBXC/PBX1_MEIS1.03	Binding site for a	0.76	1686-1702	1694
ID		Pbx1/Meis1
NO:		heterodimer
284

SEQ	V$CIZF/NMP4.01	NMP4 (nuclear	0.97	1699-1709	1704
ID		matrix protein 4)/
NO:		CIZ (Cas-
285		interacting zinc
		finger protein)

SEQ	V$STAT/STAT6.01	STAT6: signal	0.84	1702-1720	1711
ID		transducer and
NO:		activator of
286		transcription 6

SEQ	V$AP4R/TAL1BETAE47.01	Tal-1beta/E47	0.87	1710-1726	1718
ID		heterodimer
NO:
287

SEQ	V$SORY/HMGIY.01	HMGI(Y) high-	0.92	1720-1736	1728
ID		mobility-group
NO:		protein I (Y),
288		architectural
		transcription
		factor organizing
		the framework of
		a nuclear protein-
		DNA
		transcriptional
		complex

SEQ	V$MYT1/MYT1.01	MyT1 zinc finger	0.75	1723-1735	1729
ID		transcription
NO:		factor involved in
289		primary
		neurogenesis

SEQ	V$SRFF/SRF.01	serum response	0.66	1728-1746	1737
ID		factor
NO:
290

SEQ	V$HOXF/HOXA9.01	Member of the	0.87	1731-1747	1739
ID		vertebrate HOX -
NO:		cluster of
291		homeobox factors

SEQ	V$HOXT/MEIS1_HOXA9.01	Homeobox	0.79	1734-1746	1740
ID		protein MEIS1
NO:		binding site
292

SEQ	V$PIT1/PIT1.01	Pit1, GHF-1	0.86	1737-1747	1742
ID		pituitary specific
NO:		pou domain
293		transcription
		factor

SEQ	V$AP1F/AP1.01	AP1 binding site	0.95	1734-1754	1744
ID
NO:
294

SEQ	V$VBPF/VBP.01	PAR-type chicken	0.86	1746-1756	1751
ID		vitellogenin
NO:		promoter-binding
295		protein

SEQ	V$FAST/FAST1.01	FAST-1 SMAD	0.81	1757-1771	1764
ID		interacting
NO:		protein
296

SEQ	V$HOXF/EN1.01	Homeobox	0.77	1759-1775	1767
ID		protein engrailed
NO:		(en-1)
297

SEQ	V$TBPF/MTATA.01	Muscle TATA box	0.84	1763-1779	1771
ID
NO:
298

SEQ	V$ETSF/ETS2.01	c-Ets-2 binding	0.86	1774-1790	1782
ID		site
NO:
299

SEQ	V$MYT1/MYT1.02	MyT1 zinc finger	0.88	1780-1792	1786
ID		transcription
NO:		factor involved in
300		primary
		neurogenesis

SEQ	V$GFI1/GFI1.01	Growth factor	0.97	1782-1796	1789
ID		independence 1
NO:		zinc finger
301		protein acts as
		transcriptional
		repressor

SEQ	V$TBPF/TATA.01	cellular and viral	0.90	1784-1800	1792
ID		TATA box
NO:		elements
302

SEQ	V$BRNF/BRN2.01	POU factor Brn-2	0.91	1786-1802	1794
ID		(N-Oct 3)
NO:
303

SEQ	V$HOXT/MEIS1_HOXA9.01	Homeobox	0.79	1788-1800	1794
ID		protein MEIS1
NO:		binding site
304

SEQ	V$MEF2/AMEF2.01	myocyte	0.80	1783-1805	1794
ID		enhancer factor
NO:
305

SEQ	V$OCTB/TST1.01	POU-factor Tst-	0.87	1787-1801	1794
ID		1/Oct-6
NO:
306

SEQ	V$HOXF/HOXA9.01	Member of the	0.87	1787-1803	1795
ID		vertebrate HOX-
NO:		cluster of
307		homeobox factors

SEQ	V$BRNF/BRN2.01	POU factor Brn-2	0.91	1788-1804	1796
ID		(N-Oct 3)
NO:
308

SEQ	V$PARF/DBP.01	Albumin D-box	0.84	1791-1805	1798
ID		binding protein
NO:
309

SEQ	V$OCT1/OCT1.02	octamer-binding	0.82	1795-1809	1802
ID		factor 1
NO:
310

SEQ	V$FKHD/FREAC2.01	Fork head	0.84	1816-1832	1824
ID		RElated
NO:		ACtivator-2
311

SEQ	V$SORY/SOX5.01	Sox-5	0.87	1821-1837	1829
ID
NO:
312

SEQ	V$AREB/AREB6.04	AREB6 (Atp1a1	0.98	1837-1849	1843
ID		regulatory
NO:		element binding
313		factor 6)

SEQ	V$MYT1/MYT1.02	MyT1 zinc finger	0.88	1848-1860	1854
ID		transcription
NO:		factor involved in
314		primary
		neurogenesis

SEQ	V$RBPF/RBPJK.01	Mammalian	0.84	1851-1865	1858
ID		transcriptional
NO:		repressor RBP-
315		Jkappa/CBF1

SEQ	V$OCT1/OCT1.02	octamer-binding	0.82	1875-1889	1882
ID		factor 1
NO:
316

SEQ	V$FKHD/FREAC4.01	Fork head	0.78	1875-1891	1883
ID		RElated
NO:		ACtivator-4
317

SEQ	V$EBOX/MYCMAX.02	c-Myc/Max	0.92	1880-1896	1888
ID		heterodimer
NO:
318

SEQ	V$PAX6/PAX6.01	Pax-6 paired	0.75	1880-1898	1889
ID		domain protein
NO:
319

SEQ	V$IRFF/IRF3.01	Interferon	0.86	1891-1905	1898
ID		regulatory factor
NO:		3 (IRF-3)
320

SEQ	V$HNF1/HNF1.02	Hepatic nuclear	0.76	1895-1911	1903
ID		factor 1
NO:
321

SEQ	V$FKHD/FREAC2.01	Fork head	0.84	1898-1914	1906
ID		RElated
NO:		ACtivator-2
322

SEQ	V$E4FF/E4F.01	GLI-Krueppel-	0.82	1902-1914	1908
ID		related
NO:		transcription
323		factor, regulator
		of adenovirus E4
		promoter

SEQ	V$CREB/CREBP1.01	cAMP-responsive	0.80	1900-1920	1910
ID		element binding
NO:		protein 1
324

SEQ	V$VBPF/VBP.01	PAR-type chicken	0.86	1905-1915	1910
ID		vitellogenin
NO:		promoter-binding
325		protein

SEQ	V$MYT1/MYT1.01	MyT1 zinc finger	0.75	1912-1924	1918
ID		transcription
NO:		factor involved in
326		primary
		neurogenesis

SEQ	V$HNF1/HNF1.01	hepatic nuclear	0.78	1913-1929	1921
ID		factor 1
NO:
327

SEQ	V$PCAT/CAAT.01	cellular and viral	0.90	1928-1938	1933
ID		CCAAT box
NO:
328

SEQ	V$HNF6/HNF6.01	Liver enriched	0.82	1929-1943	1936
ID		Cut-
NO:		Homeodomain
329		transcription
		factor HNF6
		(ONECUT)

SEQ	V$PXRF/PXRCAR.01	Halfsite of PXR	0.98	1935-1945	1940
ID		(pregnane X
NO:		receptor)/RXR
330		resp. CAR
		(constitutive
		androstane
		receptor)/RXR
		heterodimer
		binding site

SEQ	V$RARF/RTR.01	Retinoid	0.81	1934-1952	1943
ID		receptor-related
NO:		testis-associated
331		receptor
		(GCNF/RTR)

SEQ	V$HOXF/EN1.01	Homeobox	0.77	1936-1952	1944
ID		protein engrailed
NO:		(en-1)
332

SEQ	V$NKXH/NKX25.01	homeo domain	1.00	1939-1951	1945
ID		factor Nkx-
NO:		2.5/Csx, tinman
333		homolog, high
		affinity sites

SEQ	V$GATA/GATA3.02	GATA-binding	0.91	1953-1965	1959
ID		factor 3
NO:
334

SEQ	V$TBPF/TATA.01	cellular and viral	0.90	1968-1984	1976
ID		TATA box
NO:		elements
335

SEQ	V$SRFF/SRF.01	serum response	0.66	1969-1987	1978
ID		factor
NO:
336

SEQ	V$CLOX/CDPCR3.01	cut-like	0.75	1972-1988	1980
ID		homeodomain
NO:		protein
337

SEQ	V$PAX1/PAX1.01	Pax1 paired	0.61	2016-2034	2025
ID		domain protein,
NO:		expressed in the
338		developing
		vertebral column
		of mouse
		embryos

SEQ	V$TBPF/ATATA.01	Avian C-type LTR	0.81	2019-2035	2027
ID		TATA box
NO:
339

SEQ	V$GFI1/GfI1B.01	Growth factor	0.82	2021-2035	2028
ID		independence 1
NO:		zinc finger
340		protein Gfi-1B

SEQ	V$NRSF/NRSF.01	neuron-restrictive	0.69	2025-2045	2035
ID		silencer factor
NO:
341

SEQ	V$NFAT/NFAT.01	Nuclear factor of	0.97	2033-2043	2038
ID		activated T-cells
NO:
342

SEQ	V$AREB/AREB6.04	AREB6 (Atp1a1	0.98	2034-2046	2040
ID		regulatory
NO:		element binding
343		factor 6)

SEQ	V$HNF1/HNF1.01	hepatic nuclear	0.78	2036-2052	2044
ID		factor 1
NO:
344

SEQ	V$FKHD/XFD3.01	Xenopus fork	0.82	2038-2054	2046
ID		head domain
NO:		factor 3
345

SEQ	V$PDX1/PDX1.01	Pdx1 (IDX1/IPF1)	0.74	2036-2056	2046
ID		pancreatic and
NO:		intestinal
346		homeodomain TF

SEQ	V$OCT1/OCT1.01	octamer-binding	0.77	2050-2064	2057
ID		factor 1
NO:
347

SEQ	V$TBPF/TATA.01	cellular and viral	0.90	2053-2069	2061
ID		TATA box
NO:		elements
348

SEQ	V$ETSF/GABP.01	GABP: GA	0.85	2080-2096	2088
ID		binding protein
NO:
349

SEQ	V$BEL1/BEL1.01	Bel-1 similar	0.78	2083-2105	2094
ID		region (defined in
NO:		Lentivirus LTRs)
350

SEQ	V$VMYB/VMYB.01	v-Myb	0.90	2097-2107	2102
ID
NO:
351

SEQ	V$GREF/ARE.01	Androgene	0.80	2106-2124	2115
ID		receptor binding
NO:		site
352

SEQ	V$PDX1/PDX1.01	Pdx1 (IDX1/IPF1)	0.74	2137-2157	2147
ID		pancreatic and
NO:		intestinal
353		homeodomain TF

SEQ	V$MYOD/MYOD.02	myoblast	0.98	2154-2168	2161
ID		determining
NO:		factor
354

SEQ	V$GATA/GATA1.03	GATA-binding	0.95	2169-2181	2175
ID		factor 1
NO:
355

SEQ	V$AP4R/TAL1BETAE47.01	Tal-1beta/E47	0.87	2179-2195	2187
ID		heterodimer
NO:
356

SEQ	V$OAZF/ROAZ.01	Rat C2H2 Zn	0.73	2204-2220	2212
ID		finger protein
NO:		involved in
357		olfactory
		neuronal
		differentiation

SEQ	V$GATA/GATA1.01	GATA-binding	0.96	2217-2229	2223
ID		factor 1
NO:
358

SEQ	V$MYOD/E47.02	TAL1/E47 dimers	0.93	2220-2234	2227
ID
NO:
359

SEQ	V$LTUP/TAACC.01	Lentiviral TATA	0.71	2225-2247	2236
ID		upstream
NO:		element
360

SEQ	V$RREB/RREB1.01	Ras-responsive	0.79	2239-2253	2246
ID		element binding
NO:		protein 1
361

SEQ	V$OCT1/OCT1.05	octamer-binding	0.90	2251-2265	2258
ID		factor 1
NO:
362

SEQ	V$OCT1/OCT1.02	octamer-binding	0.82	2282-2296	2289
ID		factor 1
NO:
363

SEQ	V$COUP/COUP.01	COUP	0.81	2284-2298	2291
ID		antagonizes HNF-
NO:		4 by binding site
364		competition or
		synergizes by
		direct protein -
		protein
		interaction with
		HNF-4

SEQ	V$MEF2/MEF2.01	myogenic	0.74	2290-2312	2301
ID		enhancer factor 2
NO:
365

SEQ	V$CDXF/CDX2.01	Cdx-2	0.84	2296-2314	2305
ID		mammalian
NO:		caudal related
366		intestinal transcr.
		factor

SEQ	V$MYT1/MYT1.01	MyT1 zinc finger	0.75	2301-2313	2307
ID		transcription
NO:		factor involved in
367		primary
		neurogenesis

SEQ	V$NFAT/NFAT.01	Nuclear factor of	0.97	2314-2324	2319
ID		activated T-cells
NO:
368

SEQ	V$CIZF/NMP4.01	NMP4 (nuclear	0.97	2317-2327	2322
ID		matrix protein 4)/
NO:		CIZ (Cas-
369		interacting zinc
		finger protein)

SEQ	V$GATA/GATA3.02	GATA-binding	0.91	2326-2338	2332
ID		factor 3
NO:
370

SEQ	V$HMTB/MTBF.01	muscle-specific	0.90	2351-2359	2355
ID		Mt binding site
NO:
371

SEQ	V$NOLF/OLF1.01	olfactory neuron-	0.82	2350-2372	2361
ID		specific factor
NO:
372

SEQ	V$PDX1/PDX1.01	Pdx1 (IDX1/IPF1)	0.74	2363-2383	2373
ID		pancreatic and
NO:		intestinal
373		homeodomain TF

SEQ	V$GATA/GATA3.02	GATA-binding	0.91	2395-2407	2401
ID		factor 3
NO:
374

SEQ	V$NFAT/NFAT.01	Nuclear factor of	0.97	2406-2416	2411
ID		activated T-cells
NO:
375

SEQ	V$OCTP/OCT1P.01	octamer-binding	0.86	2433-2445	2439
ID		factor 1, POU-
NO:		specific domain
376

SEQ	V$MITF/MIT.01	MIT	0.81	2438-2456	2447
ID		(microphthalmia
NO:		transcription
377		factor) and TFE3

SEQ	V$PAX8/PAX8.01	PAX 2/5/8	0.88	2441-2453	2447
ID		binding site
NO:
378

SEQ	V$TBPF/ATATA.01	Avian C-type LTR	0.81	2451-2467	2459
ID		TATA box
NO:
379

SEQ	V$GATA/GATA3.02	GATA-binding	0.91	2462-2474	2468
ID		factor 3
NO:
380

SEQ	V$CLOX/CLOX.01	Clox	0.81	2462-2478	2470
ID
NO:
381

SEQ	V$HNF6/HNF6.01	Liver enriched	0.82	2464-2478	2471
ID		Cut -
NO:		Homeodomain
382		transcription
		factor HNF6
		(ONECUT)

SEQ	V$PIT1/PIT1.01	Pit1, GHF-1	0.86	2468-2478	2473
ID		pituitary specific
NO:		pou domain
383		transcription
		factor

SEQ	V$AP4R/TAL1BETAITF2.01	Tal-1beta/ITF-2	0.85	2469-2485	2477
ID		heterodimer
NO:
384

SEQ	V$CIZF/NMP4.01	NMP4 (nuclear	0.97	2477-2487	2482
ID		matrix protein 4)/
NO:		CIZ (Cas-
385		interacting zinc
		finger protein)

SEQ	V$NFAT/NFAT.01	Nuclear factor of	0.97	2480-2490	2485
ID		activated T-cells
NO:
386

SEQ	V$STAT/STAT.01	signal	0.87	2479-2497	2488
ID		transducers and
NO:		activators of
387		transcription

SEQ	V$TBPF/TATA.02	Mammalian C-	0.89	2484-2500	2492
ID		type LTR TATA
NO:		box
388

SEQ	V$FKHD/XFD3.01	Xenopus fork	0.82	2501-2517	2509
ID		head domain
NO:		factor 3
389

SEQ	V$AP1F/AP1.01	AP1 binding site	0.95	2500-2520	2510
ID
NO:
390

SEQ	V$AP1F/AP1.01	AP1 binding site	0.95	2504-2524	2514
ID
NO:
391

SEQ	V$PCAT/CAAT.01	cellular and viral	0.90	2513-2523	2518
ID		CCAAT box
NO:
392

SEQ	V$CDXF/CDX2.01	Cdx-2	0.84	2524-2542	2533
ID		mammalian
NO:		caudal related
393		intestinal transcr.
		factor

SEQ	V$MYT1/MYT1.02	MyT1 zinc finger	0.88	2539-2551	2545
ID		transcription
NO:		factor involved in
394		primary
		neurogenesis

SEQ	V$ETSF/FLI.01	ETS family	0.81	2560-2576	2568
ID		member FLI
NO:
395

SEQ	V$MYT1/MYT1.01	MyT1 zinc finger	0.75	2569-2581	2575
ID		transcription
NO:		factor involved in
396		primary
		neurogenesis

SEQ	V$TBPF/ATATA.01	Avian C-type LTR	0.81	2576-2592	2584
ID		TATA box
NO:
397

SEQ	V$SATB/SATB1.01	Special AT-rich	0.93	2578-2594	2586
ID		sequence-binding
NO:		protein 1,
398		predominantly
		expressed in
		thymocytes,
		binds to matrix
		attachment
		regions (MARs)

SEQ	V$NKXH/NKX31.01	prostate-specific	0.84	2584-2596	2590
ID		homeodomain
NO:		protein NKX3.1
399

SEQ	V$PARF/DBP.01	Albumin D-box	0.84	2589-2603	2596
ID		binding protein
NO:
400

SEQ	V$PAX5/PAX5.02	B-cell-specific	0.75	2591-2619	2605
ID		activating protein
NO:
401

SEQ	V$ECAT/NFY.03	nuclear factor Y	0.80	2604-2618	2611
ID		(Y-box binding
NO:		factor)
402

SEQ	V$GFI1/GFI1.01	Growth factor	0.97	2608-2622	2615
ID		independence 1
NO:		zinc finger
403		protein acts as
		transcriptional
		repressor

SEQ	V$HNF6/HNF6.01	Liver enriched	0.82	2608-2622	2615
ID		Cut -
NO:		Homeodomain
404		transcription
		factor HNF6
		(ONECUT)

SEQ	V$MYT1/MYT1.01	MyT1 zinc finger	0.75	2610-2622	2616
ID		transcription
NO:		factor involved in
405		primary
		neurogenesis

SEQ	V$PAX8/PAX8.01	PAX 2/5/8	0.88	2610-2622	2616
ID		binding site
NO:
406

SEQ	V$TTFF/TTF1.01	Thyroid	0.92	2609-2623	2616
ID		transcription
NO:		factor-1 (TTF1)
407		binding site

SEQ	V$MYT1/MYT1.02	MyT1 zinc finger	0.88	2612-2624	2618
ID		transcription
NO:		factor involved in
408		primary
		neurogenesis

SEQ	V$CDXF/CDX2.01	Cdx-2	0.84	2612-2630	2621
ID		mammalian
NO:		caudal related
409		intestinal transcr.
		factor

SEQ	V$SORY/HMGIY.01	HMGI(Y) high-	0.92	2649-2665	2657
ID		mobility-group
NO:		protein I (Y),
410		architectural
		transcription
		factor organizing
		the framework of
		a nuclear protein-
		DNA
		transcriptional
		complex

SEQ	V$HOXF/EN1.01	Homeobox	0.77	2657-2673	2665
ID		protein engrailed
NO:		(en-1)
411

SEQ	V$OCT1/OCT1.06	octamer-binding	0.80	2662-2676	2669
ID		factor 1
NO:
412

SEQ	V$BCL6/BCL6.01	POZ/zinc finger	0.76	2683-2699	2691
ID		protein,
NO:		transcriptional
413		repressor,
		translocations
		observed in
		diffuse large cell
		lymphoma

SEQ	V$OCTP/OCT1P.01	octamer-binding	0.86	2715-2727	2721
ID		factor 1, POU-
NO:		specific domain
414

SEQ	V$TEAF/TEF1.01	TEF-1 related	0.84	2722-2734	2728
ID		muscle factor
NO:
415

SEQ	V$GFI1/GFI1.01	Growth factor	0.97	2723-2737	2730
ID		independence 1
NO:		zinc finger
416		protein acts as
		transcriptional
		repressor

SEQ	V$HOXT/MEIS1_HOXA9.01	Homeobox	0.79	2729-2741	2735
ID		protein MEIS1
NO:		binding site
417

SEQ	V$HOXF/HOXA9.01	Member of the	0.87	2728-2744	2736
ID		vertebrate HOX -
NO:		cluster of
418		homeobox factors

SEQ	V$PARF/DBP.01	Albumin D-box	0.84	2729-2743	2736
ID		binding protein
NO:
419

SEQ	V$VBPF/VBP.01	PAR-type chicken	0.86	2732-2742	2737
ID		vitellogenin
NO:		promoter-binding
420		protein

SEQ	V$CREB/E4BP4.01	E4BP4, bZIP	0.80	2728-2748	2738
ID		domain,
NO:		transcriptional
421		repressor

SEQ	V$OCT1/OCT1.01	octamer-binding	0.77	2733-2747	2740
ID		factor 1
NO:
422

SEQ	V$FKHD/XFD1.01	Xenopus fork	0.90	2733-2749	2741
ID		head domain
NO:		factor 1
423

SEQ	V$SRFF/SRF.01	serum response	0.66	2736-2754	2745
ID		factor
NO:
424

SEQ	V$OCTP/OCT1P.01	octamer-binding	0.86	2746-2758	2752
ID		factor 1, POU-
NO:		specific domain
425

SEQ	V$CLOX/CDPCR3.01	cut-like	0.75	2748-2764	2756
ID		homeodomain
NO:		protein
426

SEQ	V$TBPF/TATA.01	cellular and viral	0.90	2749-2765	2757
ID		TATA box
NO:		elements
427

SEQ	V$SRFF/SRF.01	serum response	0.66	2750-2768	2759
ID		factor
NO:
428

SEQ	V$TBPF/ATATA.01	Avian C-type LTR	0.81	2759-2775	2767
ID		TATA box
NO:
429

SEQ	V$TBPF/TATA.02	Mammalian C-	0.89	2762-2778	2770
ID		type LTR TATA
NO:		box
430

SEQ	V$CABL/CABL.01	Multifunctional c-	0.97	2769-2779	2774
ID		Abl src type
NO:		tyrosine kinase
431

SEQ	V$LEFF/LEF1.01	TCF/LEF-1,	0.86	2766-2782	2774
ID		involved in the
NO:		Wnt signal
432		transduction
		pathway

SEQ	V$OCT1/OCT1.06	octamer-binding	0.80	2775-2789	2782
ID		factor 1
NO:
433

SEQ	V$MEF2/MMEF2.01	myocyte	0.90	2776-2798	2787
ID		enhancer factor
NO:
434

SEQ	V$OCT1/OCT1.06	octamer-binding	0.80	2780-2794	2787
ID		factor 1
NO:
435

SEQ	V$TBPF/TATA.01	cellular and viral	0.90	2779-2795	2787
ID		TATA box
NO:		elements
436

SEQ	V$CART/CART1.01	Cart-1 (cartilage	0.84	2780-2796	2788
ID		homeoprotein 1)
NO:
437

SEQ	V$FKHD/XFD2.01	Xenopus fork-	0.89	2780-2796	2788
ID		head domain
NO:		factor 2
438

SEQ	V$MEF2/MEF2.05	MEF2	0.96	2778-2800	2789
ID
NO:
439

SEQ	V$BRNF/BRN3.01	POU transcription	0.78	2785-2801	2793
ID		factor Brn-3
NO:
440

SEQ	V$TBPF/TATA.01	cellular and viral	0.90	2786-2802	2794
ID		TATA box
NO:		elements
441

SEQ	V$GFI1/GFI1.01	Growth factor	0.97	2791-2805	2798
ID		independence 1
NO:		zinc finger
442		protein acts as
		transcriptional
		repressor

SEQ	V$HOXT/MEIS1_HOXA9.01	Homeobox	0.79	2797-2809	2803
ID		protein MEIS1
NO:		binding site
443

SEQ	V$MEF2/MMEF2.01	myocyte	0.90	2792-2814	2803
ID		enhancer factor
NO:
444

SEQ	V$MEF2/MEF2.05	MEF2	0.96	2795-2817	2806
ID
NO:
445

SEQ	V$MEF2/MMEF2.01	myocyte	0.90	2797-2819	2808
ID		enhancer factor
NO:
446

SEQ	V$HNF1/HNF1.01	hepatic nuclear	0.78	2802-2818	2810
ID		factor 1
NO:
447

SEQ	V$MEF2/MEF2.01	myogenic	0.74	2799-2821	2810
ID		enhancer factor 2
NO:
448

SEQ	V$HOXF/HOX1-3.01	Hox-1.3,	0.83	2814-2830	2822
ID		vertebrate
NO:		homeobox
449		protein

SEQ	V$PARF/DBP.01	Albumin D-box	0.84	2816-2830	2823
ID		binding protein
NO:
450

SEQ	V$PDX1/ISL1.01	Pancreatic and	0.82	2814-2834	2824
ID		intestinal lim-
NO:		homeodomain
451		factor

SEQ	V$GATA/GATA1.02	GATA-binding	0.99	2819-2831	2825
ID		factor 1
NO:
452

SEQ	V$HEAT/HSF1.01	heat shock factor 1	0.93	2845-2855	2850
ID
NO:
453

SEQ	V$MYT1/MYT1.02	MyT1 zinc finger	0.88	2853-2865	2859
ID		transcription
NO:		factor involved in
454		primary
		neurogenesis

SEQ	V$BCL6/BCL6.02	POZ/zinc finger	0.77	2857-2873	2865
ID		protein,
NO:		transcriptional
455		repressor,
		translocations
		observed in
		diffuse large cell
		lymphoma

SEQ	V$TTFF/TTF1.01	Thyroid	0.92	2863-2877	2870
ID		transcription
NO:		factor-1 (TTF1)
456		binding site

SEQ	V$EBOX/USF.02	upstream	0.94	2868-2884	2876
ID		stimulating factor
NO:
457

SEQ	V$HOXF/PTX1.01	Pituitary	0.79	2892-2908	2900
ID		Homeobox 1
NO:		(Ptx1)
458

SEQ	V$MYOD/LMO2COM.01	complex of Lmo2	0.98	2901-2915	2908
ID		bound to Tal-1,
NO:		E2A proteins, and
459		GATA-1, half-site 1

SEQ	V$REBV/EBVR.01	Epstein-Barr	0.81	2904-2924	2914
ID		virus
NO:		transcription
460		factor R

SEQ	V$ETSF/PU1.01	Pu.1 (Pu120) Ets-	0.86	2932-2948	2940
ID		like transcription
NO:		factor identified
461		in lymphoid B-
		cells

SEQ	V$MITF/MIT.01	MIT	0.81	2943-2961	2952
ID		(microphthalmia
NO:		transcription
462		factor) and TFE3

SEQ	V$HAML/AML1.01	runt-factor AML-1	1.00	2950-2964	2957
ID
NO:
463

SEQ	V$NFKB/CREL.01	c-Rel	0.91	2954-2968	2961
ID
NO:
464

SEQ	V$IKRS/IK3.01	Ikaros 3,	0.84	2958-2970	2964
ID		potential
NO:		regulator of
465		lymphocyte
		differentiation

SEQ	V$RBPF/RBPJK.01	Mammalian	0.84	2957-2971	2964
ID		transcriptional
NO:		repressor RBP-
466		Jkappa/CBF1

SEQ	V$E2FF/E2F.01	E2F, involved in	0.74	2966-2980	2973
ID		cell cycle
NO:		regulation,
467		interacts with Rb
		p107 protein

SEQ	V$E4FF/E4F.01	GLI-Krueppel-	0.82	2968-2980	2974
ID		related
NO:		transcription
468		factor, regulator
		of adenovirus E4
		promoter

SEQ	V$CREB/ATF6.02	Activating	0.85	2966-2986	2976
ID		transcription
NO:		factor 6, member
469		of b-zip family,
		induced by ER
		stress

SEQ	V$EBOX/ARNT.01	AhR nuclear	0.89	2968-2984	2976
ID		translocator
NO:		homodimers
470

SEQ	V$E4FF/E4F.01	GLI-Krueppel-	0.82	2971-2983	2977
ID		related
NO:		transcription
471		factor, regulator
		of adenovirus E4
		promoter

SEQ	V$EBOR/XBP1.01	X-box-binding	0.86	2970-2984	2977
ID		protein 1
NO:
472

SEQ	V$E2FF/E2F.01	E2F, involved in	0.74	2971-2985	2978
ID		cell cycle
NO:		regulation,
473		interacts with Rb
		p107 protein

SEQ	V$STAT/STAT.01	signal	0.87	2989-3007	2998
ID		transducers and
NO:		activators of
474		transcription

SEQ	V$BCL6/BCL6.02	POZ/zinc finger	0.77	2991-3007	2999
ID		protein,
NO:		transcriptional
475		repressor,
		translocations
		observed in
		diffuse large cell
		lymphoma

SEQ	V$XSEC/STAF.01	Se-Cys tRNA	0.77	3003-3025	3014
ID		gene
NO:		transcription
476		activating factor

SEQ	V$NF1F/NF1.01	Nuclear factor 1	0.94	3007-3025	3016
ID
NO:
477

SEQ	V$OCT1/OCT1.02	octamer-binding	0.82	3014-3028	3021
ID		factor 1
NO:
478

SEQ	V$RCAT/CLTR_CAAT.01	Mammalian C-	0.75	3019-3043	3031
ID		type LTR CCAAT
NO:		box
479

SEQ	V$SF1F/SF1.01	SF1 steroidogenic	0.95	3033-3045	3039
ID		factor 1
NO:
480

SEQ	V$OCT1/OCT1.01	octamer-binding	0.77	3038-3052	3045
ID		factor 1
NO:
481

SEQ	V$PARF/DBP.01	Albumin D-box	0.84	3042-3056	3049
ID		binding protein
NO:
482

SEQ	V$ETSF/ETS1.01	c-Ets-1 binding	0.92	3057-3073	3065
ID		site
NO:
483

SEQ	V$LEFF/LEF1.01	TCF/LEF-1,	0.86	3062-3078	3070
ID		involved in the
NO:		Wnt signal
484		transduction
		pathway

SEQ	V$MAZF/MAZ.01	Myc associated	0.90	3072-3084	3078
ID		zinc finger
NO:		protein (MAZ)
485

SEQ	V$SP1F/GC.01	GC box elements	0.88	3071-3085	3078
ID
NO:
486

SEQ	V$TBPF/TATA.01	cellular and viral	0.90	3091-3107	3099
ID		TATA box
NO:
487		elements

SEQ	V$SEF1/SEF1.01	SEF1 binding site	0.69	3099-3117	3108
ID
NO:
488

SEQ
ID		Core	Matrix
NO:	Str.	sim.	sim.	Sequence

SEQ	(+)	1.000	0.900	ggaccatCAAAgtctgt
ID
NO:
41

SEQ	(+)	1.000	0.823	agtctgtCATGtcatttgg
ID
NO:
42

SEQ	(+)	0.833	0.904	gTCATgtcatttggg
ID
NO:
43

SEQ	(+)	1.000	1.000	GTCAttt
ID
NO:
44

SEQ	(+)	1.000	0.735	ctgtcatgtcatTTGGgggagggcctatg
ID
NO:
45

SEQ	(−)	1.000	0.982	gccctCCCCcaaa
ID
NO:
46

SEQ	(+)	0.876	0.898	tgggGGAGggcctat
ID
NO:
47

SEQ	(−)	0.884	0.708	acagaggagggcATAGgccct
ID
NO:
48

SEQ	(−)	0.800	0.811	cagataCACAgaggagggcataggccctc
ID
NO:
49

SEQ	(−)	1.000	0.987	tgctattTAAGcccaga
ID
NO:
50

SEQ	(−)	1.000	0.932	tgctATTTa
ID
NO:
51

SEQ	(−)	0.750	0.865	ggtatgctATTTaag
ID
NO:
52

NO:
65

SEQ	(−)	1.000	0.894	ttatAAAGctgagga
ID
NO:
66

SEQ	(−)	1.000	0.910	agttaTAAAgctgagga
ID
NO:
67

SEQ	(−)	1.000	0.902	agtgAAAGcagagag
ID
NO:
68

SEQ	(−)	0.750	0.756	craCAGTtgacct
ID
NO:
69

SEQ	(+)	1.000	0.940	GTCTtgact
ID
NO:
70

SEQ	(−)	1.000	0.960	gagggATTAgaaaagga
ID
NO:
71

SEQ	(−)	1.000	0.906	ggaatCCAAtygtag
ID
NO:
72

SEQ	(+)	0.789	0.802	ctacraTTGGattccat
ID
NO:
73

SEQ	(−)	1.000	0.897	tacagcTAAAcactgag
ID
NO:
74

SEQ	(−)	0.840	0.865	gagcctTCATccagtagct
ID
NO:
75

SEQ	(−)	1.000	0.746	tgtcatcttagagCCTTcatc
ID
NO:
76

SEQ	(+)	1.000	0.861	agGCTCtaagatg
ID
NO:
77

SEQ	(+)	0.750	0.837	tcTAAGatgacaattaa
ID
NO:
78

SEQ	(+)	0.807	0.840	aaGATGacaattaag
ID
NO:
79

SEQ	(+)	1.000	0.994	gacaATTAa
ID
NO:
80

SEQ	(−)	1.000	1.000	cctTAATtgtcat
ID
NO:
81

SEQ	(−)	0.766	0.808	cgacgattACCTtaattgtca
ID
NO:
82

SEQ	(−)	0.750	0.768	aatgaggATCGacgattacct
ID
NO:
83

SEQ	(+)	1.000	0.886	cgatcctcATTAtagtg
ID
NO:
84

SEQ	(+)	1.000	0.868	tatagtGGAAgggcttc
ID
NO:
85

SEQ	(+)	1.000	0.904	agggcttCAAAggcagt
ID
NO:
86

SEQ	(−)	0.758	0.867	gagacTGCCtttgaagccc
ID
NO:
87

SEQ	(−)	1.000	0.971	ttcaGATAggcag
ID
NO:
88

SEQ	(−)	0.757	0.672	atgttcaGATAggcagtag
ID
NO:
89

SEQ	(−)	0.800	0.824	gGAAAtgttcagatagg
ID
NO:
90

SEQ	(+)	1.000	0.951	cctaatgCCAGatgtct
ID
NO:
91

SEQ	(+)	1.000	0.852	aatgcCAGAtgtctctt
ID
NO:
92

SEQ	(−)	1.000	0.851	gagaCATCtggca
ID
NO:
93

SEQ	(−)	1.000	0.984	aggataggttTAAAgagacatct
ID
NO:
94

SEQ	(−)	1.000	0.774	gGATAggtttaaagaga
ID
NO:
95

SEQ	(+)	1.000	0.813	tgtctcttTAAAcctatcctggc
ID
NO:
96

SEQ	(+)	1.000	0.877	ctcttTAAAcctatcct
ID
NO:
97

SEQ	(+)	1.000	0.845	ctcccttcATTAaggta
ID
NO:
98

SEQ	(−)	1.000	0.834	gagatacctTAATgaagggag
ID
NO:
99

SEQ	(+)	0.944	0.926	gGTATctcatttttt
ID
NO:
100

SEQ	(−)	1.000	0.972	gcAAAAaatga
ID
NO:
101

SEQ	(−)	0.764	0.720	ggaaCAGAggagagcaa
ID
NO:
102

SEQ	(−)	0.881	0.964	aaaactgaATCAgtggnggaa
ID
NO:
103

SEQ	(+)	1.000	0.886	actgATTCagt
ID
NO:
104

SEQ	(+)	0.850	0.956	nccactgaTTCAgtttttctg
ID
NO:
105

SEQ	(−)	0.876	0.910	aaaAACTgaat
ID
NO:
106

SEQ	(−)	1.000	0.975	agAAAAactga
ID
NO:
107

SEQ	(+)	1.000	0.875	ctgatccctctTGTTctcc
ID
NO:
108

SEQ	(−)	1.000	0.971	gaaaaagagaAGGGa
ID
NO:
109

SEQ	(−)	1.000	0.987	ggAAAAagaga
ID
NO:
110

SEQ	(−)	1.000	0.982	ggagGAAAaag
ID
NO:
111

SEQ	(−)	1.000	0.910	ggtgGAGGgaagg
ID
NO:
112

SEQ	(−)	1.000	0.932	gggggTGGGagggtg
ID
NO:
113

SEQ	(+)	1.000	0.972	tcccaCCCCcatg
ID
NO:
114

SEQ	(−)	1.000	0.815	aggaagggGAAAggg
ID
NO:
115

SEQ	(−)	1.000	0.911	aaaataggAAATaagga
ID
NO:
116

SEQ	(−)	1.000	0.883	aaaataGGAAataagga
ID
NO:
117

SEQ	(−)	0.760	0.792	aGAGAaaataggaaata
ID
NO:
118

SEQ	(−)	0.763	0.817	cccccagagaaAATAgg
ID
NO:
119

SEQ	(−)	1.000	0.934	ccacaCCCCcaga
ID
NO:
120

SEQ	(+)	0.983	0.894	gggtgtgGATTttat
ID
NO:
121

SEQ	(−)	1.000	0.942	caccaTAAAatccacac
ID
NO:
122

SEQ	(−)	0.866	0.813	aacataTGCAcagaagggcttccaccata
ID
NO:
123

SEQ	(−)	1.000	0.790	catATGCacagaagg
ID
NO:
124

SEQ	(−)	1.000	0.910	caacatATGCaca
ID
NO:
125

SEQ	(+)	0.757	0.666	ctgtgcaTATGttgtctta
ID
NO:
126

SEQ	(−)	0.750	0.828	caataagacaaCATAtg
ID
NO:
127

SEQ	(−)	1.000	0.776	ccAATAagacaacatat
ID
NO:
128

SEQ	(−)	1.000	0.836	tcaaccaatAAGAcaac
ID
NO:
129

SEQ	(−)	1.000	0.960	atcaaCCAAtaagac
ID
NO:
130

SEQ	(+)	1.000	0.844	tcttatTGGTtgata
ID
NO:
131

SEQ	(−)	1.000	0.943	tcaaCCAAtaa
ID
NO:
132

SEQ	(+)	1.000	0.956	ggttGATAaataa
ID
NO:
133

SEQ	(+)	0.757	0.791	gGTTGataaataaagca
ID
NO:
134

SEQ	(−)	0.750	0.797	gTGCTttatttat
ID
NO:
135

SEQ	(+)	1.000	0.912	gttgtCCAAtaggga
ID
NO:
136

SEQ	(+)	0.750	0.843	aataggGAAAcaagata
ID
NO:
137

SEQ	(+)	1.000	0.960	tagggaaacaAGATagg
ID
NO:
138

SEQ	(+)	1.000	0.970	acaaGATAggtgg
ID
NO:
139

SEQ	(−)	0.750	0.867	cccaCCTAtct
ID
NO:
140

SEQ	(−)	1.000	0.929	ggatcacatgGCAAccctc
ID
NO:
141

SEQ	(−)	0.895	0.936	ggatCACAtggcaacc
ID
NO:
142

SEQ	(+)	1.000	0.863	gggttgcCATGtgatccta
ID
NO:
143

SEQ	(+)	1.000	0.950	ctaggaGGAAttgacac
ID
NO:
144

SEQ	(−)	1.000	0.800	catgtgtcAATTcct
ID
NO:
145

SEQ	(−)	1.000	1.000	tGTCAat
ID
NO:
146

SEQ	(−)	1.000	0.835	ccattctCATGtgtcaatt
ID
NO:
147

SEQ	(+)	0.846	0.800	caCATGagaatgggg
ID
NO:
148

SEQ	(+)	1.000	0.998	gaaaGATAagtcc
ID
NO:
149

SEQ	(−)	1.000	0.672	atattttTATAaggactta
ID
NO:
150

SEQ	(−)	1.000	0.867	atatattTTTAtaaggact
ID
NO:
151

SEQ	(+)	1.000	0.894	tccttaTAAAaatatat
ID
NO:
152

SEQ	(+)	1.000	0.740	agtccttaTAAAaatatatatta
ID
NO:
153

SEQ	(+)	1.000	0.963	ccttaTAAAaatatata
ID
NO:
154

SEQ	(−)	1.000	0.870	acTAATatatattttta
ID
NO:
155

SEQ	(−)	1.000	0.855	caTAATtactaatatat
ID
NO:
156

SEQ	(−)	1.000	0.943	cataattacTAATatat
ID
NO:
157

SEQ	(−)	1.000	0.816	cccATAAttactaatat
ID
NO:
158

SEQ	(−)	0.757	0.765	ccCATAattactaatat
ID
NO:
159

SEQ	(+)	1.000	0.989	agtaATTAt
ID
NO:
160

SEQ	(−)	1.000	0.976	ccatAATTactaa
ID
NO:
161

SEQ	(−)	1.000	0.886	aacccataATTActaat
ID
NO:
162

SEQ	(−)	1.000	0.775	attaacccaTAATtactaata
ID
NO:
163

SEQ	(+)	0.826	0.844	tatgggttAATAattaa
ID
NO:
164

SEQ	(−)	0.755	0.857	aCTTAattattaaccca
ID
NO:
165

SEQ	(+)	1.000	0.966	gGTTAataattaagtca
ID
NO:
166

SEQ	(+)	1.000	0.972	taatAATTaag
ID
NO:
167

SEQ	(−)	1.000	0.995	cttaATTAt
ID
NO:
168

SEQ	(−)	1.000	0.873	ctgacttaATTAttaac
ID
NO:
169

SEQ	(+)	1.000	0.988	taatAATaagtc
ID
NO:
170

SEQ	(+)	1.000	0.931	taataATTAagtc
ID
NO:
171

SEQ	(+)	1.000	0.881	taataatTAAGtcagag
ID
NO:
172

SEQ	(−)	0.766	0.819	tagctctgACTTaattattaa
ID
NO:
173

SEQ	(+)	0.750	0.874	ataattaAGTCagagct
ID
NO:
174

SEQ	(+)	0.856	0.928	ctagCCATtaa
ID
NO:
175

SEQ	(−)	1.000	0.903	tctTAATggctag
ID
NO:
176

SEQ	(−)	0.770	0.842	ctagtGTTTcttaatggctag
ID
NO:
177

SEQ	(+)	1.000	0.891	gcttcataATTAatata
ID
NO:
178

SEQ	(−)	1.000	0.995	attaATTAt
ID
NO:
179

SEQ	(+)	1.000	0.988	tcatAATTaatat
ID
NO:
180

SEQ	(+)	1.000	0.952	tcataATTAatat
ID
NO:
181

SEQ	(+)	1.000	0.945	ttcataatTAATatagt
ID
NO:
182

SEQ	(−)	1.000	0.885	actatattAATTatg
ID
NO:
183

SEQ	(−)	1.000	0.854	gatactatATTAattat
ID
NO:
184

SEQ	(+)	0.750	0.875	tgtatgttCATTtgg
ID
NO:
185

SEQ	(+)	0.850	0.887	gtatgttCATTtggg
ID
NO:
186

SEQ	(−)	1.000	0.816	cCCCAaatgaacata
ID
NO:
187

SEQ	(−)	1.000	0.849	tcagcccCAAAtgaa
ID
NO:
188

SEQ	(+)	1.000	0.828	tggggcTGACacagttctggg
ID
NO:
189

SEQ	(+)	1.000	0.833	ggggcTGACacagttctggga
ID
NO:
190

SEQ	(+)	0.750	0.791	aggAAGAytactt
ID
NO:
191

SEQ	(−)	0.804	0.820	cctacaATCCatgtacc
ID
NO:
192

SEQ	(−)	1.000	0.864	atagagCAAAggactac
ID
NO:
193

SEQ	(−)	1.000	0.907	catagagCAAAggacta
ID
NO:
194

SEQ	(−)	1.000	0.700	tagacatagagcAAAGgacta
ID
NO:
195

SEQ	(+)	0.804	0.831	gtctaaATCCatatatg
ID
NO:
196

SEQ	(+)	0.833	0.929	ctaaaTCCAtatatg
ID
NO:
197

SEQ	(+)	1.000	0.851	aaatCCATatatgaatgag
ID
NO:
198

SEQ	(−)	1.000	0.761	actcattcatatATGGa
ID
NO:
199

SEQ	(−)	1.000	0.919	actcATTCata
ID
NO:
200

SEQ	(−)	0.807	0.901	tggtATGTa
ID
NO:
201

SEQ	(−)	1.000	0.922	gaaagayAAACatggta
ID
NO:
202

SEQ	(−)	0.789	0.898	gtgAGGTaacccc
ID
NO:
203

SEQ	(+)	1.000	0.854	atgggGTTAcctcactcagga
ID
NO:
204

SEQ	(+)	1.000	0.903	gTTACctcact
ID
NO:
205

SEQ	(−)	0.758	0.870	cgcAGGCaaatgaat
ID
NO:
206

SEQ	(+)	0.758	0.850	tcattTGCCtgcgaatttt
ID
NO:
207

SEQ	(+)	1.000	0.869	tgcgaatTTTAagattcca
ID
NO:
208

SEQ	(−)	1.000	0.990	taaaaCAATggaatctt
ID
NO:
209

SEQ	(−)	1.000	0.931	aggaataaAACAatgga
ID
NO:
210

SEQ	(+)	1.000	0.865	ccattgtTTTAttcctctg
ID
NO:
211

SEQ	(−)	0.894	0.876	gaggAATAaaacaat
ID
NO:
212

SEQ	(+)	1.000	0.824	tcctctgagTAATactccatt
ID
NO:
213

SEQ	(−)	1.000	0.925	ttacaCAATggagtatt
ID
NO:
214

SEQ	(−)	0.901	0.920	ggtacATTAcacaatggagta
ID
NO:
215

SEQ	(−)	1.000	0.871	aTTACacaatg
ID
NO:
216

SEQ	(+)	0.929	0.955	tccattgtGTAAtgtacca
ID
NO:
217

SEQ	(+)	1.000	0.859	tccattgtgTAATgtaccaca
ID
NO:
218

SEQ	(−)	1.000	1.000	aaaatgTGGTacatt
ID
NO:
219

SEQ	(+)	0.750	0.819	aatgtaccacaTTTTctcc
ID
NO:
220

SEQ	(+)	1.000	0.896	taCATTcttcagt
ID
NO:
221

SEQ	(+)	1.000	0.990	caGTTGagg
ID
NO:
222

SEQ	(−)	1.000	0.932	gcaatagCCAGaacctg
ID
NO:
223

SEQ	(−)	1.000	0.945	gcaatagCCAG
ID
NO:
224

SEQ	(−)	1.000	0.951	attTGCAatagcc
ID
NO:
225

SEQ	(+)	1.000	0.853	tggctattGCAAataaccc
ID
NO:
226

SEQ	(+)	1.000	0.809	ctggctattgcAAATaaccctgc
ID
NO:
227

SEQ	(+)	1.000	0.889	ctattgcAAATaacc
ID
NO:
228

SEQ	(−)	1.000	0.900	ggttATTTg
ID
NO:
229

SEQ	(+)	0.975	0.761	acatatgtcattATTGt
ID
NO:
230

SEQ	(+)	0.944	0.938	cATATgtcattattg
ID
NO:
231

SEQ	(+)	1.000	0.836	catatgtcATTAttgta
ID
NO:
232

SEQ	(−)	1.000	0.889	ttcatacaaTAATgacatatg
ID
NO:
233

SEQ	(−)	1.000	0.870	tcataCAATaatgacat
ID
NO:
234

SEQ	(−)	0.944	0.914	aATATgtaaaacaga
ID
NO:
235

SEQ	(−)	1.000	0.856	tttaaaatatGTAAaacagat
ID
NO:
236

SEQ	(+)	1.000	0.886	tTTACatattt
ID
NO:
237

SEQ	(+)	1.000	0.841	tatttTAAAccatctct
ID
NO:
238

SEQ	(−)	1.000	0.783	caagCAATctaga
ID
NO:
239

SEQ	(+)	1.000	0.765	tctctagATTGcttgtaatat
ID
NO:
240

SEQ	(−)	1.000	0.997	tttaaCAATattacaag
ID
NO:
241

SEQ	(+)	1.000	0.885	tattgtTAAAcatagag
ID
NO:
242

SEQ	(+)	1.000	0.839	catagagagTAATaatgctat
ID
NO:
243

SEQ	(−)	1.000	0.872	atagcattATTActctc
ID
NO:
244

SEQ	(−)	0.826	0.843	tttatagcaTTATtactctct
ID
NO:
245

SEQ	(+)	1.000	0.829	agTAATaatgctataaa
ID
NO:
246

SEQ	(−)	1.000	0.906	tttaattTTTAtagcatta
ID
NO:
247

SEQ	(+)	1.000	0.983	aataatgctaTAAAaattaaaaa
ID
NO:
248

SEQ	(−)	0.755	0.805	tTTTAatttttatagca
ID
NO:
249

SEQ	(+)	1.000	0.832	gctataaaAATTaaa
ID
NO:
250

SEQ	(+)	1.000	0.991	tgctaTAAAaattaaaa
ID
NO:
251

SEQ	(−)	1.000	0.989	tttTAATttttat
ID
NO:
252

SEQ	(+)	1.000	0.944	taaaaATTAaaaa
ID
NO:
253

SEQ	(+)	1.000	0.807	ataaaaatTAAAaataatgataa
ID
NO:
254

SEQ	(+)	1.000	0.872	aataatgatAAGAaaga
ID
NO:
255

SEQ	(+)	1.000	0.993	taatGATAagaaa
ID
NO:
256

SEQ	(+)	1.000	0.931	gaaAGATcctata
ID
NO:
257

SEQ	(+)	1.000	0.915	tacAGATgaaaat
ID
NO:
258

SEQ	(+)	0.763	0.867	cagATGAaaatttag
ID
NO:
259

SEQ	(+)	0.985	0.964	aaaatttaGAAAtacttta
ID
NO:
260

SEQ	(−)	0.958	0.866	agcTAAAgtatttct
ID
NO:
261

SEQ	(−)	1.000	0.763	TCGTcagtggtag
ID
NO:
262

SEQ	(+)	1.000	0.923	taccacTGACgaaatttgtat
ID
NO:
263

SEQ	(−)	1.000	0.959	tttaattCCAGacattc
ID
NO:
264

SEQ	(−)	1.000	0.977	cttTAATtccaga
ID
NO:
265

SEQ	(+)	1.000	0.923	ctggaATTAaaga
ID
NO:
266

SEQ	(+)	1.000	0.898	ctggAATTaaagaaa
ID
NO:
267

SEQ	(−)	1.000	0.915	cagTAATttcttt
ID
NO:
268

SEQ	(+)	1.000	0.922	aaagaaattacTGTTcttt
ID
NO:
269

SEQ	(−)	1.000	0.934	ttataTAAAgaacagta
ID
NO:
270

SEQ	(−)	1.000	0.890	attataTAAAgaacagt
ID
NO:
271

SEQ	(−)	0.891	0.923	tattaTATAaagaacag
ID
NO:
272

SEQ	(−)	0.769	0.856	ctattattatATAAagaacag
ID
NO:
273

SEQ	(+)	1.000	0.836	tttatataaTAATagactgta
ID
NO:
274

SEQ	(+)	0.791	0.760	tataataATAGactgtaaaat
ID
NO:
275

SEQ	(+)	1.000	0.912	gactgTAAAatggcaac
ID
NO:
276

SEQ	(+)	0.750	0.817	gtaaaatgGCAActt
ID
NO:
277

SEQ	(+)	1.000	0.907	ctgtaaaatgGCAActttt
ID
NO:
278

SEQ	(−)	1.000	0.882	taaAAGTtgccat
ID
NO:
279

SEQ	(+)	1.000	0.878	tatttgctAATTcac
ID
NO:
280

SEQ	(−)	0.777	0.865	tcctgTGAAttagcaaatatt
ID
NO:
281

SEQ	(+)	1.000	0.969	tgCTAAttcacag
ID
NO:
282

SEQ	(−)	0.850	0.866	tcctgtgAATTagca
ID
NO:
283

SEQ	(+)	0.750	0.788	ttgctaatTCACaggat
ID
NO:
284

SEQ	(−)	1.000	0.973	agAAAAaatcc
ID
NO:
285

SEQ	(−)	1.000	0.908	agatgTTCCaaagaaaaaa
ID
NO:
286

SEQ	(−)	1.000	0.919	ttgttCAGAtgttccaa
ID
NO:
287

SEQ	(+)	1.000	0.953	tgaacaAATTtccctta
ID
NO:
288

SEQ	(+)	0.750	0.757	acaAATTtccctt
ID
NO:
289

SEQ	(+)	1.000	0.771	tttccctTATAtgaatcac
ID
NO:
290

SEQ	(−)	1.000	0.908	agtGATTcatataaggg
ID
NO:
291

SEQ	(−)	1.000	0.797	gTGATtcatataa
ID
NO:
292

SEQ	(−)	1.000	0.912	agtgATTCata
ID
NO:
293

SEQ	(+)	0.881	0.958	ttatatgaATCActtacattt
ID
NO:
294

SEQ	(+)	1.000	0.860	cTTACattttt
ID
NO:
295

SEQ	(+)	0.850	0.829	gcctgttCATTtaaa
ID
NO:
296

SEQ	(−)	1.000	0.832	gtttTTTAaatgaacag
ID
NO:
297

SEQ	(+)	1.000	0.853	tcattTAAAaaactgca
ID
NO:
298

SEQ	(+)	1.000	0.866	actgcAGGAaagttgtg
ID
NO:
299

SEQ	(+)	1.000	0.891	ggaAAGTtgtgat
ID
NO:
300

SEQ	(−)	1.000	1.000	ataAATCacaacttt
ID
NO:
301

SEQ	(−)	1.000	0.931	cattaTAAAtcacaact
ID
NO:
302

SEQ	(−)	1.000	0.933	tgcattatAAATcacaa
ID
NO:
303

SEQ	(+)	1.000	0.924	gTGATttataatg
ID
NO:
304

SEQ	(−)	0.866	0.827	agttgcatTATAaatcacaactt
ID
NO:
305

SEQ	(+)	0.894	0.898	tgtgATTTataatgc
ID
NO:
306

SEQ	(+)	1.000	0.971	tgtGATTtataatgcaa
ID
NO:
307

SEQ	(+)	1.000	0.916	gtgatttaTAATgcaac
ID
NO:
308

SEQ	(+)	0.884	0.891	atttaTAATgcaact
ID
NO:
309

SEQ	(+)	1.000	0.861	ataATGCaactgcac
ID
NO:
310

SEQ	(+)	1.000	0.910	cagtctTAAAcaatgct
ID
NO:
311

SEQ	(+)	1.000	0.992	ttaaaCAATgctaacca
ID
NO:
312

SEQ	(+)	1.000	0.981	actgtGTTTcagc
ID
NO:
313

SEQ	(−)	1.000	0.889	gggAAGTttatgc
ID
NO:
314

SEQ	(−)	1.000	0.878	tgtgTGGGaagttta
ID
NO:
315

SEQ	(+)	0.763	0.826	actATGAaaacacat
ID
NO:
316

SEQ	(+)	1.000	0.786	actatgaaAACAcatgc
ID
NO:
317

SEQ	(+)	0.895	0.920	gaaaaCACAtgcttaaa
ID
NO:
318

SEQ	(−)	0.773	0.791	cctttAAGCatgtgttttc
ID
NO:
319

SEQ	(+)	1.000	0.874	cttaaaggCAAAtct
ID
NO:
320

SEQ	(−)	0.858	0.782	aGGTAaagatttgcctt
ID
NO:
321

SEQ	(−)	1.000	0.853	ctgaggTAAAgatttgc
ID
NO:
322

SEQ	(−)	0.789	0.830	ctgAGGTaaagat
ID
NO:
323

SEQ	(+)	0.766	0.820	aaatctttACCTcagttaact
ID
NO:
324

SEQ	(+)	1.000	0.862	tTTACctcagt
ID
NO:
325

SEQ	(−)	0.750	0.775	gaaTAGTtaactg
ID
NO:
326

SEQ	(+)	1.000	0.811	aGTTAactattccatag
ID
NO:
327

SEQ	(+)	0.856	0.925	agagCCATtga
ID
NO:
328

SEQ	(−)	1.000	0.873	tgaacTCAAtggctc
ID
NO:
329

SEQ	(−)	1.000	0.980	ctTGAActcaa
ID
NO:
330

SEQ	(+)	1.000	0.854	attgagtTCAAgtgcattt
ID
NO:
331

SEQ	(+)	0.782	0.813	tgagTTCAagtgcattt
ID
NO:
332

SEQ	(+)	1.000	1.000	gttcAAGTgcatt
ID
NO:
333

SEQ	(+)	1.000	0.928	agaAGATataatg
ID
NO:
334

SEQ	(−)	0.891	0.912	atataTATAtggccata
ID
NO:
335

SEQ	(+)	1.000	0.777	atggccaTATAtatatata
ID
NO:
336

SEQ	(−)	1.000	0.806	atatatatatatATGGc
ID
NO:
337

SEQ	(−)	0.750	0.675	CTGTgctgatatatatata
ID
NO:
338

SEQ	(+)	0.750	0.827	atatataTCAGcacagt
ID
NO:
339

SEQ	(+)	1.000	0.904	ataTATCagcacagt
ID
NO:
340

SEQ	(+)	1.000	0.704	atcAGCAcagtggaaacagtt
ID
NO:
341

SEQ	(+)	1.000	0.970	agtgGAAAcag
ID
NO:
342

SEQ	(−)	1.000	0.991	taactGTTTccac
ID
NO:
343

SEQ	(−)	1.000	0.798	tGTTAttaactgtttcc
ID
NO:
344

SEQ	(+)	0.826	0.824	aaacagttAATAacatt
ID
NO:
345

SEQ	(+)	1.000	0.749	ggaaacagtTAATaacatttt
ID
NO:
346

SEQ	(−)	1.000	0.863	taTATGctaaaatgt
ID
NO:
347

SEQ	(−)	0.891	0.908	tagtaTATAtgctaaaa
ID
NO:
348

SEQ	(+)	1.000	0.897	gaggctGGAAgggggct
ID
NO:
349

SEQ	(+)	1.000	0.787	gctggaagggggcTCAGcagtta
ID
NO:
350

SEQ	(−)	0.876	0.901	attAACTgctg
ID
NO:
351

SEQ	(+)	0.750	0.840	atagcacatacTATTcttc
ID
NO:
352

SEQ	(+)	0.782	0.747	gtttggtttTCATcacccatg
ID
NO:
353

SEQ	(−)	1.000	0.988	gaacCACCtgacatg
ID
NO:
354

SEQ	(−)	1.000	0.958	tacaGATAgaaat
ID
NO:
355

SEQ	(+)	1.000	0.924	gtaacCAGAtgatacga
ID
NO:
356

SEQ	(−)	0.750	0.762	agGTACccaaggggact
ID
NO:
357

SEQ	(−)	1.000	0.960	aggtGATAgaggt
ID
NO:
358

SEQ	(−)	1.000	0.939	atagCAGGtgataga
ID
NO:
359

SEQ	(+)	0.759	0.710	cacctgctattctCACCcaaaga
ID
NO:
360

SEQ	(+)	1.000	0.805	aCCCAaagacacaca
ID
NO:
361

SEQ	(−)	0.944	0.904	tGTATgtgagtgtgt
ID
NO:
362

SEQ	(+)	1.000	0.854	tgcATGCacatagtt
ID
NO:
363

SEQ	(−)	0.977	0.855	tGAACtatgtgcatg
ID
NO:
364

SEQ	(+)	0.750	0.767	catagttcAAAAaataaaatttt
ID
NO:
365

SEQ	(−)	1.000	0.896	ttaaaatTTTAttttttga
ID
NO:
366

SEQ	(−)	0.750	0.798	taaAATTttattt
ID
NO:
367

SEQ	(+)	1.000	0.991	aaagGAAAaaa
ID
NO:
368

SEQ	(+)	1.000	0.977	ggAAAAaaagc
ID
NO:
369

SEQ	(−)	1.000	0.946	aaaAGATttgagc
ID
NO:
370

SEQ	(−)	1.000	0.901	aggaATTTt
ID
NO:
371

SEQ	(+)	0.806	0.820	taaaatTCCTatgagtgtgtgat
ID
NO:
372

SEQ	(−)	0.782	0.753	tactgacttTGATcacacact
ID
NO:
373

SEQ	(−)	1.000	0.942	cacAGATtatacc
ID
NO:
374

SEQ	(+)	1.000	0.971	tgtgGAAAaca
ID
NO:
375

SEQ	(+)	0.980	0.879	ctcagtATTCaca
ID
NO:
376

SEQ	(−)	1.000	0.827	ctactttCATGtgtgaata
ID
NO:
377

SEQ	(−)	0.850	0.952	cttTCATgtgtga
ID
NO:
378

SEQ	(+)	1.000	0.838	aagtagcTAAGaataaa
ID
NO:
379

SEQ	(−)	1.000	0.960	aatAGATtttatt
ID
NO:
380

SEQ	(+)	0.806	0.819	aataaaATCTattcatc
ID
NO:
381

SEQ	(+)	0.785	0.846	taaaaTCTAttcatc
ID
NO:
382

SEQ	(+)	1.000	0.890	atctATTCatc
ID
NO:
383

SEQ	(−)	1.000	0.881	aaaaaCAGAtgaataga
ID
NO:
384

SEQ	(−)	1.000	0.981	ggAAAAacaga
ID
NO:
385

SEQ	(−)	1.000	0.976	taagGAAAaac
ID
NO:
386

SEQ	(−)	1.000	0.872	aggattttaaGGAAaaaca
ID
NO:
387

SEQ	(+)	1.000	0.897	ttcctTAAAatcctggc
ID
NO:
388

SEQ	(−)	1.000	0.880	actgagtcAACActgta
ID
NO:
389

SEQ	(−)	1.000	0.984	accactgaGTCAacactgtag
ID
NO:
390

SEQ	(+)	0.964	0.984	agtgttgaCTCAgtggttgct
ID
NO:
391

SEQ	(−)	0.826	0.904	gcaaCCACtga
ID
NO:
392

SEQ	(+)	1.000	0.883	tttaaatTTTAtgctcaaa
ID
NO:
393

SEQ	(+)	1.000	0.891	caaAAGTtgaagc
ID
NO:
394

SEQ	(+)	1.000	0.829	tgaaCCGGtaattctac
ID
NO:
395

SEQ	(−)	1.000	0.757	acaAAGTagaatt
ID
NO:
396

SEQ	(−)	0.750	0.816	aagtattTAATacaaag
ID
NO:
397

SEQ	(−)	1.000	0.939	acaagtattTAATacaa
ID
NO:
398

SEQ	(−)	1.000	0.865	taacAAGTattta
ID
NO:
399

SEQ	(+)	1.000	0.882	acttgTTATgcatcg
ID
NO:
400

SEQ	(−)	1.000	0.758	aacttgatttgttgAGCGatgcataacaa
ID
NO:
401

SEQ	(+)	0.750	0.809	ctcaaCAAAtcaagt
ID
NO:
402

SEQ	(+)	1.000	0.976	acaAATCaagtttta
ID
NO:
403

SEQ	(+)	1.000	0.830	acaaaTCAAgtttta
ID
NO:
404

SEQ	(−)	0.750	0.756	taaAACTtgattt
ID
NO:
405

SEQ	(+)	1.000	0.907	aaaTCAAgtttta
ID
NO:
406

SEQ	(+)	1.000	0.936	caaatCAAGttttaa
ID
NO:
407

SEQ	(+)	1.000	0.887	atcAAGTtttaac
ID
NO:
408

SEQ	(+)	1.000	0.883	atcaagtTTTAacacacca
ID
NO:
409

SEQ	(−)	1.000	0.925	ttaaaaAATTtaagata
ID
NO:
410

SEQ	(+)	1.000	0.780	atttTTTAaatgggcat
ID
NO:
411

SEQ	(−)	0.750	0.818	tttatgccCATTtaa
ID
NO:
412

SEQ	(+)	1.000	0.796	ctaTTCCtacagaagtc
ID
NO:
413

SEQ	(+)	1.000	0.860	ctgaaaATGCatt
ID
NO:
414

SEQ	(+)	1.000	0.898	tgCATTcctgatt
ID
NO:
415

SEQ	(−)	1.000	0.981	ataAATCaggaatgc
ID
NO:
416

SEQ	(+)	1.000	0.929	cTGATttatgtaa
ID
NO:
417

SEQ	(+)	1.000	0.964	cctGATTtatgtaaata
ID
NO:
418

SEQ	(+)	1.000	0.861	ctgatTTATgtaaat
ID
NO:
419

SEQ	(−)	1.000	0.929	tTTACataaat
ID
NO:
420

SEQ	(+)	1.000	0.943	cctgatttatGTAAatatatg
ID
NO:
421

SEQ	(+)	1.000	0.895	ttTATGtaaatatat
ID
NO:
422

SEQ	(+)	1.000	0.940	tttatgTAAAtatatgt
ID
NO:
423

SEQ	(+)	1.000	0.691	atgtaaaTATAtgtatata
ID
NO:
424

SEQ	(+)	0.849	0.883	atgtatATACata
ID
NO:
425

SEQ	(+)	0.888	0.755	gtatatacatatATAGc
ID
NO:
426

SEQ	(−)	0.891	0.903	ggctaTATAtgtatata
ID
NO:
427

SEQ	(+)	1.000	0.709	atatacaTATAtagcctta
ID
NO:
428

SEQ	(−)	1.000	0.816	ttgttttTAAGgctata
ID
NO:
429

SEQ	(+)	1.000	0.899	agcctTAAAaacaaaga
ID
NO:
430

SEQ	(+)	1.000	0.973	aaAACAaagat
ID
NO:
431

SEQ	(+)	1.000	0.863	ttaaaaaCAAAgattgt
ID
NO:
432

SEQ	(+)	1.000	0.811	aagattgtAATTttt
ID
NO:
433

SEQ	(−)	1.000	0.900	acaatttaTAAAaattacaatct
ID
NO:
434

SEQ	(−)	1.000	0.844	tttataaaAATTaca
ID
NO:
435

SEQ	(−)	1.000	0.956	atttaTAAAaattacaa
ID
NO:
436

SEQ	(+)	1.000	0.875	tgTAATttttataaatt
ID
NO:
437

SEQ	(−)	1.000	0.903	aatttaTAAAaattaca
ID
NO:
438

SEQ	(−)	1.000	0.973	tcacaatttaTAAAaattacaat
ID
NO:
439

SEQ	(−)	0.750	0.798	atcACAAtttataaaaa
ID
NO:
440

SEQ	(+)	1.000	0.927	ttttaTAAAttgtgatt
ID
NO:
441

SEQ	(−)	1.000	0.997	aaaAATCacaattta
ID
NO:
442

SEQ	(+)	1.000	0.806	gTGATttttaaaa
ID
NO:
443

SEQ	(−)	1.000	0.923	tattttttTAAAaatcacaattt
ID
NO:
444

SEQ	(+)	1.000	0.990	ttgtgattttTAAAaaaataaac
ID
NO:
445

SEQ	(+)	1.000	0.905	gtgattttTAAAaaaataaacct
ID
NO:
446

SEQ	(−)	0.755	0.796	gGTTTatttttttaaaa
ID
NO:
447

SEQ	(+)	0.750	0.775	gatttttaAAAAaataaacctgc
ID
NO:
448

SEQ	(+)	1.000	0.848	aaacctgcATTAtcttc
ID
NO:
449

SEQ	(−)	0.884	0.851	gaagaTAATgcaggt
ID
NO:
450

SEQ	(−)	1.000	0.853	tgctgaagaTAATgcaggttt
ID
NO:
451

SEQ	(−)	1.000	0.993	tgaaGATAatgca
ID
NO:
452

SEQ	(+)	0.867	0.951	TGAAtgttcct
ID
NO:
453

SEQ	(+)	1.000	0.893	cctAAGTtttgta
ID
NO:
454

SEQ	(+)	1.000	0.772	agttttgTAGAacttga
ID
NO:
455

SEQ	(−)	1.000	0.927	cgtgtCAAGttctac
ID
NO:
456

SEQ	(−)	1.000	0.997	tctgccaCGTGtcaagt
ID
NO:
457

SEQ	(+)	1.000	0.795	aggattTTAGtctacac
ID
NO:
458

SEQ	(−)	1.000	0.981	gatgCAGGtgtagac
ID
NO:
459

SEQ	(−)	1.000	0.832	ctgtcctcagatgcaGGTGta
ID
NO:
460

SEQ	(+)	1.000	0.873	ctaacaGGAAaggagac
ID
NO:
461

SEQ	(+)	1.000	0.829	ggagacaCATGtgtggtag
ID
NO:
462

SEQ	(+)	1.000	1.000	catgtgTGGTagttc
ID
NO:
463

SEQ	(+)	1.000	0.919	tgtggtagTTCCcag
ID
NO:
464

SEQ	(−)	1.000	0.841	aactgGGAActac
ID
NO:
465

SEQ	(−)	1.000	0.842	aaacTGGGaactacc
ID
NO:
466

SEQ	(−)	0.750	0.784	ttcacgtCAAAactg
ID
NO:
467

SEQ	(−)	1.000	0.830	ttcACGTcaaaac
ID
NO:
468

SEQ	(+)	1.000	0.985	cagttttGACGtgaaaagtcc
ID
NO:
469

SEQ	(+)	1.000	0.891	gttttgaCGTGaaaagt
ID
NO:
470

SEQ	(+)	1.000	0.909	ttgACGTgaaaag
ID
NO:
471

SEQ	(+)	1.000	0.890	tttgACGTgaaaagt
ID
NO:
472

SEQ	(+)	1.000	0.837	ttgacgtGAAAagtc
ID
NO:
473

SEQ	(+)	1.000	0.937	cattcttactGGAAacctc
ID
NO:
474

SEQ	(+)	0.800	0.805	ttcttacTGGAaacctc
ID
NO:
475

SEQ	(+)	0.782	0.791	acctCCCTgaatccatgccaagc
ID
NO:
476

SEQ	(−)	1.000	0.964	gctTGGCatggattcaggg
ID
NO:
477

SEQ	(+)	1.000	0.820	tccATGCcaagcact
ID
NO:
478

SEQ	(+)	1.000	0.787	gCCAAgcactacccatcaccttgac
ID
NO:
479

SEQ	(−)	1.000	0.954	cagtCAAGgtgat
ID
NO:
480

SEQ	(−)	1.000	0.800	ctTATGccagtcaag
ID
NO:
481

SEQ	(−)	1.000	0.862	agtgcTTATgccagt
ID
NO:
482

SEQ	(−)	1.000	0.920	atcaaAGGAaatgagtg
ID
NO:
483

SEQ	(−)	1.000	0.969	ggggcatCAAAggaaat
ID
NO:
484

SEQ	(−)	1.000	0.912	gaggGAGGggcat
ID
NO:
485

SEQ	(−)	0.876	0.920	tgagGGAGgggcatc
ID
NO:
486

SEQ	(+)	1.000	0.973	tattaTAAAagcacagt
ID
NO:
487

SEQ	(−)	1.000	0.700	gaaagagacgaCTGTgctt
ID
NO:
488

Claims

We claim:

1. A method for identifying agents which modulate INGAP expression comprising:

contacting a host cell comprising a reporter construct having at least one INGAP regulatory region selected from nucleotides from the group consisting of SEQ ID NO: 1, 2, 23, 32, 35, 37, 28, 24, 25, 26, 27, 29, 30, 31, 33, 34, 38, and 36 and a region encoding a detectable product with a test agent;

determining expression of the detectable product in the cell; and identifying the test agent as a modulator of INGAP expression if the test agent modulates expression of the detectable product in the cell.

2. The method of claim 5 wherein the regulatory sequence comprises nucleotides 1-3137 of SEQ ID NO: 2.

3. The method of claim 1 wherein the reporter construct further comprises: a promoter element interposed between the regulatory region nucleotide sequence and the nucleotide sequence encoding the detectable product.

4. The method of claim 3 wherein the promoter element is selected from SEQ ID NO: 2.

5. An in vitro method for identifying agents which modulate INGAP expression, comprising: a. contacting a reporter construct having at least one INGAP regulatory region and a nucleotide sequence encoding a detectable product with a test substance under conditions sufficient for transcription and translation of said nucleotide sequence; determining expression of the detectable protein or nucleic acid product; and identifying the test substance as a modulator of INGAP expression if the test substance modulates expression of the detectable product.

6. The method of claim 5 wherein the regulatory region nucleotide sequence comprises of one or more regions chosen from nucleotides from the group consisting of SEQ ID NO: 1, -2, 23, 32, 35, 37, 28, 24, 25, 26, 27, 29, 30, 31, 33, 34, 38, and 36.

7. The method of claim 6 wherein the regulatory sequence comprises nucleotides 1-3137 of SEQ ID NO: 2.

8. The method of claim 5 wherein the reporter construct further comprises: a promoter element interposed between the regulatory region nucleotide sequence and the nucleotide sequence encoding the detectable product.

9. The method of claim 8 wherein the promoter element is selected from SEQ ID NO: 2.

10. A method for inducing INGAP expression in a mammal in need thereof, comprising administering to the mammal an effective amount of a factor that stimulates INGAP expression in the said mammal.

11. The method of claim 10 wherein the factor that stimulates INGAP expression was identified by:

contacting a host cell comprising a reporter construct having at least one INGAP regulatory region and a region encoding a detectable product with a test agent;

determining expression of the detectable product in the cell; and

identifying the test agent as a modulator of INGAP expression if the test agent modulates expression of the detectable product in the cell; wherein the regulatory region nucleotide sequence comprises of one or more regions chosen from nucleotides from the group consisting of SEQ ID NO: 1, -2, 23, 32, 35, 37, 28, 24, 25, 26, 27, 29, 30, 31, 33, 34, 38, and 36.

12. The method of claim 11 wherein the factor that stimulates INGAP expression was identified by:

contacting the SEQ ID NOS: 1, -2, 23, 32, 35, 37, 28, 24, 25, 26, 27, 29, 30, 31, 33, 34, 38, and 36 or fragments thereof with a test agent;

determining binding of the test agent to the nucleic acid; and

identifying the test agent as a potential modulator of INGAP expression if the test agent binds to the nucleic acid

15. The method of claim 10 wherein the factor that stimulates INGAP expression is selected from hLIF or PMA.