CA2341051A1 - Cell specific promoters of uncoupling protein 3 - Google Patents

Abstract

The present invention is in the field of the gene promoters which mediate the transcription of proteins which play a part in the energy management of cells and in obesity. The invention relates to DNA molecules which contain recombinant cell-specific promoters of uncoupling protein 3 (UCP 3) or functional derivatives thereof. It also relates to cells which contain these DNA molecules. The invention also relates to uses of these DNA molecules and the cells according to the invention, and processes for finding substances which are capable of influencing transcription. These processes can also be carried out by the High Throughput Screening method. Processes are also disclosed which can be used to find substances or factors which bind to the DNA molecules according to the invention.

Description

Cell specific promoters of uncoupling protein 3 5 The present invention is in the field of the gene promoters of proteins which play a part in the energy management of cells and in obesity. The subject matter of the invention is recombinant DNA molecules (DNA: deoxyribonucleic acid), which contain cell specific promoters of uncoupling protein 10 3 (UCP 3) or functional derivatives thereof. The invention also relates to cells which contain these recombinant DNA
molecules, the uses of these DNA molecules and the cells according to the invention and process for finding substances which influence the transcription of the 15 promoters according to the invention or which bind to the DNA molecules according to the invention.
Obesity is a disease in which the fatty tissue increases as a result of a positive energy balance sheet. This can be 20 the result of an excessive food intake or a symptom of a metabolic disorder (ROCHE Lexicon of Medicine, 3rd Edition, Urban & Schwarzenberg). Obesity is a problem which is frequently caused by food in the industrial western countries and plays an important part as a cause of illness 25 and death (McGinnis and Foege, 1993; Manson et al., 1995).
Since obesity is caused by a constant imbalance between food intake and energy use, a chronic reduction in energy use might be a risk factor for this condition. In fact, a lower energy use at rest is a risk factor for obesity 30 (Ravussin et al., 1988; Griffiths et al., 1990). Genetic factors contribute significantly to the level of basic energy use (Bogardus et al., 1986; Bouchard et al., 1989).
Brown Adipose Tissue (BAT) is specialised for thermogenesis, one of the main factors of energy conversion 35 (Himms-Hagen, 1989). The so-called uncoupling proteins 1,

2 and 3 (UCPs for short) have central importance in the thermogenic function of BAT (Klaus et al., 1991; Boss et al., 1997; Fleury et al. 1997; Gimeno et al., 1997; Gong et al., 1997; Vidal-Puig et al., 1997). These proteins stimulate the production of heat by uncoupling substrate oxidation from ATP synthesis (Ricquier et al. 1991).
Whereas the importance of BAT has been shown as a regulator of the body fat store for rodents (Lowell et al., 1993;
Kopecky et al., 1995), its role in obesity in humans is unclear as adults have very little BAT (Krief et al. 1993).
Regardless of this restriction, a significantly lower UCP1-mRNA content (RNA: ribonucleic acid; mRNA: messenger ribonucleic acid) was found in the intraperitoneal fatty tissue of obese individuals than in slim control subjects (Oberkofler et al., 1997). A major part of the fluctuations in the quantity of UCP1-mRNA in obese individuals was explained by normal changes in sequence in the UCP1 gene locus (Esterbauer et al., in press).
Therefore, it is possible that UCP1 and BAT contribute to the basic energy conversion.
UCP2 and UCP3, two other recently discovered members of the UCP family, are expressed in different tissues in humans and rodents. UCP2-mRNA can be found in white fatty tissue, BAT, lungs, liver, spleen and macrophages (Fleury et al., 1997; Gimeno et al., 1997), whereas large amounts of UCP3-mRNA are observed in the skeletal muscle and BAT (Boss et al., 1997; Gong et al., 1997; Vidal-Puig et al., 1997).
Studies in mice deficient in the UCP1 gene (Enerback et al., 1997) and ~.n slender rats which over-express leptin (Zhou et al., 1997) support a model in which UCP2 may act as a reserve system for thermogenesis if UCP1 is deficient and/or the quantity of leptin increases as the result of overweight. UCP3 could have profound effects on energy homeostasis, as muscle tissue contains a major proportion of catecholamine and is responsible for nutrition-induced thermogenesis both in humans (Astrup et al., 1986) and in rats (Thurlby and Ellis, 1986).
The human UCP2 and UCP3 genes are located in chromosome region 11q13 (Fleury et al., 1997; Solanes et al., 1997;
Boss et al., 1998). Investigation of the family trees of the Quebec family study produced very powerful indications that this chromosomal region is associated with energy conversion in the resting state, the body mass index (BMI) and the fatty mass in adults (Bouchard et al., 1997).
Moreover, the syntenic region on chromosome 7 in the mouse is responsible for obesity and non-insulin-dependent Diabetes mellitus (Hashimoto et al., 1994; Warden et al., 1995) .
Compared with the slim control subjects, the quantity of UCP2-mRNA in the intraperitoneal tatty tissue of morbidly obese people was reduced. In accordance with the role in the pathophysiology of obesity, the quantity of UCP2-mRNA
in patients who have overcome obesity is low, both before and after weight reduction (Oberkafler et al., in press).
By contrast, the quantity of UCP3-mRNA in muscle tissue did not vary between obese and slender individuals (Millet et al., 1997), but these results must be interpreted cautiously. Firstly, tissue-specific differences were found in the regulation of UCP3 expression in rodents (Gong et al., 1997; Larkin et al., 1997; Boss et al., 1998).
Secondly, two different isofortns (UCP3L and UCP3S) of the human UCP3 gene~were found by cloning the DNA complementary to mRNA (complementary DNA; cDNA). A polyadenylation signal in Intron 6 is used in a significant proportion of the UCP3 transcripts for forming UCP3S, whilst a second polyadenylation signal in exon 7 is used for forming UCPL
Because of a C-terminal truncation, the UCP3S form lacks the sixth predicted transmembrane domain and the purine nucleotide binding domain which has been deemed responsible

3 for inhibiting UCP activity by nucleotides (Jezek et al., 1994). The truncation of the UCP3 molecule could increase the UCP3 activity in this way, but defective membrane insertion could affect the stability and function of UCP3.
It is desirable to find better methods of treating obesity.
Substances which can be administered to the patient in as painfree a manner as possible and with as few side effects as possible are advantageous. One possibility of simplifying the search for such substances is to identify factors native to the body which play an important role in the pattern of this illness. These might be a target molecule for suitable substances, interaction with which might influence the activity or properties of the native factor in a manner which is positive for the patient.
Suitable target molecules could also be defined if known factors native to the body can be shown to participate in the events which precipitate the disease. After a suitable target molecule has been identified, these substances might be found with greater prospects of success by measuring the influence of as many compounds as possible on the activity or properties of the target molecule. These compounds might be derived from a library of natural or other substances, and combinatorial chemistry could make a valuable contribution. To speed up this process the analyses are carried out by high throughput screening (HTS). Naturally, only a few substances are found but these could be used as the basis for chemical derivatisation and optimisation and subsequent pharmacological characterisation.
For the UCP3 gene, the amino acid sequence derived from cDNA, the cDNA sequence (Gene Bank Accession number U84763), the genomic DNA sequence including the position of the exons and introns (Boss et al., 1998) and part of the 5'-non-coding region are already known in the prior art

4 (Gene Bank Accession number AF032871). Moreover the position of a promoter and a TATA signal were known (Entry AF032871 in the Gene Bank databank). The genomic DNA
sequence of the UCP3 gene including the introns and exons and the 5~-region is enclosed for inspection with this application (see SEQ ID N0: 17).
Surprisingly, it has now been found within the scope of this invention that there is an additional promoter in the region upstream of TATA signal which is preferentially active in fat cells (see Example 1). The UCP3 gene is otherwise only strongly expressed in the skeletal muscle but is expressed there using the known promoter, as has surprisingly been found within the scope of this invention (see Example 1). It is advantageous to influence the promoter which is preferentially active in fatty cells or in muscle cells, since this could serve as a treatment for obesity. This is particularly advantageous as it can be used to modulate a factor which is active only in certain parts of the body. DNA constructs can thus be produced which make it possible to investigate the fat cell-specific or muscle cell-specific transcription of the UCP3 gene and find corresponding substances for modulating them. For this purpose, only the corresponding part of the UCP3 promoter which is active in the other type of cell need be removed.
The objective of preparing a new suitable target molecule can thus be achieved with the present invention as set forth in the specification and claims. According to the invention, recombinant DNA molecules with cell specific promoters of the UCP3 gene are prepared. In connection with this, recombinant DNA molecules which contain functional derivatives of the promoters according to the invention or comprise certain parts of the 5~-sequence of the UCP-3 promoter are also disclosed by the present

5

6 PCT/EP99/06152 invention. The present invention also includes cells which contain DNA molecules according to the invention. In another embodiment, the use of these DNA molecules or the cells according to the invention for transcribing a gene or for discovering substances which influence transcription is also disclosed. The invention further includes processes which make it possible to discover substances which influence the transcription rate. The process according to the invention in the high throughput screening format is particularly preferred. Processes are also disclosed which make it possible to find substances or factors which bind to the DNA molecules according to the invention.
This invention discloses a recombinant DNA molecule which contains the UCP3 promoter preferentially active in fat cells but not the known UCP3 promoter which is active in muscle cells. This recombinant DNA molecule contains the sequences SEQ ID N0: 1 TATATTAAA and SEQ ID NO: 2 CACCTC, but not SEQ ID N0: 3 TATAAGA and SEQ ID NO: 4 CAATCC.
However, the sequences which are important for the promoter which is active in muscle cells can also be altered by point mutation or deletions or combinations thereof so that they lose their function in transcription. Between the sequences SEQ ID NO: 1 and SEQ ID N0: 2 there may be 30 to 50 base pairs, preferably 40 to 45 base pairs, most preferably 42 base pairs. In another embodiment the DNA
molecule described is further characterised in that upstream of SEQ ID N0: 1 there is additionally an RXR/PPAR
element (Schoon~ans et al., 1996) which preferably includes the sequence SEQ ID N0: 5 TGACCTTTGGACT, whilst there are preferably 65 to 75 base pairs between the sequences SEQ ID
N0: 1 and SEQ ID N0: 5. A summary of essential promoter elements is provided by Locker and Buzard (1990). Another embodiment of the invention is characterised in that, upstream of SEQ ID N0: 1, there is additionally an Alu sequence, whilst there may be 255 to 265 base pairs between the sequence SEQ ID N0: 1 and the Alu sequence. For the purposes of the invention an Alu sequence means a section of about 300 base pairs which occurs only in the human genome, which belongs to the highly repetitive DNA
sequences and carries a cutting site for the restriction enzyme Alu I more or less in the middle. The DNA molecule described may be further characterised in that, upstream of SEQ ID N0: 1, there is additionally an E2A element (Locker and Buzard, 1990; Aronheim et al., 1991; Leshkowitz et al, 1992; Park and Walker, 1992) which corresponds to the sequence SEQ ID N0: 6 CAGATG, whilst there may be 440 to 450 base pairs between the sequences SEQ ID N0: 1 and SEQ
ID N0: 6. The DNA molecule described may be further characterised in that there is additionally an E box (Aronheim et al., 1991; Leshkowitz et al, 1992; Park and Walker, 1992) upstream of SEQ ID NO: 1, which preferably includes the sequence SEQ ID NO: 7 CACTTG, whilst between the sequences SEQ ID N0: 1 and SEQ ID N0: 7 there may be 450 to 460 base pairs. The DNA molecule described may be further characterised in that there is additionally another E box (Aronheim et al., 1991; Leshkowitz et al, 1992; Park and Walker, 1992) upstream of SEQ ID NO: 1, which preferably includes the sequence SEQ ID NO: 8 CATTTG, whilst there may be 460 to 470 base pairs between the sequences SEQ ID N0: 1 and SEQ ID N0: 8. The DNA molecule according to the invention may be further characterised in that, upstream of SEQ ID N0: 1, there may additionally be an octamer sequence (Locker and Buzard, 1990) which preferably includes the sequence SEQ ID N0: 9 ATGAAAATGT, whilst there may be 515 to 525 base pairs between the sequences SEQ ID N0: 1 and SEQ ID N0: 9. The DNA molecule according to the invention may be further characterised in that, upstream of SEQ ID N0: 1, there may additionally be another CART box (Locker and Buzard, 1990) which preferably includes the sequence SEQ ID NO: 10 CCAAT, whilst there may be 560 to 570 base pairs between the sequences SEQ ID N0: 1

7 and SEQ ID NO: 10. The CAAT box (Locker and Buzard, 1990) is part of a base sequence which is conserved in many eukaryotic genes, observed in the 5~-flanking section of the coding region. The DNA molecule according to the invention may be further characterised in that, upstream of SEQ ID N0: 1, there may additionally be another CAAT box (Locker and Buzard, 1990) which preferably contains the sequence SEQ ID NO: 11 ATTGG, whilst there may be 670 to 680 base pairs between the sequences SEQ ID N0: 1 and SEQ
ID N0: 11. The DNA molecule according to the invention may be further characterised in that a CAAT box (Locker and Buzard, 1990) may additionally be provided upstream of SEQ
ID N0: 1, preferably comprising the sequence SEQ ID N0: 12 ATTGG, whilst there may be 730 to 740 base pairs between the sequences SEQ ID NO: 1 and SEQ ID N0: 12. The DNA
molecule according to the invention may be further characterised in that, upstream of SEQ ID N0: 1, there is additionally a binding site for an upstream binding stimulating factor (USF; Locker and Buzard, 1992) which preferably includes the sequence SEQ ID N0: 13 CCACGTGC, whilst there may be 845 to 855 base pairs between the sequences SEQ ID N0: 1 and SEQ ID N0: 13.
This invention discloses another recombinant DNA molecule which does not contain the UCP3 promoter preferentially active in fat cells but rather contains the promoter which is active in muscle cells. This recombinant DNA molecule contains the sequences SEQ ID NO: 3 TATAAGA and SEQ ID N0:
4 CAATCC, but not the sequences SEQ ID N0: 1 TATATTAAA and SEQ ID N0: 2 CACCTC. However, the sequences which are important for the promoter active in fat cells may be altered by point mutation or deletions or combinations thereof so that they lose their function in transcription.
There may be 45 to 70 base pairs, preferably 52 to 58 base pairs, most preferably 55 base pairs between sequences SEQ
ID NO: 3 and SEQ ID N0: 4. In another embodiment the DNA

8 molecule described is further characterised in that, upstream of SEQ ID NO: 3, there is additionally an RXR/PPAR
element which preferably includes the sequence SEQ ID N0: 5 TGACCTTTGGACT. A further embodiment of the invention is characterised in that upstream of SEQ ID N0: 3 there is additionally an Alu sequence. The DNA molecule described may be further characterised in that upstream of SEQ ID N0:
3 there is additionally an E2A element which corresponds to the sequence SEQ ID NO: 6 CAGATG. The DNA molecule described may be further characterised in that, upstream of SEQ ID N0: 3, there is additionally an E box which preferably includes the sequence SEQ ID N0: 7 CACTTG. The DNA molecule described may be further characterised in that, upstream of SEQ ID N0: 3, there is additionally another E box which preferably contains the sequence SEQ ID
N0: 8 CATTTG. The DNA molecule according to the invention may be further characterised in that, upstream of SEQ ID
N0: 3, there may additionally be an octamer sequence which preferably includes the sequence SEQ ID N0: 9 ATGAAAATGT.
The DNA molecule according to the invention may be further characterised in that upstream of SEQ ID N0: 3 there may additionally be another CAAT box which preferably includes the sequence SEQ ID N0: 10 CCAAT. The CART box is part of a base sequence which is conserved in many eukaryotic genes and observed in the 5'-flanking section of the coding region. The DNA molecule according to the invention may be further characterised in that, upstream of SEQ ID NO: 3, there may additionally be another CAAT box which preferably includes the seC~uence SEQ ID N0: 11 ATTGG. The DNA
molecule according to the invention may be further characterised in that, upstream of SEQ ID NO: 3, there may additionally be a CAAT box which preferably includes the sequence SEQ ID N0: 12 ATTGG. The DNA molecule according to the invention may be further characterised in that, upstream of SEQ ID NO: 3, there is additionally a binding

9 site for an upstream binding stimulation factor which preferably includes the sequence SEQ ID NO: 13 CCACGTGC.
The invention also include DNA molecules which contain the sequence SEQ ID NO 14 or a sequence which hybridises to SEQ
ID NO 14 under stringent conditions. By stringent conditions is meant conditions which select for more than 85 0, preferably more than 90 °s homology (Sambrook et al., 1989). The hybridisations are carried out in 6x SSC/5x Denhardt's solution/0.1 o SDS (SDS: sodium dodecylsulphate) at 65°C. The degree of stringency is determined in the washing step. Thus, for selection for DNA sequences with approximately 85 o homology or more, the conditions of 0.2 x SSC/0.01 % SDS/65°C are suitable and for selection for DNA sequences with about 90 % homology or more, the conditions of O.lx SSC/0.01 o SDS/65°C are suitable. The composition of the reagents is described in Sambrook et al.
(1989) .
The invention further comprises functional derivatives of the DNA molecules according to the invention with the cell specific UCP3-promoters. Under the terms of the invention, the term functional derivatives includes all DNA sequences which have come into being by point mutations or deletions or combinations of point mutations or deletions from the original sequence. These functional derivatives have according to the invention, the common ability of mediating transcription of a gene fused at the 3'-end of the functional derivative. It is within the capabilities of the average skilled person to produce these functional derivatives by targeted or random mutagenesis or by inserting deletions from the sequences according to the invention. The precise methods are described by Sambrook et al. (1989). For example, oligonucleotide-directed or random mutagenesis methods may be used. For the latter process, polymerase chain reaction may also be used, which operates imprecisely if it is carried out under suboptimal conditions (Lin-Goerke et al., 1997). The deletions may be inserted, for example, by using oligonucleotides with methods of targeted mutagenesis or preferably by amplification of desired areas by polymerase chain reaction. The average skilled person can find a functional derivative by determining the activity of a reporter gene such as luciferase fused at the 3~-end of the functional derivative. It is particularly preferred to determine the activity of a functional derivative by the chloramphenicol transferase test ("CAT assay") carried out according to Sambrook et al. (1989). The average skilled person will regard a sequence obtained by point mutation or deletion or a combination of both changes, which produces a signal above the background in one of the two tests described above, as a functional derivative.
In a preferred embodiment of the invention the DNA
molecules according to the invention are present in the form of vectors, particularly expression vectors. In a particularly preferred embodiment the DNA molecule according to the invention is a plasmid. In another embodiment the DNA molecule according to the invention is a viral vector.
In another preferred embodiment, DNA molecules are disclosed which in addition to the DNA sequence of the promoters according to the invention contain other genes which are functionally linked to the promoters according to the invention. For the purposes of this invention the term functional means that the linking is carried out in a way which makes it possible either to transcribe the gene or to transcribe the gene and obtain its translation product.
The genes may be the cDNA or the genomic sequence of the uncoupling protein 3 or they may be reporter genes. The translation products of the reporter genes are preferably proteins the quantity of which can easily be determined by measuring the activity, absorption, luminescence or fluorescence, e.g. green fluorescent protein (GFP), chloramphenicol-acetyl-transferase, (3-galactosidase, secreted alkaline phosphatase or luciferase. For the purposes of this invention green fluorescent protein also includes all the variants thereof which fluoresce in other wavelengths but are derived from the amino acid sequence of green fluorescent protein. Most preferably, the proteins coded by the reporter gene are enzymes which catalyse a reaction the end product of which is easy to determine quantitatively. Thus, for example, the enzyme luciferase catalyses a chemical reaction in which light is emitted by luminescence which can be measured in a luminometer.
Another aspect of the invention is a DNA molecule which contains the sequence SEQ ID NO 15 or a sequence which hybridises with SEQ ID NO 15 under stringent conditions.
By stringent conditions, the skilled person means conditions which select for more than 85 %, preferably more than 90 % homology (Sambrook et al., 1989). The hybridisations are carried out in 6x SSC/5x Denhardt's solution/O.lo SDS at 65°C. The degree of stringency is determined in the washing step. Thus, for selection for DNA sequences with about 85 % homology or more, the suitable conditions include 0.2 x SSC/0.01% SDS/65°C and for selection for DNA sequences with about 90 o homology or more, the suitable conditions include O.lx SSC/0.01%
SDS/65°C. The composition of the reagents described is also described in Sambrook et al. (1989).
A further aspect of the invention is a host cell into which a DNA molecule according to the invention has been introduced. This may be a eukaryotic host cell, preferably a yeast or mammalian cell. Particularly preferred host cells are adipocytes in primary culture, preferably from humans or from mice, adipocyte cell lines such as, for example, NIH-3T3L1 (a murine adipocyte cell line), muscle cells in primary culture, muscle cell lines such as for example C2C12 (a muscle cell line from the mouse) or cell lines such as HEK293 or HeLa. The average skilled person knows how to introduce suitable DNA molecules into certain cells using standard methods. These methods are described in Sambrook et al. (1989). For eukaryotic cells it is preferable to use the calcium precipitation method, lipofection or electroporation. It is also within the capabilities of the average skilled person to take parameters from the literature and develop them without too much effort so as to use the methods for introducing DNA
molecules into these cells successfully.
A further aspect of the invention is the use of a DNA
molecule according to the invention with above-mentioned cell-specific promoters for the transcription of a gene.
In order to produce suitable DNA molecules, the skilled man will use molecular biological methods as described by Sambrook et al. (1989) which he will select with a knowledge of the sequence of the DNA molecules according to the invention, the sequence of the gene to be transcribed and other elements. The transcripts or the translation product is or are preferably detected by standard methods, e.g. detection of RNA by sequence-specific hybridisation (Northern blot), detection of the translation product by means of antibodies (e. g. Western blot) or by its activity in suitable detection systems. The translation product may also have an enzymatic activity. The methods involved are described by Sambrook et al. (1989).
A particularly preferred embodiment of the invention is the use of the DNA molecules according to the invention for discovering substances which influence the transcription of the UCP3 promoters according to the invention. For this, DNA molecules are prepared which include the sequence of the promoters according to the invention, the sequence SEQ
ID NO 14 or SEQ ID NO 15. These may also contain functional derivatives thereof. Preferably, these DNA
molecules are linked to other DNA molecules which contain the sequences for genes which allow easy detection of the gene product (reporter genes). These reporter genes may be, for example, the luciferase gene or green fluorescent protein (GFP for short). The RNA transcribed by the promoter according to the invention can also be detected and quantified. In another embodiment of the invention, cells are used here which have been transformed with the DNA molecules according to the invention.
A preferred aspect of the invention is a process for discovering substances which are capable of influencing transcription of the UCP3-promoter which is preferentially active in fat cells or preferentially active in muscle cells and in which the DNA molecules according to the invention can be used. The process according to the invention may be carried out in a cell-free or cell-based system.
One embodiment of such a process consists of a cell-free in vitro transcription system which contains as components at least cell extract, ribonucleotides and a DNA molecule according to the invention. A preferred embodiment consists in measuring the transcription rate of the promoter used in the present of a test substance and comparing it with the transcription rate in the absence of the test substance. If the quantity of RNA transcribed per unit of time in the presence of the test substance is lower than the comparison value (i.e. in the absence of test substance), the test substance inhibits transcription in this test. If the quantity of RNA transcribed per unit of time in the presence of the test substance is higher than the comparison value (i.e. in the absence of the test substance), the test substance increases transcription in this test.
Another embodiment of the process for finding substances capable of influencing the transcription of the promoter according to the invention consists in measuring the change in activity of a reporter gene fused to the 3'-end of a DNA
molecule according to the invention, e.g, the luciferase gene or green fluorescent protein. Such a process can be carried out in a cell-free system. One embodiment of the process according to the invention comprises converting the RNA obtained after in vitro transcription in the presence of a test substance into proteins by in vitro translation, then determining the quantity, activity, absorption, luminescence or fluorescence of said proteins. The RNA
obtained is converted into proteins which catalyse an enzymatic reaction the product of which is easily determined. It is most particularly preferred to use luciferase or green fluorescent protein.
A particularly preferred embodiment is a cell based process according to the invention wherein cells which contain a DNA molecule according to the invention grow in the presence of a test substance and under conditions under which transcription is carried out by the UCP3-promoters according to the invention. The principle of the process is based on using the UCP3-promoter according to the invention to express a reporter gene in order to investigate the effects of added test substances. In this way, the expression of the reporter gene simulates the expression of the UCP3 gene. The promoter-reporter constructs according to the invention can be used in tests after being introduced into the cell or after a cell line has been produced which has these constructs stably integrated in the genome. Preferably, at a given time, the quantity, activity, luminescence or fluorescence of the translation product of the reporter gene fused to the 3'-end of the cell-specific UCP3-promoter according to the invention will be determined, the cells possibly having been lysed beforehand. A preferred embodiment of such a process comprises measuring the results in the presence of a test substance and comparing them with results in the absence of the test substance. If the quantity, activity, absorption, luminescence or fluorescence of the reporter protein produced per unit of time in the presence of the test substance is lower than the comparison value (i.e. in the absence of test substance), the test substance inhibits the transcription in this test. If the quantity, activity, absorption or fluorescence of the reporter protein produced per unit of time in the presence of the test substance is higher than the comparison value (i.e. in the absence of test substance), the test substance increases transcription in this test. The signal level is a measurement of the activity of the UCP3-promoter.
In practice, the promoters according to the invention could be cloned into plasmids which harbour reporter genes such as luciferase, (3-galactosidase, chloramphenicol-acetyl-transferase or secreted alkaline phosphatase. Plasmids which contain a reporter gene include, for example, the commercially obtainable pGL2basic or pGL3basic (Promega, Madison, Wisconsin, USA) and pSEAP2basic or pbgal-basic (Clontech, Heidelberg, Germany). Ln the same way it is possible to use cells which have the above-mentioned DNA
constructs stably integrated in their genome. Cells which may be used for the screening test include, for example, primary cell cultures e.g. of adipocytes or muscle tissue,' or cell lines such as HEK293, HeLa, C2C12 or NIH-3T3. If primary cell cultures are cultivated for longer periods, the UCP3-expression is lost. No UCP3-expression can be detected in some cell lines. However, these cell lines are suitable for finding activators of UCP3 transcription since they also have an activating effect in cells which express UCP-3. Activators of UCP-3-transcription in the muscle tissue are particularly suitable for the preparation of pharmaceutical compositions for treating obesity. However, activators of UCP-3-transcription in the fatty tissue can also be used for this purpose.
The average skilled person can perform a test of this kind (see Example 2), by using standard methods and ready-made reagents such as those sold ready-made by Promega (Madison, Wisconsin, USA), for example (Luciferase Assay System). He will also obtain instructions as to how to carry out the test with the commercially available reagents. The skilled person produces suitable constructs using standard methods and transfect them into suitable cell cultures (Sambrook et al., 1989). After growth in the presence of the test substance, the cell cultures are optionally washed and the cells are then lysed. After centrifugation to remove the cell debris the supernatant is mixed with the test reagent containing luciferin and the light emitted is measured in a luminometer.
In a preferred embodiment a process according to the invention is carried out by high throughput screening (HTS). A large number of test substances are tested simultaneously in a suitable arrangement. An HTS method of this kind may advantageously be fully or partially automated and evaluation may be carried out by electronic data processing. Advantageously, a test substance which exhibited an increasing effect in the cell-free system is additionally tested in a cell-based system. The process described in the previous paragraph can readily be adapted by anyone skilled in the art to the requirements of the high throughput screening without any inventive step.

Another embodiment of the invention comprises using the DNA
molecules according to the invention to identify other factors or substances which bind to them. Preferably, factors which mediate, lower or raise the transcription of a gene fused at the 3'-end (transcription factors) are sought. For this purpose, the DNA molecules according to the invention may be bound to insoluble carriers and brought into contact with a mixture of different factors or substances, e.g. a core extract or a library of natural substances, under suitable conditions. After one or more washing steps, and possibly repetition of the binding process, the bound factors or substances are identified by suitable methods, such as amino acid sequencing, mass spectroscopy, gel electrophoresis.
The DNA molecules for the purposes of this invention are all molecules which consist of naturally occurring deoxyribonucleotides. However, according to the invention, they also include molecules which have retained the basic chemical nature of the DNA after chemical derivatisation.
The possible types of derivatisation include for example derivatisation with fluorescent dyes, changes in the basic structure such as the replacement of oxygen atoms for sulphur atoms in order to stabilise the molecule or convert the DNA molecule into peptide nucleic acids (PNA for short ) .

Examples Example 1 - Identification of two transcription start sites in the 5~-region of the UCP3 gene Test subjects, fatty tissue samples from the skeletal muscle and abdominal cavity A total of 63 unrelated patients, 38 morbidly obese people, people who have overcome obesity and 15 non-obese people are examined. Tissue samples are taken from the Musculus rectus abdominis and in the abdominal cavity of the fatty

10 tissue of the omentum of morbidly obese people in whom the stomach had been surgically bandaged for weight reduction.
Control subjects and subjects who had overcome obesity were subjected to certain surgical interventions such as removal of the gall bladder, inguinal hernia operations and regulation or removal of the band around the stomach.
After some instruction, the test subjects had consented to the study, which had also been authorised by the Ethical Commission of the Institute. The subjects were anaesthetised on an empty stomach with fast acting barbiturates and kept unconscious with alfentanil-hydrochloride ((INN); IUPAC: N-{1-[2-(4-ethyl-5-oxo-2-tetrazolin-1-yl)ethylJ-4-methoxy-methyl-4-piperidyl}-propionanilide). Tissue samples were taken at the start of surgical intervention, divided into aliquots and frozen at -?OTC. The ratio of the weight to the size was determined after measurements of the weight and size (Body mass index;
BMI ) .
UCP-3 Gene structure A ~,-EMBL3-SP6/T7 genomic library from the human placenta (produced by: Clontech, Palo Alto, California, USA) was screened by plaque hybridisation using a probe which corresponded almost to the total UCP3-cDNA with a length of 1049 base pairs and included nucleotides +159 to +1207 (Gene Bank Accession Number U84763). Three overlapping clones with a size of about 16.5 kBp and with the complete human UCP3 gene were isolated and subcloned into the ZERO-Background~ cloning system (Invitrogen, Carlsbad, California, USA). Sequencing of the plasmid DNA was carried out with ready assembled, commercially obtainable reagents (PRISMS Ready Reaction dRhodamine Terminator Kit, manufacturered by Perkin Elmer-Applied Biosystems, Foster City, California, USA) using dRhodamine Terminators and an ABI PRISMS 310 DNA sequencing machine (Perkin Elmer-Applied Biosystems, Foster City, California, USA), synthesising successive suitable oligonucleotides in order to perform the sequencing reactions (~~Migrating on the DNA ~~ , ~~ Primer walking ~~ ) , RNA isolation, experiments on rapid amplification of the 5' and 3 ' cDNA ends (Rapi d ampl i fi ca ti on of cDNA ends;
abbrevi a ted to : RACE) Total RNA was isolated from 0.5 g of human skeletal muscle tissue using the method of Chumczynski and Sacchi (1987).
The integrity of the RNA samples was confirmed by analysising their electrophoretic flow properties in formaldehyde gels (Sambrook et al., 1989), RNA
concentrations were determined by absorption measurements at 260 nm. 5' and 3' RACE were carried out as described by Frohman et al. (1988}. For the 5'-RACE, 3 ~,g of total RNA
from human skeletal muscle was reverse transcribed with Superscripts II Reverse Transcriptase (GibcoBRL Life Technologies, Paisley, Great Britain) and a UCP3 gene-specific oligonucleotide from the intron 1 (5'-TACACCTGCT
TGACGGAG-3'). After digestion with ribonuclease H
(produced by Boehringer Mannheim Corp., Indianapolis, Indiana, USA) and lengthening of the polyA-tail (polyA-tailing) with terminal transferase (made by Boehringer Mannheim Corp., Indianapolis, Indiana, USA) the first strand cDNA was subjected to polymerase chain reaction (PCR) with 5'-GCTGTGTCCA GTGGAAAGGT AACGAGGTCA GCAA-3~ as the gene specific oligonucleotide and 5'-GAGGACTCGA

GCTCAAGCT~2p~-3' as the adapter oligonucleotide. The PCR-products were amplified again using 5'~-GAGGACTCGA
GCTCAAGC-3' as the anchor oligonucleotide and 5'-TGGGAGGCAC GTCTGAAG-3~ as the internal (nested) gene specific oligonucleotide. (For the 3~ RACE, 3 ~g of human skeletal muscle RNA were reverse transcribed using the above-mentioned polyA-specific adapter-oligonucleotide.
The anchor oligonucleotide and two nested oligonucleotides in the coding strand 5'-CCTCGACTGT ATGATAAAGA TG- 3' (+921 to +942) and 5'-CCTCCTGGGC CACCATCTT-3' (+ 937 to +955, Gene Bank Accession Number U84763) were used for the amplification). 5' and 3' RACE-PCR products were subloned into a common vector using the standard methods known to those skilled in the art (Sambrook et al., 1989) and sequenced after being gel-purified.
Test for protection of the UCP3-5'-transcrip t region fram degradation by ribonuclease (RlVAse Protection Assay) A probe covering the 425 by long intron 1 (+6816 to +9074;
sequence SEQ ID NO 17) was prepared by reverse transcription-PCR (RT-PCR) with the oligonucleotides 5'-CCTCACCAGC CAGCCTCTTG TC-3' (+ 6816 to +6837) and 5'-GCTGTGTCCA GTGGAAAGGTA-3' (+9054 to +9074), in the coding and non-coding regions. The PCR products were cloned into the pZERO~ plasmid vector and the sequence was verified by sequencing with dye-coupled terminators (Dye-Terminator cycle sequencing).
32p-labelled counterstrand RNA was obtained with a combined system which uses the SP6 and the T7 promoter (Riboprobe Combination System SP6/ T7; manufactured by Promega Corp., Madison, Wisconsin, USA), and a32P-dUTp (3000 Ci/mmol;
manufactured by Amersham Life Science, Buckinghamshire, Great Britain) in accordance with the manufacturer's instructions. RNA transcribed in vitro was gel-purified and the radioactivity incorporated was determined by liquid WO 00/12696 PC'T/EP99/06152 scintillation counting (manufacturer: Wallac 1450 Microbeta PLUS, EG&G Berthold, Bad Wildbach, Germany). After denaturing at 95°C for 5 minutes, aliquots of the 32P-labelled RNA with an activity of 8x104 cpm (counts per minute), were hybridised overnight at 43°C with 5 ~g of total RNA from human muscle or 15 ~.g of total RNA from fatty tissue. Unprotected RNA was digested at 37°C for 30 minutes in a total volume of 220 ~1 with 0.5 units of ribonuclease A and 20 units of ribonuclease T1 (Ambion RPAII Kit; Ambion Inc., Austin, Texas, USA). The ribonuclease inactivation/precipitation mixture supplied by the manufacturer was added in order to precipitate the 32P-labelled RNA-RNA hybrids. The precipitates were washed with 70o ethanol and protected fragments were separated by electrophoresis in 4% polyacrylamide-urea gels (Sambrook et al., 1989).
Identification of two transcription starting sites The 5 -end of the UCP3-mRNA from the skeletal muscle was determined by 5~-RACE experiments using a counterstrand oligonucleotide from intron 1. Two specific PCR-fragments were obtained and characterised by sequencing. The products went 184 by and 331 by beyond the transcription start in the 5~-direction, which can be explained by two transcriptional start sites (Fig. lA). The use of the most remote initiation site was demonstrated by RT-PCR (data not shown) .
Ribonuclease protection tests (RNAse protection assays) showed that the majority of the transcripts were started in the muscle tissue of numerous obese and slender people at the downstream site at -184. The proportion of UCP3-mRNA
which originates from the upstream site at -331 was less than 5%. However, the upstream site was predominantly, although not exclusively, used in the fatty tissue (Fig.
1B). Similar results were found in the fatty tissue of ZO

obese and 4 slender individuals (data not shown). These experiments show that certain promoter regions can be used in the fatty tissue and in the skeletal muscle. Computer analysis of the sequences adjacent to the alternative starting sites showed that both regions contain eukaryotic consensus sequences for initiating transcription. Two TATA-like sequences (Locker and Buzard, 1990) are found 29 to 36 by upstream and two conserved sites, on which a modified 7-methylguanosine group can be hooked onto the transcribed RNA (cap site; Locker and Buzard, 1990), are found 16 to 33 by downstream from the corresponding starting site. By sequence comparison, fundamental promoter elements such as CART boxes at -749, -861 and -922 were found, separated from the transcription starting site by an Alu sequence, relative to the transcription starting site located downstream, an octamer motif was found at -713 and a conserved binding site for an upstream activating factor (USF) was found at -1038 (Fig, lA). In addition, three successive E-box elements were found at -653, -640 and -631, a putative peroxisome-proliferator-activated receptor/retinoid-X-receptor affected element (PPAR/RXR) was found at -265 and a putative thyroid response element (TRE) (Locker and Buzard, 1990) was found at position -3340, located in an Alu-sequence from -3396 to -3094.
Example 2 - Screening test for finding substances which modulate the transcription of the UCP3-promoter The average skilled person carries out such a test by using standard methods and ready-assembled reagents such as those sold by Promega (Madison, Wisconsin, USA) as the ~Luciferase Assay System'. With this system he also obtains instructions as to how the test should be carried out with the commercially obtainable reagents. However, he can also refer to the the teaching of Example 1 of US
Patent 5,283,179 in which the procedure of the test is described.

By a combination of suitable cloning techniques and PCR-techniques the sequence SEQ ID NO 16 is prepared (Sambrook et al., 1989), which no longer contains the muscle cell-s specific UCP3-promoter. This DNA sequence is inserted by standard methods through suitable restriction cutting sites into the vector pGL2basic or pGL3basic (Promega, Madison, Wisconsin, USA). This vector is transfected by standard methods (Sambrook et al., 1989) into primary human adipocyte cell cultures obtained from obese persons as described in Example 1 who had undergone surgical treatment. This cell culture is grown under standard conditions in standard cell culture medium in a cell culture dish 100 mm in diameter. The cells are then cultivated in the presence of an aqueous solution or a solution in dimethylsulphoxide of a test substance for a certain length of time. At ambient temperature, 1 ml of buffer which lyses the cells (25 mM Tris-phosphate pH 7.8, 2 mM dithiothreitol, 10 o glycerol, 1 % Triton° X-100, 1 mg/ml bovine serum albumin, 2 mM cyclohexylene diamine tetraacetate (CDTA)), is added for about 2 to 5 minutes and the cell debris is eliminated by brief centrifugation.
Optionally, the growth medium can previously be removed from the cultivated cells and the cells may be washed once or twice with PBS buffer (137 mM NaCl, 2.7 mM KC1, 4.3 mM
Na2HP04, 1.4 mM KH2P04, pH 7.3; Mg2+- and Ca2+-free). Part of the supernatant is mixed with five times its volume of test reagent (2p mM tricine (N-tris-(hydroxymethyl)-methylglycine) pH 7.8, 33.3 mM dithiothreitol (DTT), 8 mM
Mgz+, 0.13 mM ethylenediamine tetraacetic acid (EDTA), 0.53 mM adenosine triphosphate (ATP), 0.47 mM luciferin (a polyheterocyclic organic acid: D-(-)-2-(6~-hydroxy-2'-benzothiazolyl)+~2-thiazolin-4-carboxylic acid) and 0.27 mM
of coenzyme A (CoA)) and the light emitted is measured in a luminometer. The volume of the test reagent may be up to 25 times the volume of the solution to be tested. Then the signal is compared with the signal from a control (aqueous solution or dimethylsulphoxide solution without the text substance).
In order to find substances which influence the transcription of the muscle cell-specific UCP3-promoter, the skilled person can prepare a DNA molecule which no longer contains the fat cell-specific UCP3-promoter. To do this, he removes nucleotides 6739 to 6795 which contain the fat cell-specific part, from the DNA sequence SEQ ID N0: 14 using standard methods (Sambrook et al., 1989) and clones them into the vectors mentioned above. Moreover, he proceeds as described above except that he uses muscle cells in primary culture or suitable cell lines.
General activators of the UCP3-promoter are found by the same experimental procedure, and sequence SEQ ID NO: 14 which contains both promoters can be used. Here again, cells are used in which there is no or only very slight UCP3 expression, such as for example the cell line HEK293.
The skilled person can adapt a test of this kind to the particular circumstances of the microtitre plate format without any inventive step.

Figures:
Fig. 1: Characterisation of the UCP3 promoter region and evidence for various transcription initiation sites in the skeletal muscle and in the fatty tissue A) Part of the nucleotide sequence of the human UCP3 gene; basic promoter elements such as e.g. CAAT box, octamer motifs and upstream binding sites for stimulation factor as well as putative transcription factor binding sites such as E boxes and a PPAR/RXR response element are emphasised by small frames. Half an Alu sequence is emphasised by a large frame. TATA-like sequences are printed in bold and underlined, conserved sites onto which a modified 7-methylguanosine group is atttached to the transcribed RNA (known as cap sites), are printed in bold italics. The two transcription starting sites are indicated by arrows and the translation start codon is printed in bold. Part of the sequence of intron 1 is shown in lower-case letters.
B) Autoradiogram of the ribonuclease protection test (known as the RNAse protection assay) of RNA from human skeletal muscle and fatty tissue. The sizes of the protected fragments, calculated f.or transcripts initiated at the upstream or downstream site, are 425 and 316 nucleotides, respectively, as indicated on the right hand side.
Examining the gel:
M: end labelled size markers with the specified sizes 1: undigested 32P-UCP3 counterstrand probe of nucleotide 6816 to 9074 (sequence SEQ ID NO 17) 2: 32P-UCP3-counterstrand probe hybridised with yeast RNA and subjected to ribonuclease digestion 3-5: Ribonuclease protection assay of 5 ~.g of total RNA from the skeletal muscle of three individuals 6-7: Ribonuclease protection assay of 15 ug of total RNA from intraperitoneal fatty tissue from two individuals Literature:
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SEQUENCE LISTING
<110> Boehringer Ingelheim International GmbH
<120> Cell specific promoters of uncoupling protein 3 <130> 1-1061 <190>
<191>
<150> DE19838837.3 <151> 1998-08-27 <160> 17 <170> PatentIn Ver. 2.1 <210> 1 <211> 9 <212> DNA
<213> Homo Sapiens <220>
<221> TATA signal <222> (1)..(9) <900> 1 tatattaaa <210>2 <211>6 <212>DNA

<213>Homo Sapiens <220>

<221>CAAT
signal <222>_ (1). (6) <400>2 cacctc <210>3 <211>7 <212>DNA

<213>Homo Sapiens <220>

<221>TATA signal <222>(1)..(7) <900>3 tataaga <210>9 <211>6 <212>DNA

<213>Homo Sapiens <220>

<221>CAAT
signal <222>_ (1). (6) <400>9 caatcc WO 00/t2696 PCT/EP99/06152 <210> 5 <211> 13 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <222> (1). (13) <223> RXR/PPAR-Element <900> 5 tgacctttgg act <210> 6 <211> 6 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <222> (1). (6) <223> E2A-Element <900> 6 cagatg <210> 7 <211> 6 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <222> (1) . (5) <223> E-Box <900> 7 cacttg <210> 8 <211> 6 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <222> (1). (6) <223> E-Box <400> 8 catttg <210> 9 <211> 10 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <222> (1). (10) <223> octamer <900> 9 atgaaaatgt <210> 10 <211> 5 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <222> (1). (5) <223> CHAT-Box <900> 10 ccaat <210> 11 <211> 5 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <222> (1) . (5) <223> CHAT-Box <400> 11 attgg <210>12 <2I1>5 <212>DNA

<213>Homo Sapiens <220>

<221>misc feature <222>_ (1). (5) <223>CART-Box <900> 12 attgg <210> 13 <211> 8 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <222> (1) . (8) <223> USF-Element <900> 13 ccacgtgc <210> 14 <211> 6959 <212> DNA
<213> Homo sapiens <220>
<221> promoter <222> (1)..(6959) <900> 14 aattcttggg ctcaagcgat cctcccacca cagcctcctg agtagctggg accacaggtg 60 tgcaccacta caccctgcta attttttttt tccttttttt ttttttgaga cagggtttcc 120 ctatgttgac caagctggtc acaaactcct agactcatgc gatccccctg ccttggcctc 180 ccaaagtgct ggggttacag acgtgagcta cccagcccaa cagaggtctt tttatggtca 290 tttcatgaac tgaggtagtt ggcccttcca gccatggaga acaagactca tctaagtctc 300 tctaaaacag agaagacatc tcttctagaa aatggggaaa caaatgcctg gttttaggat 360 ttgagataga atactatgct ctaaggcctg ttttcccatc tggctcataa aacaaacatc 920 tccctacttc cccttcagag tagcagagaa agaaatggaa ggtaagatac aactgatgac 980 ccagaaaatc tacctgcagt acagctgggg gtcaggaatg ggacttgtgt catcctaaat 590 cccaaatagc tcaggaaaca gccatcttgg atcttgggag tagagaaaga tatacacaag 600 cttaaagtgc tacatagagc ctgagagagt ttaacttaac taaagacctg gcatatggta 660 ggacaacaac cactggttct agaatgaatg aatgagaagc ttactacaaa gagtctcctc 720 cccacccaat ttagacctgt ggttaccctg gcctggtccc acccacactg gtctagcagc 780 tcccaggctc ctgtcttgga actggcctcg ctgggatccc aagcctcaga cccaggccgt 890 gccctgcagg agcacccagt gtggaagtgg gagagcaaca ggcagaggct ggccactggc 900 ctcccctggt ctgaggcatc atgcagtgca ggtgcttcct gtattttgga aggaagaact 960 gcaaacacca gcaaaaagtg ggtttccttc ttcccttcta gcctagacct gcctagaagg 1020 cagggagata gatcttctag tctctgctgt gcagcccagc cctagtatca ctttgctctt 1080 ggttataagg aaaggctgcc tgtgggctca tagcactgag agcttcccag attgtagaca 1190 ttcccttggc accttagaat tctagactgg cagggaccct caaggcttcc catccacact 1200 tctatttcat gggtgggaaa ctgacatcca ggcagtgaga tcagggatgc ctgactccac 1260 tccccttatc tcattctggc aattctaatt ctttaggcag atctctctgc ctccagggct 1320 taactctgag ctgagaaagc ctaaaacgga gttctgttta tttctgcgcc cctctcaagt 1380 aggtattaaa aaagattgaa gacatgaaag aaagaataac tgaatgttac tgatgccaga 1990 agcaactctc gctgggcgca actctcgctg ggcgcaactc tcgctgggcc tcagtttctc 1500 ataagcagaa ctgcaggggg taggtggtcc cagtctctag ggtctccacc aagcttcttc 1560 tcagtgccca ggaagtggta cagtgtgctc tcaatagtcc ttcagcttat gacagcctca 1620 gctcatggga cttgagacag ggaagagcaa gctgcatgcc atgaagtcag ccaggtttgc 1680 ctgtggaggc tgctcccatc tcctttcaga actgccccct cccctatcag gcccccactt 1790 cttccccagg gccttgctct cagccagctg tctgggatgg ctttcctgta tagctttgag 1800 ctccttcagc acaggagcct gacatggagt aagaaaaaag aaagaaaaat gagttagagg 1860 agtccagagg accatgatac catagcccac aggtttaagt accttaaagg cggaattagt 1920 gatgccctgt cagccagagt cagagagatc aaagtttggt agccaagcag taggtaggtg 1980 ctttatgtca cctggcaact ccaggagctc caaagggcca aacagagagt gtattattca 2090 ccgccatctc cctgagagtt ggatatgttc ccagcatcac acatgggact aaacccagag 2100 gacaaatgac ttgtctaaag ccatgcaaca ggagaaggga tgaggattca aacctatcct 2160 ggaggtgacg ctgcctcctt ctccagaggc acagaaagag tcagggctgg ggttcacgtc 2220 ccagctctgc tactcagagc tgtgggacct tgagtttatt ccacctgaat gtagtttcct 2280 tatccacgac atggggagaa tgatataccc cccatatggg gttgaggtaa gggtcaagca 2390 agataaggta cgtaaagcgc tttgtaaacc aggcagctct acataaatat taaccaaagg 2400 accaaaagat gagagaaacc agcgtcatcc attggtggtg ccatatcctc agtggtaacc 2460 tagctgactt cttcctctcc aggacaagag cgaagccacc aggggagctc tctcccaaag 2520 gccttgtcgc cccagaccta actcgctccc cctcaacctg cctgaggaag aaactctcag 2580 gattgcacgg atattttctt ctcagtactc ccagaaagac tgacgcagcc tgaggggctg 2690 gggggaagga gacacctgcc caccctccgt cagctttgtc cagcttgcag gaggcaccag 2700 gtctggctcc ttcagggctg tcacagtcct gaaaccacca cttgcctagg ccacggatgc 2760 ctcaagagac ccggtcagcc cagactggag gagtgcccca aaccagtcca gtgtccactt 2820 gccagaattt cagctccttt tttctgtggt gaggcaaagg ctagaaataa aatggaatcc 2880 gcgcccaagt gggacccaag caggcatctt tcggtggaga aacgcccccc agtgtccttg 2940 acacagctga ctgctggcat gagcccaccc tctgcctgaa gatgcaggac catttttgcc 3000 ttaaaagttg gggaggaggg acatgtagat tgtgtgcatt gtgcatagtc aaggaaatcc 3060 tagggccacc tccagttcat ttgtgtggga acaaggatat tttatagata caaattattt 3120 ttatgctgtg ttgaattaat caattaggag aggaagggga aatcacttcc ttcaaacttt 3180 ttatctgatt gtctaaaatt ctaaccatgc ttttaactta ttatttttac ccagctctga 3290 aggtcattgt tcttgcctgt gtttgaataa aatcatattg gtgtttgtaa tctgtgcaca 3300 agtgtttcgc tggagtgggg atgctaggaa ttcgtgtgtg ccctaactgc cagagagaaa 3360 gattaacaac catacacccc acgcagacga agatcaatca ccatgagact tctggctcct 3420 ccagaatcag gttggtccag atgacagtga cacccagtat ttcctttgct gatgcttgaa 3980 atccatcaga caaagccccg tggggaggac aagaaaaggg ccatggatgg gtgcagtggc 3590 tcacacctgt aatccaaaca ctttgggaag ccgaggcagg cagatcacct gaggtcagga 3600 gtttgagact accctggcca acctggcaaa accccgtctc tactaaaaaa aaaaaaaata 3660 caaaaattag ctgggcgtgg tgcacgcctg tagtcctagc tactcaggag gctgaggcag 3720 gagaatcact tgaacccaag aggtggaggt tgcagtgaac cgagaccacg ccactgcact 3780 ccagcctgga caacagagca agactccgta tcacaaaaaa aaaaaaaaaa aatggggtcg 3890 cgggagccaa atgtgcaagt gagcagtgtg gctgggcaac aggctttcac ccccaagtac 3900 atgtcacttc actcagtcct caaaacagct ctctaactct agatattatg atatctagag 3960 tttctgtaag ttcagtgttt tgcctctgtt tgtgtagtta ggaagtgatt aaccacacaa 4020 gaaatcccag aggtattgca aggctactgc tttcagtaat caaaacaagg tacagccaat 4080 aagtgctctg aatttaggga cttcatggag aaagaccatg tgggctgggg cagtcaggga 4190 aggcttccta gaagagacag gtcttggggt gagcacagag aattggccca ggctgtggac 9200 agctatagag agagagccag gaaagcccgt gagcagtgtg cagctggaga tagagaccag 9260 tctcactgcg tctgagcctc tgtggcctcg tctgtaaaac agagataatc accccagctt 9320 catggggttg tgaggaagat caaatgagat gacatttgtg aaagtgcttc gcctactttt 9380 ggcacatggt ggaagcttag gaaatgtcag ccccacccac tctcctgact ttcgggagca 9990 aaccagtaga gaggcaagca tgcagccact ggggcaggca gagcactcct gggcctcaga 9500 gggtgcaaaa tgatgcggga acctcaagga aggagtgggt gctgccttct tggtgacaag 9560 ccctcccgct tctatttatc tctgctccga cgcctgccag cccacccctc cccagcacca 9620 cagaggccag cctccctctc aagtcaccag cacagagcat tcaaggccca gggccccact 9680 tcccttgggg cccaggggac ctaaagaggg gcagtcaggg cccaggcctg agggggaaag 4790 ccccaggtaa agaatattcc tccaaatccc actccagctc ccgcagacaa cctgatcggg 9800 gtcaggagga cacactccta ccccaggctg agagcagcct ctgataacac aaaaggaccc 9860 tgagggtgga gacctcccac ctccacttca aaacagtgtg ttatttatca atatcttatc 9920 cccggaagtt gaatctatct cccagtgcca actccgagat aaatgacttg accaggcgtg 9980 tggcatggat taaggcatga gataggtgtt cccaccacca gaacgagcca gtggctgcct 5040 ctcttccctt tgagccctcc ctccacagag acctgtgaat aggtgtttct gatccctagg 5100 ctggttgcat cccaacccag agcaggcagc cttcggactt ctagcatggg ctggcctcag 5160 gacatggagc caaagcaggc agacctggcc ctgccctcaa gctcccaagc taaagagagc 5220 ctggccctcc ctcccactag gtttctccag agcctgctgc ctcctggttt gggcttctac 5280 tctattcttc ccccacagac tccctgcaat ttactgcatc acctctagac tagcaattac 5390 agatggagct cagaacctac ttcctgagcc ttcctaatct cagcagccct gacagccact 5900 tccctcttaa cactaatgca gctgcttatt ctgctgacat taaggtcagg gcctggtcca 5460 aggaagagga caggtacagc ccaagctttg cacttgaaca tccatgcttc tgaccacctg 5520 ccctgtgacg ctggctctgt gccccagtcc agaaaagact tctgcctact cctcctctgc 5580 cctacccagt taactccctt tccttccctc ccttctgctt ctcactcctc ccctcccttc 5690 tcttcttctt ctccccttcc cccatcacct ggggcccgat tcagctgtgc ccagccctta 5700 ctctgagtgc ccacagatgg agcctccagt agcttctgtg gggcaccctt ccaccaggtc 5760 ccagctccct tggctccagc agtgtccatg ctaaagcctc caagtgtcat gttggagaga 5820 atggtggtca cagtagataa gcccaaaatg ccttacagtt tacaggctgg agtcaggccc 5880 cgccacgtgc tggctacatg acttccccga gattccattt cctcctcagt aaaataagtg 5940 gtaagatttt aggatcccca gcactaaaaa gaaacgaaat actgatacag gctccaacat 6000 ggatgaattt tgaagcatta ctatactaag tgaaagaagc cagtcacaaa caagcacata 6060 ttggatgatt ccatttctag gaagtgttcc gaacaggcaa atttatagag acagaaagta 6120 gattgattag tggttgcctg aggctgggga gcgggggaag ggaggtgact accaatgtgt 6180 acggagtttt tccagggtga gagggtgatg aaaatgttct aaaatagatt gtgttgatgg 6240 ttgtgccact cagaatatac taaaaaccat ttgaattgtg cacttgaaac agatgaattg 6300 tacggtatgt gaattctata tcaataaatc tgtaatttaa aaaaaaaaaa ttaggtcggg 6360 tgcagtggct cacacctata atcccagcac tttgccagac tgaggcagga ggatcactta 6920 agcccaggag ttcaagacca gcctggggaa cacagcaaga cctcgtctct actaaaaaat 6980 tttaaattac aaaaaaaaaa agtaaaaaaa atagaatcct aatagtacct atctcatagg 6540 attgtggaaa atagtagtaa tgtatgtaaa atatttagca catagtaggc acaaagaaat 6600 gacattatta ttaagaggcc tgggagagct gtgcccagcc tatcgtggga ggccttgacc 6660 tttggactca aaagtggcag caggtccacc cccccataca cccttgtcac caaggaagcg 6720 tccacagctt aaaggagcta tattaaagca ccccaagtca agaggactga accagatctg 6780 gaactcactc acctcccctc tcacctcact gccctcacca gccagcctct tgtcaagtga 6890 tcaggctgtc aaccaacttc tctaggataa ggtttcaggt cagcccgtgt gtataagacc 6900 agtgccaagc cagaagcagc agagacaaca gtgaatgaca aggaggggcc atccaatcc 6959 <210> 15 <211> 3952 <212> DNA
<213> Homo Sapiens <220>
<221> promoter <222> (1)..(3952) <400> 15 aattcttggg ctcaagcgat cctcccacca cagcctcctg agtagctggg accacaggtg 60 tgcaccacta caccctgcta attttttttt tccttttttt ttttttgaga cagggtttcc 120 ctatgttgac caagctggtc acaaactcct agactcatgc gatccccctg ccttggcctc 180 ccaaagtgct ggggttacag acgtgagcta cccagcccaa cagaggtctt tttatggtca 240 tttcatgaac tgaggtagtt ggcccttcca gccatggaga acaagactca tctaagtctc 300 tctaaaacag agaagacatc tcttctagaa aatggggaaa caaatgcctg gttttaggat 360 ttgagataga atactatgct ctaaggcctg ttttcccatc tggctcataa aacaaacatc 420 tccctacttc cccttcagag tagcagagaa agaaatggaa ggtaagatac aactgatgac 980 ccagaaaatc tacctgcagt acagctgggg gtcaggaatg ggacttgtgt catcctaaat 540 cccaaatagc tcaggaaaca gccatcttgg atcttgggag tagagaaaga tatacacaag 600 cttaaagtgc tacatagagc ctgagagagt ttaacttaac taaagacctg gcatatggta 660 ggacaacaac cactggttct agaatgaatg aatgagaagc ttactacaaa gagtctcctc 720 cccacccaat ttagacctgt ggttaccctg gcctggtccc acccacactg gtctagcagc 780 tcccaggctc ctgtcttgga actggcctcg ctgggatccc aagcctcaga cccaggccgt 890 gccctgcagg agcacccagt gtggaagtgg gagagcaaca ggcagaggct ggccactggc 900 ctcccctggt ctgaggcatc atgcagtgca ggtgcttcct gtattttgga aggaagaact 960 gcaaacacca gcaaaaagtg ggtttccttc ttcccttcta gcctagacct gcctagaagg 1020 cagggagata gatcttctag tctctgctgt gcagcccagc cctagtatca ctttgctctt 1080 ggttataagg aaaggctgcc tgtgggctca tagcactgag agcttcccag attgtagaca 1190 ttcccttggc accttagaat tctagactgg cagggaccct caaggcttcc catccacact 1200 tctatttcat gggtgggaaa ctgacatcca ggcagtgaga tcagggatgc ctgactccac 1260 tccccttatc tcattctggc aattctaatt ctttaggcag atctctctgc ctccagggct 1320 taactctgag ctgagaaagc ctaaaacgga gttctgttta tttctgcgcc cctctcaagt 1380 aggtattaaa aaagattgaa gacatgaaag aaagaataac tgaatgttac tgatgccaga 1990 a~aaacacaa gttgagcgca actctcgctg ggcgcaactc tcgctgggcc tcagtttctc 1500 g g g ggggg taggtggtcc cagtctctag ggtctccacc aagcttcttc 1560 tcagtgccca ggaagtggta cagtgtgctc tcaatagtcc ttcagcttat gacagcctca 1620 g~t~atggga cttgagacag ggaagagcaa gctgcatgcc atgaagtcag ccaggtttgc 1680 g ggaggc tgctcccatc tcctttcaga actgccccct cccctatcag gcccccactt 1790 cttccccagg gccttgctct cagccagctg tctgggatgg ctttcctgta tagctttgag 1800 ctccttcagc acaggagcct gacatggagt aagaaaaaag aaagaaaaat gagttagagg 1860 agtccagagg accatgatac catagcccac aggtttaagt accttaaagg cggaattagt 1920 gatgccctgt cagccagagt cagagagatc aaagtttggt agccaagcag taggtaggtg 1980 ctttatgtca cctggcaact ccaggagctc caaagggcca aacagagagt gtattattca 2090 ccgccatctc cctgagagtt ggatatgttc ccagcatcac acatgggact aaacccagag 2100 gacaaatgac ttgtctaaag ccatgcaaca ggagaaggga tgaggattca aacctatcct 2160 ggaggtgacg ctgcctcctt ctccagaggc acagaaagag tcagggctgg ggttcacgtc 2220 ccagctctgc tactcagagc tgtgggacct tgagtttatt ccacctgaat gtagtttcct 2280 tatccacgac atggggagaa tgatataccc cccatatggg gttgaggtaa gggtcaagca 2340 agataaggta cgtaaagcgc tttgtaaacc aggcagctct acataaatat taaccaaagg 2400 accaaaagat gagagaaacc agcgtcatcc attggtggtg ccatatcctc agtggtaacc 2960 tagctgactt cttcctctcc aggacaagag cgaagccacc aggggagctc tctcccaaag 2520 gccttgtcgc cccagaccta actcgctccc cctcaacctg cctgaggaag aaactctcag 2580 gattgcacgg atattttctt ctcagtactc ccagaaagac tgacgcagcc tgaggggctg 2690 gggggaagga gacacctgcc caccctccgt cagctttgtc cagcttgcag gaggcaccag 2700 gtctggctcc ttcagggctg tcacagtcct gaaaccacca cttgcctagg ccacggatgc 2760 ctcaagagac ccggtcagcc cagactggag gagtgcccca aaccagtcca gtgtccactt 2820 gccagaattt cagctccttt tttctgtggt gaggcaaagg ctagaaataa aatggaatcc 2880 gcgcccaagt gggacccaag caggcatctt tcggtggaga aacgcccccc agtgtccttg 2990 acacagctga ctgctggcat gagcccaccc tctgcctgaa gatgcaggac catttttgcc 3000 ttaaaagttg gggaggaggg acatgtagat tgtgtgcatt gtgcatagtc aaggaaatcc 3060 tagggccacc tccagttcat ttgtgtggga acaaggatat tttatagata caaattattt 3120 ttatgctgtg ttgaattaat caattaggag aggaagggga aatcacttcc ttcaaacttt 3180 ttatctgatt gtctaaaatt ctaaccatgc ttttaactta ttatttttac ccagctctga 3290 aggtcattgt tcttgcctgt gtttgaataa aatcatattg gtgtttgtaa tctgtgcaca 3300 agtgtttcgc tggagtgggg atgctaggaa ttcgtgtgtg ccctaactgc cagagagaaa 3360 gattaacaac catacacccc acgcagacga agatcaatca ccatgagact tctggctcct 3920 ccagaatcag gttggtccag atgacagtga cacccagtat ttcctttgct gatgcttgaa 3980 atccatcaga caaagccccg tggggaggac aagaaaaggg ccatggatgg gtgcagtggc 3540 tcacacctgt aatccaaaca ctttgggaag ccgaggcagg cagatcacct gaggtcagga 3600 gtttgagact accctggcca acctggcaaa accccgtctc tactaaaaaa aaaaaaaata 3660 caaaaattag ctgggcgtgg tgcacgcctg tagtcctagc tactcaggag gctgaggcag 3720 gagaatcact tgaacccaag aggtggaggt tgcagtgaac cgagaccacg ccactgcact 3780 ccagcctgga caacagagca agactccgta tcacaaaaaa aaaaaaaaaa aatggggtcg 3840 cgggagccaa atgtgcaagt gagcagtgtg gctgggcaac aggctttcac ccccaagtac 3900 atgtcacttc actcagtcct caaaacagct ctctaactct agatattatg at 3952 <210> 16 <211> 6795 <212> DNA
<213> Homo Sapiens <220>

<221> promoter <222> (1)..(6795) <400> 16 aattcttggg ctcaagcgat cctcccacca cagcctcctg agtagctggg accacaggtg 60 tgcaccacta caccctgcta attttttttt tccttttttt ttttttgaga cagggtttcc 120 ctatgttgac caagctggtc acaaactcct agactcatgc gatccccctg ccttggcctc 180 ccaaagtgct ggggttacag acgtgagcta cccagcccaa cagaggtctt tttatggtca 290 tttcatgaac tgaggtagtt ggcccttcca gccatggaga acaagactca tctaagtctc 300 tctaaaacag agaagacatc tcttctagaa aatggggaaa caaatgcctg gttttaggat 360 ttgagataga atactatgct ctaaggcctg ttttcccatc tggctcataa aacaaacatc 920 tccctacttc cccttcagag tagcagagaa agaaatggaa ggtaagatac aactgatgac 9gp ccagaaaatc tacctgcagt acagctgggg gtcaggaatg ggacttgtgt catcctaaat 540 cccaaatagc tcaggaaaca gccatcttgg atcttgggag tagagaaaga tatacacaag 600 cttaaagtgc tacatagagc ctgagagagt ttaacttaac taaagacctg gcatatggta 660 ggacaacaac cactggttct agaatgaatg aatgagaagc ttactacaaa gagtctcctc 720 cccacccaat ttagacctgt ggttaccctg gcctggtccc acccacactg gtctagcagc 780 tcccaggctc ctgtcttgga actggcctcg ctgggatccc aagcctcaga cccaggccgt 890 gccctgcagg agcacccagt gtggaagtgg gagagcaaca ggcagaggct ggccactggc 900 ctcccctggt ctgaggcatc atgcagtgca ggtgcttcct gtattttgga aggaagaact 960 gcaaacacca gcaaaaagtg ggtttccttc ttcccttcta gcctagacct gcctagaagg 1020 cagggagata gatcttctag tctctgctgt gcagcccagc cctagtatca ctttgctctt 1080 ggttataagg aaaggctgcc tgtgggctca tagcactgag agcttcccag attgtagaca 1140 ttcccttggc accttagaat tctagactgg cagggaccct caaggcttcc catccacact 1200 tctatttcat gggtgggaaa ctgacatcca ggcagtgaga tcagggatgc ctgactccac 1260 tccccttatc tcattctggc aattctaatt ctttaggcag atctctctgc ctccagggct 1320 taactctgag ctgagaaagc ctaaaacgga gttctgttta tttctgcgcc cctctcaagt 1380 aggtattaaa aaagattgaa gacatgaaag aaagaataac tgaatgttac tgatgccaga 1490 agcaactctc gctgggcgca actctcgctg ggcgcaactc tcgctgggcc tcagtttctc 1500 ataagcagaa ctgcaggggg taggtggtcc cagtctctag ggtctccacc aagcttcttc 1560 tcagtgccca ggaagtggta cagtgtgctc tcaatagtcc ttcagcttat gacagcctca 1620 gctcatggga cttgagacag ggaagagcaa gctgcatgcc atgaagtcag ccaggtttgc 1680 ctgtggaggc tgctcccatc tcctttcaga actgccccct cccctatcag gcccccactt 1790 cttccccagg gccttgctct cagccagctg tctgggatgg ctttcctgta tagctttgag 1800 ctccttcagc acaggagcct gacatggagt aagaaaaaag aaagaaaaat gagttagagg 1860 agtccagagg accatgatac catagcccac aggtttaagt accttaaagg cggaattagt 1920 gatgccctgt cagccagagt cagagagatc aaagtttggt agccaagcag taggtaggtg 1980 ctttatgtca cctggcaact ccaggagctc caaagggcca aacagagagt gtattattca 2090 ccgccatctc cctgagagtt ggatatgttc ccagcatcac acatgggact aaacccagag 2100 gacaaatgac ttgtctaaag ccatgcaaca ggagaaggga tgaggattca aacctatcct 2160 ggaggtgacg ctgcctcctt ctccagaggc acagaaagag tcagggctgg ggttcacgtc 2220 ccagctctgc tactcagagc tgtgggacct tgagtttatt ccacctgaat gtagtttcct 2280 tatccacgac atggggagaa tgatataccc cccatatggg gttgaggtaa gggtcaagca 2390 agataaggta cgtaaagcgc tttgtaaacc aggcagctct acataaatat taaccaaagg 2900 accaaaagat gagagaaacc agcgtcatcc attggtggtg ccatatcctc agtggtaacc 2960 tagctgactt cttcctctcc aggacaagag cgaagccacc aggggagctc tctcccaaag 2520 gccttgtcgc cccagaccta actcgctccc cctcaacctg cctgaggaag aaactctcag 2580 gattgcacgg atattttctt ctcagtactc ccagaaagac tgacgcagcc tgaggggctg 2690 gggggaagga gacacctgcc caccctccgt cagctttgtc cagcttgcag gaggcaccag 2700 gtctggctcc ttcagggctg tcacagtcct gaaaccacca cttgcctagg ccacggatgc 2760 ctcaagagac ccggtcagcc cagactggag gagtgcccca aaccagtcca gtgtccactt 2820 gccagaattt cagctccttt tttctgtggt gaggcaaagg ctagaaataa aatggaatcc 2880 gcgcccaagt gggacccaag caggcatctt tcggtggaga aacgcccccc agtgtccttg 2940 acacagctga ctgctggcat gagcccaccc tctgcctgaa gatgcaggac catttttgcc 3000 ttaaaagttg gggaggaggg acatgtagat tgtgtgcatt gtgcatagtc aaggaaatcc 3060 tagggccacc tccagttcat ttgtgtggga acaaggatat tttatagata caaattattt 3120 ttatgctgtg ttgaattaat caattaggag aggaagggga aatcacttcc ttcaaacttt 3180 ttatctgatt gtctaaaatt ctaaccatgc ttttaactta ttatttttac ccagctctga 3290 aggtcattgt tcttgcctgt gtttgaataa aatcatattg gtgtttgtaa tctgtgcaca 3300 agtgtttcgc tggagtgggg atgctaggaa ttcgtgtgtg ccctaactgc cagagagaaa 3360 gattaacaac catacacccc acgcagacga agatcaatca ccatgagact tctggctcct 3920 ccagaatcag gttggtccag atgacagtga cacccagtat ttcctttgct gatgcttgaa 3480 atccatcaga caaagccccg tggggaggac aagaaaaggg ccatggatgg gtgcagtggc 3590 tcacacctgt aatccaaaca ctttgggaag ccgaggcagg cagatcacct gaggtcagga 3600 gtttgagact accctggcca acctggcaaa accccgtctc tactaaaaaa aaaaaaaata 3660 caaaaattag ctgggcgtgg tgcacgcctg tagtcctagc tactcaggag gctgaggcag 3720 gagaatcact tgaacccaag aggtggaggt tgcagtgaac cgagaccacg ccactgcact 3780 ccagcctgga caacagagca agactccgta tcacaaaaaa aaaaaaaaaa aatggggtcg 3890 cgggagccaa atgtgcaagt gagcagtgtg gctgggcaac aggctttcac ccccaagtac 3900 atgtcacttc actcagtcct caaaacagct ctctaactct agatattatg atatctagag 3960 tttctgtaag ttcagtgttt tgcctctgtt tgtgtagtta ggaagtgatt aaccacacaa 9020 gaaatcccag aggtattgca aggctactgc tttcagtaat caaaacaagg tacagccaat 4080 aagtgctctg aatttaggga cttcatggag aaagaccatg tgggctgggg cagtcaggga 4140 aggcttccta gaagagacag gtcttggggt gagcacagag aattggccca ggctgtggac 9200 agctatagag agagagccag gaaagcccgt gagcagtgtg cagctggaga tagagaccag 9260 tctcactgcg tctgagcctc tgtggcctcg tctgtaaaac agagataatc accccagctt 9320 catggggttg tgaggaagat caaatgagat gacatttgtg aaagtgcttc gcctactttt 9380 ggcacatggt ggaagcttag gaaatgtcag ccccacccac tctcctgact ttcgggagca 9440 aaccagtaga gaggcaagca tgcagccact ggggcaggca gagcactcct gggcctcaga 9500 gggtgcaaaa tgatgcggga acctcaagga aggagtgggt gctgccttct tggtgacaag 9560 ccctcccgct tctatttatc tctgctccga cgcctgccag cccacccctc cccagcacca 9620 cagaggccag cctccctctc aagtcaccag cacagagcat tcaaggccca gggccccact 9680 tcccttgggg cccaggggac ctaaagaggg gcagtcaggg cccaggcctg agggggaaag 9790 ccccaggtaa agaatattcc tccaaatccc actccagctc ccgcagacaa cctgatcggg 4800 gtcaggagga cacactccta ccccaggctg agagcagcct ctgataacac aaaaggaccc 9860 tgagggtgga gacctcccac ctccacttca aaacagtgtg ttatttatca atatcttatc 4920 cccggaagtt gaatctatct cccagtgcca actccgagat aaatgacttg accaggcgtg 4980 tggcatggat taaggcatga gataggtgtt cccaccacca gaacgagcca gtggctgcct 5040 ctcttccctt tgagccctcc ctccacagag acctgtgaat aggtgtttct gatccctagg 5100 ctggttgcat cccaacccag agcaggcagc cttcggactt ctagcatggg ctggcctcag 5160 gacatggagc caaagcaggc agacctggcc ctgccctcaa gctcccaagc taaagagagc 5220 ctggccctcc ctcccactag gtttctccag agcctgctgc ctcctggttt gggcttctac 5280 tctattcttc ccccacagac tccctgcaat ttactgcatc acctctagac tagcaattac 5390 agatggagct cagaacctac ttcctgagcc ttcctaatct cagcagccct gacagccact 5900 tccctcttaa cactaatgca gctgcttatt ctgctgacat taaggtcagg gcctggtcca 5460 aggaagagga caggtacagc ccaagctttg cacttgaaca tccatgcttc tgaccacctg 5520 ccctgtgacg ctggctctgt gccccagtcc agaaaagact tctgcctact cctcctctgc 5580 cctacccagt taactccctt tccttccctc ccttctgctt ctcactcctc ccctcccttc 5690 tcttcttctt ctccccttcc cccatcacct ggggcccgat tcagctgtgc ccagccctta 5700 ctctgagtgc ccacagatgg agcctccagt agcttctgtg gggcaccctt ccaccaggtc 5760 ccagctccct tggctccagc agtgtccatg ctaaagcctc caagtgtcat gttggagaga 5820 atggtggtca cagtagataa gcccaaaatg ccttacagtt tacaggctgg agtcaggccc 5880 cgccacgtgc tggctacatg acttccccga gattccattt cctcctcagt aaaataagtg 5940 gtaagatttt aggatcccca gcactaaaaa gaaacgaaat actgatacag gctccaacat 6000 ggatgaattt tgaagcatta ctatactaag tgaaagaagc cagtcacaaa caagcacata 6060 ttggatgatt ccatttctag gaagtgttcc gaacaggcaa atttatagag acagaaagta 6120 gattgattag tggttgcctg aggctgggga gcgggggaag ggaggtgact accaatgtgt 6180 acggagtttt tccagggtga gagggtgatg aaaatgttct aaaatagatt gtgttgatgg 6290 ttgtgccact cagaatatac taaaaaccat ttgaattgtg cacttgaaac agatgaattg 6300 tacggtatgt gaattctata tcaataaatc tgtaatttaa aaaaaaaaaa ttaggtcggg 6360 tgcagtggct cacacctata atcccagcac tttgccagac tgaggcagga ggatcactta 6920 agcccaggag ttcaagacca gcctggggaa cacagcaaga cctcgtctct actaaaaaat 6980 tttaaattac aaaaaaaaaa agtaaaaaaa atagaatcct aatagtacct atctcatagg 6590 attgtggaaa atagtagtaa tgtatgtaaa atatttagca catagtaggc acaaagaaat 6600 gacattatta ttaagaggcc tgggagagct gtgcccagcc tatcgtggga ggccttgacc 6660 tttggactca aaagtggcag caggtccacc cccccataca cccttgtcac caaggaagcg 6720 tccacagctt aaaggagcta tattaaagca ccccaagtca agaggactga accagatctg 6780 gaactcactc acctc <210> 17 <211> 16357 <212> DNA
<213> Homo sapiens <220>
<221> promoter <222> (1)..(16357) <900> 17 aattcttggg ctcaagcgat cctcccacca cagcctcctg agtagctggg accacaggtg 60 tgcaccacta caccctgcta attttttttt tccttttttt ttttttgaga cagggtttcc 120 ctatgttgac caagctggtc acaaactcct agactcatgc gatccccctg ccttggcctc 180 ccaaagtgct ggggttacag acgtgagcta cccagcccaa cagaggtctt tttatggtca 290 tttcatgaac tgaggtagtt ggcccttcca gccatggaga acaagactca tctaagtctc 300 tctaaaacag agaagacatc tcttctagaa aatggggaaa caaatgcctg gttttaggat 360 - g _ ttgagataga atactatgct ctaaggcctg ttttcccatc tggctcataa aacaaacatc 420 tccctacttc cccttcagag tagcagagaa agaaatggaa ggtaagatac aactgatgac 980 ccagaaaatc tacctgcagt acagctgggg gtcaggaatg ggacttgtgt catcctaaat 540 cccaaatagc tcaggaaaca gccatcttgg atcttgggag tagagaaaga tatacacaag 600 cttaaagtgc tacatagagc ctgagagagt ttaacttaac taaagacctg gcatatggta 660 ggacaacaac cactggttct agaatgaatg aatgagaagc ttactacaaa gagtctcctc 720 cccacccaat ttagacctgt ggttaccctg gcctggtccc acccacactg gtctagcagc 780 tcccaggctc ctgtcttgga actggcctcg ctgggatccc aagcctcaga cccaggccgt 890 gccctgcagg agcacccagt gtggaagtgg gagagcaaca ggcagaggct ggccactggc 900 ctcccctggt ctgaggcatc atgcagtgca ggtgcttcct gtattttgga aggaagaact 960 gcaaacacca gcaaaaagtg ggtttccttc ttcccttcta gcctagacct gcctagaagg 1020 cagggagata gatcttctag tctctgctgt gcagcccagc cctagtatca ctttgctctt 1080 ggttataagg aaaggctgcc tgtgggctca tagcactgag agcttcccag attgtagaca 1190 ttcccttggc accttagaat tctagactgg cagggaccct caaggcttcc catccacact 1200 tctatttcat gggtgggaaa ctgacatcca ggcagtgaga tcagggatgc ctgactccac 1260 tccccttatc tcattctggc aattctaatt ctttaggcag atctctctgc ctccagggct 1320 taactctgag ctgagaaagc ctaaaacgga gttctgttta tttctgcgcc cctctcaagt 1380 aggtattaaa aaagattgaa gacatgaaag aaagaataac tgaatgttac tgatgccaga 1490 agcaactctc gctgggcgca actctcgctg ggcgcaactc tcgctgggcc tcagtttctc 1500 ataagcagaa ctgcaggggg taggtggtcc cagtctctag ggtctccacc aagcttcttc 1560 tcagtgccca ggaagtggta cagtgtgctc tcaatagtcc ttcagcttat gacagcctca 1620 gctcatggga cttgagacag ggaagagcaa gctgcatgcc atgaagtcag ccaggtttgc 1680 ctgtggaggc tgctcccatc tcctttcaga actgccccct cccctatcag gcccccactt 1740 cttccccagg gccttgctct cagccagctg tctgggatgg ctttcctgta tagctttgag 1800 ctccttcagc acaggagcct gacatggagt aagaaaaaag aaagaaaaat gagttagagg 1860 agtccagagg accatgatac catagcccac aggtttaagt accttaaagg cggaattagt 1920 gatgccctgt cagccagagt cagagagatc aaagtttggt agccaagcag taggtaggtg 1980 ctttatgtca cctggcaact ccaggagctc caaagggcca aacagagagt gtattattca 2040 ccgccatctc cctgagagtt ggatatgttc ccagcatcac acatgggact aaacccagag 2100 gacaaatgac ttgtctaaag ccatgcaaca ggagaaggga tgaggattca aacctatcct 2160 ggaggtgacg ctgcctcctt ctccagaggc acagaaagag tcagggctgg ggttcacgtc 2220 ccagctctgc tactcagagc tgtgggacct tgagtttatt ccacctgaat gtagtttcct 2280 tatccacgac atggggagaa tgatataccc cccatatggg gttgaggtaa gggtcaagca 2340 agataaggta cgtaaagcgc tttgtaaacc aggcagctct acataaatat taaccaaagg 2900 accaaaagat gagagaaacc agcgtcatcc attggtggtg ccatatcctc agtggtaacc 2960 tagctgactt cttcctctcc aggacaagag cgaagccacc aggggagctc tctcccaaag 2520 gccttgtcgc cccagaccta actcgctccc cctcaacctg cctgaggaag aaactctcag 2580 gattgcacgg atattttctt ctcagtactc ccagaaagac tgacgcagcc tgaggggctg 2690 gggggaagga gacacctgcc caccctccgt cagctttgtc cagcttgcag gaggcaccag 2700 gtctggctcc ttcagggctg tcacagtcct gaaaccacca cttgcctagg ccacggatgc 2760 ctcaagagac ccggtcagcc cagactggag gagtgcccca aaccagtcca gtgtccactt 2820 gccagaattt cagctccttt tttctgtggt gaggcaaagg ctagaaataa aatggaatcc 2880 gcgcccaagt gggacccaag caggcatctt tcggtggaga aacgcccccc agtgtccttg 2980 acacagctga ctgctggcat gagcccaccc tctgcctgaa gatgcaggac catttttgcc 3000 ttaaaagttg gggaggaggg acatgtagat tgtgtgcatt gtgcatagtc aaggaaatcc 3060 tagggccacc tccagttcat ttgtgtggga acaaggatat tttatagata caaattattt 3120 ttatgctgtg ttgaattaat caattaggag aggaagggga aatcacttcc ttcaaacttt 3180 ttatctgatt gtctaaaatt ctaaccatgc ttttaactta ttatttttac ccagctctga 3240 aggtcattgt tcttgcctgt gtttgaataa aatcatattg gtgtttgtaa tctgtgcaca 3300 agtgtttcgc tggagtgggg atgctaggaa ttcgtgtgtg ccctaactgc cagagagaaa 3360 gattaacaac catacacccc acgcagacga agatcaatca ccatgagact tctggctcct 3920 ccagaatcag gttggtccag atgacagtga cacccagtat ttcctttgct gatgcttgaa 3980 atccatcaga caaagccc~g tggggaggac aagaaaaggg ccatggatgg gtgcagtggc 3540 tcacacctgt aatccaaaca ctttgggaag ccgaggcagg cagatcacct gaggtcagga 3600 gtttgagact accctggcca acctggcaaa accccgtctc tactaaaaaa aaaaaaaata 3660 caaaaattag ctgggcgtgg tgcacgcctg tagtcctagc tactcaggag gctgaggcag 3720 gagaatcact tgaacccaag aggtggaggt tgcagtgaac cgagaccacg ccactgcact 3780 ccagcctgga caacagagca agactccgta tcacaaaaaa aaaaaaaaaa aatggggtcg 3890 cgggagccaa atgtgcaagt gagcagtgtg gctgggcaac aggctttcac ccccaagtac 3900 atgtcacttc actcagtcct caaaacagct ctctaactct agatattatg atatctagag 3960 tttctgtaag ttcagtgttt tgcctctgtt tgtgtagtta ggaagtgatt aaccacacaa 9020 gaaatcccag aggtattgca aggctactgc tttcagtaat caaaacaagg tacagccaat 4080 aagtgctctg aatttaggga cttcatggag aaagaccatg tgggctgggg cagtcaggga 4140 aggcttccta gaagagacag gtcttggggt gagcacagag aattggccca ggctgtggac 4200 agctatagag agagagccag gaaagcccgt gagcagtgtg cagctggaga tagagaccag 9260 tctcactgcg tctgagcctc tgtggcctcg tctgtaaaac agagataatc accccagctt 4320 catggggttg tgaggaagat caaatgagat gacatttgtg aaagtgcttc gcctactttt 4380 ggcacatggt ggaagcttag gaaatgtcag ccccacccac tctcctgact ttcgggagca 9490 aaccagtaga gaggcaagca tgcagccact ggggcaggca gagcactcct gggcctcaga 9500 gggtgcaaaa tgatgcggga acctcaagga aggagtgggt gctgccttct tggtgacaag 4560 ccctcccgct tctatttatc tctgctccga cgcctgccag cccacccctc cccagcacca 4620 cagaggccag cctccctctc aagtcaccag cacagagcat tcaaggccca gggccccact 4680 tcccttgggg cccaggggac ctaaagaggg gcagtcaggg cccaggcctg agggggaaag 4740 ccccaggtaa agaatattcc tccaaatccc actccagctc ccgcagacaa cctgatcggg 9800 gtcaggagga cacactccta ccccaggctg agagcagcct ctgataacac aaaaggaccc 9860 tgagggtgga gacctcccac ctccacttca aaacagtgtg ttatttatca atatcttatc 9920 cccggaagtt gaatctatct cccagtgcca actccgagat aaatgacttg accaggcgtg 9980 tggcatggat taaggcatga gataggtgtt cccaccacca gaacgagcca gtggctgcct 5090 ctcttccctt tgagccctcc ctccacagag acctgtgaat aggtgtttct gatccctagg 5100 ctggttgcat cccaacccag agcaggcagc cttcggactt ctagcatggg ctggcctcag 5160 gacatggagc caaagcaggc agacctggcc ctgccctcaa gctcccaagc taaagagagc 5220 ctggccctcc ctcccactag gtttctccag agcctgctgc ctcctggttt gggcttctac 5280 tctattcttc ccccacagac tccctgcaat ttactgcatc acctctagac tagcaattac 5390 agatggagct cagaacctac ttcctgagcc ttcctaatct cagcagccct gacagccact 5900 tccctcttaa cactaatgca gctgcttatt ctgctgacat taaggtcagg gcctggtcca 5460 aggaagagga caggtacagc ccaagctttg cacttgaaca tccatgcttc tgaccacctg 5520 ccctgtgacg ctggctctgt gccccagtcc agaaaagact tctgcctact cctcctctgc 5580 cctacccagt taactccctt tccttccctc ccttctgctt ctcactcctc ccctcccttc 5690 tcttcttctt ctccccttcc cccatcacct ggggcccgat tcagctgtgc ccagccctta 5700 ctctgagtgc ccacagatgg agcctccagt agcttctgtg gggcaccctt ccaccaggtc 5760 ccagctccct tggctccagc agtgtccatg ctaaagcctc caagtgtcat gttggagaga 5820 atggtggtca cagtagataa gcccaaaatg ccttacagtt tacaggctgg agtcaggccc 5880 cgccacgtgc tggctacatg acttccccga gattccattt cctcctcagt aaaataagtg 5990 gtaagatttt aggatcccca gcactaaaaa gaaacgaaat actgatacag gctccaacat 6000 ggatgaattt tgaagcatta ctatactaag tgaaagaagc cagtcacaaa caagcacata 6060 ttggatgatt ccatttctag gaagtgttcc gaacaggcaa atttatagag acagaaagta 6120 gattgattag tggttgcctg aggctgggga gcgggggaag ggaggtgact accaat t t 6180 acggagtttt tccagggtga gagggtgatg aaaatgttct aaaatagatt gtgttgatgg 6290 ttgtgccact cagaatatac taaaaaccat ttgaattgtg cacttgaaac agatgaattg 6300 tacggtatgt gaattctata tcaataaatc tgtaatttaa aaaaaaaaaa ttaggtcggg 6360 tgcagtggct cacacctata atcccagcac tttgccagac tgaggcagga ggatcactta 6920 agcccaggag ttcaagacca gcctggggaa cacagcaaga cctcgtctct actaaaaaat 6980 tttaaattac aaaaaaaaaa agtaaaaaaa atagaatcct aatagtacct atctcatagg 6590 attgtggaaa atagtagtaa tgtatgtaaa atatttagca catagtaggc acaaagaaat 6600 gacattatta ttaagaggcc tgggagagct gtgcccagcc tatcgtggga ggccttgacc 6660 tttggactca aaagtggcag caggtccacc cccccataca cccttgtcac caaggaagcg 6720 tccacagctt aaaggagcta tattaaagca ccccaagtca agaggactga accagatctg 6780 gaactcactc acctcccctc tcacctcact gccctcacca gccagcctct tgtcaagtga 6840 tcaggctgtc aaccaacttc tctaggataa ggtttcaggt cagcccgtgt gtataagacc 6900 agtgccaagc cagaagcagc agagacaaca gtgaatgaca aggaggggcc atccaatccc 6960 tgctgccacc tcctgggatg gagccctagg gagcccctgt gctgcccctg ccgtggcagg 7020 actcacaggt aagacccctt tctcctccct catcccttcc cctctccctc tcccttctcc 7080 ttgttctccc tttcattggg gctttcagag agcagccccg agcagtcagg gctcactagc 7140 tgcagcttgt cagacctgat agagattcag tccagccgcc accttatgaa aagggagctg 7200 tggccttgat gagggtactg tggcagggct ggggcttgaa cccaacaccc gtgtcactca 7260 ctcaagactc acaccccctt tgccttgctg gctgcctctg gtgggatttt gcaaatcccc 7320 ~atagacagga agtggctttc ttctttgcct gccccagaat ctctgcgatt cctccagagc 7380 ataaatccct ctctttccat gaggaccctg gggccctctt cctgagtagg gatgacaggg 7990 gcacttctga cctgaggcgt ggtccaggtc atttgctggg agctttacag agcccatggt 7500 ctctgcccag acggcttctt cagtgggctg ctgtgaaggc tttgccggga gggtgggttg 7560 gagttgggga ggcaactggt gttgggtagg atgtctcaaa atggggtcct cttcccctgc 7620 ttcagagcta ccacagggag ttttcctaat gcagattcct aggccccacc ccagacctaa 7680 atcaggatct ctggggctga gagctgagaa tctgctctgt aaacaagcag ctcaagggat 7740 ccttggctct ccctgaagtc tgagactctc tgggcagtga aacaggcgca gcttcagatg 7800 tcagacaaac gtgggcacca atctcagctc cagcacttca gctgtatgat agcaaaagcc 7860 ctggaagcct caggtccctg gtttacgaaa tgagaataat aatagcaact acttgtagcc 7920 ttatgaaggg atcaaatcag tcatgtctgt aaagccctca gcacggtatc tggtgcaaga 7980 agcaaccagc aaacattaat ggaccatgct gactagaaca tcccatccct caggagcccc 8090 agcagagcta cagtaatgag ggttccactt ttgacttctt cctccactgg ccagtggcaa 8100 aaggctgccg gctgctaggg gtctaggaga gtctggagtg aattgggaag aagattgggg 8160 agtgctggcc tcaaggcacc tcctacctgt gcccaccact gtggctttcc ctcctcccgc 8220 agcttgacta ctgaaagttc tagagcccca aggtgggctt ttgacctgag tctgtgtcca 8280 tccattccat tttccatgag tggctaagaa ctgcccctct tgtcaagtga tcacgctgag 8390 gccaagagtt caagaccaga ataggcaaca tagagagacc cccatctcta caaaaaataa 8900 aaaattagct gggtatggtg atgcacacct gtagtcccag ctactcggga ggctgaaggt 8960 gggagggtca cttgagtcca agaggtcaag gctgcagtga gcctggattg caccactgca 8520

- 11 -ctccagccca ggtaacagag tgagacctgt ctcaaaaaaa aaaggaggca gtttgatatt 8580 ggggagaaca gatgcctgag cctcggtttc ctcatgtata cagtgcaggt accactatca 8640 gctctgccta cccctggtaa ggaggggagg gagagggtca ggaggaggat tgcaaaattc 8700 aagggatagg aacgtgacct gtttttatag gccaaattca tgcagcttaa gtatggcacc 8760 acccaggctt ctccctttct aaagcccctc ctgggtaagg aagagttcct gggagccagg 8820 ccagacatca ctccatcagc cttctctggc ctgtctcctg cagccccacc gctgcactga 8880 agcccagggc tgtggagcag cctctctcct tggacctcct ctcggcccta aagggactgg 8940 gcagagcctt ccaggactat ggttggactg aagccttcag acgtgcctcc caccatggct 9000 gtgaagttcc tgggggcagg cacagcagcc tgttttgctg acctcgttac ctttccactg 9060 gacacagcca aggtccgcct gcaggtaggt gccctttggc caagggtcat tgatcacatg 9120 gaaggagggg ctagttctct cccatatccc ccatgacgtg tgcccacatg cccttcctca 9180 gaaccctgac aaagactctc actccactgc ttaggaccct tccttgcctc ctcccatcac 9290 catccaccag gacaaaaaaa tctaaattct ttgcatgatg tgacagggcc ctttatgggc 9300 taggccctac tttgtaaagc atgcagtgtg aggtaaaagt aaggaattaa ctgtgtgacc 9360 ttgggcaagc cacgaagcac ttataaaatg ggaaaaacaa tctgtccctc tgatttactc 9920 tgaggatcaa acaccaagcc atgtgtataa tactgctttg tgaatggtaa aatgctgccc 9480 agacaccagt gatttctact gtgaccagca tggttgttct caggcccagc ccaggcaggc 9590 ccagccccag cagggttcct gtgcacgcag ccccttcttg ccttcccatc tgagtcctca 9600 ccccctgcta ttgtccctca gatccagggg gagaaccagg cggtccagac ggcccggctc 9660 gtgcagtacc gtggcgtgct gggcaccatc ctgaccatgg tgcggactga gggtccctgc 9720 agcccctaca atgggctggt ggccggcctg cagcgccaga tgagcttcgc ctccatccgc 9780 atcggcctct atgactccgt caagcaggtg tacaccccca aaggcgcgga cagtgagtga 9840 ccaggtccct gaacaccaaa ggggtggctg aaagtgtgtg ggtcaagaga ccagggaagt 9900 ctagactcag aggcagagcc aggggcgggg ggaagctggt accggacgct tatgaggagg 9960 tctgagtgga catcaaggaa gctgcagggg cagccccgca gagaacagca tgtcccagag 10020 agctgcttag tagggacact ggcccactct ctctgcccct cccagactcc agcctcacta 10080 cccggatttt ggccggctgc accacaggag ccatggcggt gacctgtgcc cagcccacag 10140 atgtggtgaa ggtccgattt caggccagca tacacctcgg gccatccagg agcgacagaa 10200 aatacagcgg gactatggac gcctacagaa ccatcgccag ggaggaagga gtcaggggcc 10260 tgtggaaagg taggtctgga ctctggacgc aggcggtctt aggcagagct ttccctcccc 10320 tcagactggg gcagggaccc cagtaaggag gggactccca gcatggcgtg ttccagtgat 10380 tctgaaagaa catcacaacc aaagatactt cactgacctg ccacagcccc tcaaactcag 10940 ttcattttac cagccctttg ccatgtgcag gttgatgtga gggagccaga aatgaactta 10500 agacaccttc acacgcccag ggcatgagga cagcagagga gataagatgc agctacacca 10560 caggcaggat gtggtagggg ttgccccaga ggtggagctc cagaggcggg cttgcagaga 10620 aggtgacacc taagctgggc ctggaagact gaacaggctc taggtgtgtg gagacggaag 10680 gggaggggcc ctcaagcagg gtccggagga aaaagaggag catcagaaaa gcacagctgt 10790 gaggagtggg cgcagggaga tgcaatgagg aagcgcttcc ttgggagcaa agctggaggg 10800 ctccctatgt gtccacatgg cagccactgc gatgaatgca ggatctctcc gcatgtgaac 10860 cagaggttgc aggaacgttt gcagaagaaa ctgacccagt gaagtttaag ggcaggacac 10920 ctcttaagtt ggggctcttc atcacttgtt gggcaccctt cagagcttgt ccccttacct 10980 gtgaaaccag gggtttgatc ctgacagttt cctagggccc tgctggcacc acattctgtc 11040 actgttccaa gagctcagcc tctcgctgaa tgactttctt ttctggctgc agctgggtct 11100 ccaggaagca tattttaatt ttgacagcta ttgcagatca ccctccaaat gtggccaaat 11160 gaacacaagt gggcctctct gttctctgtc tctgaggaaa acatggataa tctgagagtt 11220 gttaacccta gaaaggaaaa tgtggaatct gctcagctgg ggtgggatcc tctggctgag 11280 accattggaa tggggcacta tggccccaaa actggggcct gtggccttgc agccagggca 11340 tccatttctc ccatttccca ttcctccctc cccatccatt tcacatccct ccccaccgcc 11400 ttcctaacag gaactttgcc caacatcatg aggaatgcta tcgtcaactg tgctgaggtg 11960 gtgacctacg acatcctcaa ggagaagctg ctggactatc acctgctcac tggtgaggcc 11520 ctgggctcca ggcaggcagc tctccctcag cagggaggga acccagaact ccgtggagtg 11580 ggcaccaccc agaggcaact gggttttaga aggagcagag agagaagcag tgcctagtaa 11640 aaagtgccag gtacattgtg gtgacaagca ggaaagaccc ctgggctggg aggctggaga 11700 cttgggttcc agtcccagca ccacctctca ctatatagct ttaagcaggg gtctctcacc 11760 ttctccgact tcagtttcct caaacagcct gcatgacctc ccacctctgg gtcagcccag 11820 gcctagtttg ccagtactta ccaagagctt agcccagggc actgtgagag atatggaaaa 11880 tactgtccta tgctcaggga gttcacggtt gagttgggga caaacagtgc atacatatgg 11990 acagaacaca aatgcactcc ttgatatttg cttgtccttc ctctgcagac aacttcccct 12000 gccactttgt ctctgccttt ggagccggct tctgtgccac agtggtggcc tccccggtgg 12060 acgtggtgaa gacccggtat atgaactcac ctccaggcca gtacttcagc cccctcgact 12120 gtatgataaa gatggtggcc caggagggcc ccacagcctt ctacaagggg tgagcctcct 12180 cctgcctcca gcactccctc ccagagaaca ggggcttctt tcttttcgaa tgtggctacc 12290 gtgggtcaac ctgggatgta gcggtgaaga gtacagatgt aaatgccaca aagaagaagt 12300 ttaaaaaacc atgcaagtaa aagaaaaaaa gtgaaccata cctgatgggg agggttaggg 12360 aagcctgact gagaacaaac actccaggaa taggtaaaag tactgcctgt ctccagagga 12920 agttagcaat cctgggacct cctggacctc ctgccatggc cattgagcac cacactgacc 12480 atggccagtg ccttcctcac tgtctccaca cgctccacgt tttcttgcac ttactgctcc 12540 ctctgcgtgg aatgcctcat catctacagg ctgtcaattt tagccatcct tcaagacgag 12600

- 12 -ttcaaatgcc acctcctccc taacactctc aggtgtaaat ttttcctcct ccctgggaac 12660 ttctgcaatg ccatttgata ccatttttat ggtatttatc atctcctgcc ttgtattata 12720 gtatttgtaa gcttaaatta ttcctcatgc aaagagcaag ttcctgacag caaaagtggc 12780 tcagacatct tttatctccc acagtccctc acacaaagtg agcactcgat aatgcaggtt 12890 gtttatgatt atcacaatag ctaagtcact ctatattagg cctcgtgctg agcactttac 12900 acacgttatc ccaacagccc cttgaactgg gtagtattgt ccacattaac taaggaaaag 12960 actgagtgtc agaaaagtta agtaacttat ccaagatcac aggttaaaat ggtggagcca 13020 tggctcaaac cctgaccgtc agacaccaca cccaacaatg ttgtttatcc tactggtaag 13080 ctcttagctt ggccctttca cctcccactg ctgatgtctt caacagagag ttttttggtg 13140 cccagtgtta gaatggaccc aacaagtgaa caagagctgc tataggttct caagcctggg 13200 aatgacgtaa taaaactata ctgcaattga cagactgttc ttccaaaaag tgcctctatc 13260 attacagtct tcagctgtag ccacttgtct cagttactgc tttcacttgt ccaacatttc 13320 tggagcatct ttgtaggtgc caggccctgg gttatgcctc cctcaaagag cagcagataa 13380 gttggtggta tttactgagc atgtattgat gctgggccct gtgctgagtg ctgtccaaca 13990 tttaactcac ccaatctgca cgactaactc cacaaggcag atactgttat tttcctcatt 13500 ttacagataa ggaaactgag gcttagaaag attaagtgat gtgtccagat tgtaaagcta 13560 gaaactggga gagcttggat ttgaacccag gtctgactcc ggagtttaca tttgttgtca 13620 cagtactatc gtccccacaa gagtcaagaa aacccatggc atgaggtcac agtgcccaaa 13680 ctgagtcctc cagagcaaag agcaaccagc cagggaagga ggagaggagg ggacagtcca 13790 ggcagaggga gcaagaggag caaaggcatg gagggaagag ggcctggcat cgtcagggaa 13800 tgtgactagc tgagtctggc gggagcaaac gggcccagga ggtggttagc ggagggacag 13860 gctgagagag gggcaggggc cagctcctgg gcttctccct gagttggtga gccgcagctg 13920 aggtggggac actgtgctat gccatcacag cgcagccagc ctctctggag aagagctaaa 13980 tctggtgcca cactgtattc accctgcaaa gcccaagctt ctccatgtcc tggcaggggg 19090 ccatgttagg gctggccacc cggggtgtaa ctgagcccag aaacacccag cagcagggtg 14100 gagttagaac cgcacctctg acacttacta gccgcgggtc tttggttgag ctcttaacct 19160 ccctgggcct cagtttgtga aaaggagcct ggcagcaaca tggctgcctt atagaactgt 19220 gagaattcgc tgcctaacac agtaacccgt ctcaaaacgt gagttttttt ttcttttcct 14280 tactccgact tctgcctaaa tccccttagc agaaaaaaaa aagagagaga gagactgaaa 19340 ggattcagaa aatgcttgtg atgaacagaa gtctggatcc tctggcacta ccactgtgtc 19400 ccgggagagc acacgcatct gttgtggtcc cctagcactc cacctgatgt gttggttgtt 14960 tttcttatca gatttacacc ctcctttttg cgtttgggat cctggaacgt ggtgatgttc 14520 gtaacctatg agcagctgaa acgggccctg atgaaagtcc agatgttacg ggaatcaccg 19580 ttttgaacaa gacaagaagg ccactggtag ctaacgtgtc cgaaaccagt taagaatgga 19640 agaaaacggt gcatccacgc acacatggac acagacccac acatgtttac agaactgttg 14700 tttacttgtt gctgattcaa gaaacagaag tagaagagga ggagggattc tggtcttcac 19760 tgccatgcct caagaacacc tttgttttgc actgacaaga tggaaaataa attatattaa 19820 tttttgaaac ccattaggca tgcctaatat ttaggcaaga gaaaataaac caagatagat 14880 ccatttggac aaaatggaag gttggagacg tgtatccccg tgaaatctgg ttagataatg 19990 aatgataagc aggaaggatg gcaagcacgg gacaggaggg gcccacaatg gagtgggaga 15000 tcagccacgg agcctggagg gatgccaccc agcaacacag agctggcgac tgcagctgca 15060 ccatcacaca tgcatcatca gcctatttgt aatatgtctg ccacagagag tcctttggga 15120 ttctaggaaa cccaaggaac aagagaaaaa actagagcct gtgctaaaga agccctgctg 15180 ggcccatgtg aggctggggc tcgtaaatat tccctgacga cactgaagaa tcaagagggc 15290 agcccccact ttcctacaaa atggagggag ccatcccttc cctgtccacc tcaccagggg 15300 tgctatgaca tgcaagtgag aagctgggca tgaacgcact ttataaaagc aaaagctctg 15360 tgtaaatcta actacaagga caatgccttg ggagagattt tgtcgggaca gagaggagtt 15420 gccagggaag aaggtttgaa agatacggtt gtctagaggt gagaccaaag gatccagaga 15980 cttggggacc agaggtgaca gtggatgacg tgaagccaca ggagccccac ccccatgcag 15540 cctcttcccc accccccccc accacgcgct caatcatgag tacctcaaag gattgttggg 15600 cttgggggaa aagaggtgga ttcctgggca agaacctaaa gtagcaggac tcggaattct 15660 cgggaaatta ttatgactca ataaaagaat tcacacctta ggtgtgggag taagaacagc 15720 cacttctctg ccttttcttt cttggaattt tcctttctca cttctatttc aggctttcta 15780 tgtgtcaggg cagggccaga tccagcccca catgcctaca cttcatctgc cccctctcac 15890 cctgtttaat tgcaggcaag tagctttatt tttttagggt tccagctcct gcttctgcaa 15900 aaggcagggt tgaaccagac gaccgacttc caagcttaag actgtacatt tttcgaattg 15960 ataatgggga cccaaaatgc cactatcttt ttctacttct tggcagcctt gcgtagctct 16020 gatgattgtc aggactgggt tcaaacctca ccccattcta ccttactaac cacctagcca 16080 cagggaatcc ttgcaccttg gtgtgctacc agagaagtgg gaataacaat cgctgcttca 16190 caggcttgtt gtgagggttg acctaaaact ccttggaaag cagacatgtg gtgtgcacct 16200 gctacctggg aggcttaagc gagaggactg cttgagccca gagttcaggc tgcagtgagc 16260 catgactgca cctgtgaata atgactgcac tccagccttg gcaacagagc ataactcctt 16320 ctctgaaaca aaacaaacaa aaatcgttgg catacag 16357

Claims (93)

Claims:

1. Recombinant DNA molecule which contains the DNA
sequence of the UCP-3 promoter active in fat cells but does not contain a functional sequence of the UCP-3 promoter active in muscle cells.

2. Recombinant DNA molecule according to claim 1, which contains the sequences SEQ ID NO: 1 TATATTAAA and SEQ
ID NO: 2 CACCTC but does not contain the sequences SEQ
ID NO: 3 TATAAGA and SEQ ID NO: 4 CAATCC.

3. Recombinant DNA molecule according to claim 1, which contains the sequences SEQ ID NO: 1 TATATTAAA and SEQ
ID NO: 2 CACCTC and derivatives of the sequences SEQ
ID NO: 3 TATAAGA and SEQ ID NO: 4 CAATCC formed by point mutations, as a result of which the sequences SEQ ID NO: 3 and SEQ ID NO: 4 lose their function in the transcription.

4. Recombinant DNA molecule according to claim 1, which contains the sequences SEQ ID NO: 1 TATATTAAA and SEQ
ID NO: 2 CACCTC and derivatives of the sequences SEQ
ID NO: 3 TATAAGA and SEQ ID NO: 4 CAATCC formed by deletions, as a result of which the sequences SEQ ID
NO: 3 and SEQ ID NO: 4 lose their function in the transcription.

5. Recombinant DNA molecule according to claim 1, which contains the sequences SEQ ID NO: 1 TATATTAAA and SEQ
ID NO: 2 CACCTC and derivatives of the sequences SEQ
ID NO: 3 TATAAGA and SEQ ID NO: 4 CAATCC formed by combinations of point mutations and deletions, as a result of which the sequences SEQ ID NO: 3 and SEQ ID
NO: 4 lose their function in the transcription.

6. Recombinant DNA molecule according to one of claims 2 to 5, characterised in that between the sequences SEQ
ID NO: 1 and SEQ ID NO: 2 there are 30 to 50 base pairs.

7. Recombinant DNA molecule according to one of claims 2 to 6, characterised in that between the sequences SEQ

ID NO: 1 and SEQ ID NO: 2 there are 40 to 50 base pairs.

8. Recombinant DNA molecule according to one of claims 2 to 7, characterised in that between the sequences SEQ
ID NO: 1 and SEQ ID NO: 2 there are 42 base pairs.

9. Recombinant DNA molecule according to one of claims 2 to 8, characterised in that upstream of SEQ ID NO: 1 there is additionally an RXR/PPAR element.

10. Recombinant DNA molecule according to claim 9, characterised in that RXR/PPAR element includes the sequence SEQ ID NO: 5 TGACCTTTGGACT.

11. Recombinant DNA molecule according to claim 10, characterised in that between the sequences SEQ ID NO:
1 and SEQ ID NO: 5 there are 65 to 75 base pairs.

12. Recombinant DNA molecule according to one of claims 2 to 11, characterised in that upstream of SEQ ID NO: 1 there is additionally an Alu sequence.

13. Recombinant DNA molecule according to claim 12, characterised in that between the sequence SEQ ID NO:
1 and the Alu sequence there are 255 to 265 base pairs.

14. Recombinant DNA molecule according to one of claims 2 to 13, characterised in that upstream of SEQ ID NO: 1 there is additionally an E2A element.

15. Recombinant DNA molecule according to claim 14, characterised in that the E2A element includes the sequence SEQ ID NO: 6 CAGATG.

16. Recombinant DNA molecule according to claim 15, characterised in that between the sequences SEQ ID NO:
1 and SEQ ID NO: 6 there are 440 to 450 base pairs.

17. Recombinant DNA molecule according to one of claims 2 to 16, characterised in that upstream of SEQ ID NO:
there is additionally and E box.

18. Recombinant DNA molecule according to claim 17, characterised in that the E box includes the sequence SEQ ID NO: 7 CACTTG.

.delta.

19. Recombinant DNA molecule according to claim 18, characterised in that between the sequences SEQ ID NO:
1 and SEQ ID NO: 7 there are 450 to 460 base pairs.

20. Recombinant DNA molecule according to one of claims 2 to 19, characterised in that upstream of SEQ ID NO: 1 there is additionally an E box.

21. Recombinant DNA molecule according to claim 20, characterised in that the E box includes the sequence SEQ ID NO: 6 CATTTG.

22. Recombinant DNA molecule according to claim 21, characterised in that between the sequences SEQ ID NO:
1 and SEQ ID NO: 8 there are 460 to 470 base pairs.

23. Recombinant DNA molecule according to one of claims 2 to 22, characterised in that upstream o1 SEQ ID NO: 1 there is additionally an octamer sequence.

24. Recombinant DNA molecule according to claim 23, characterised in that the octamer sequence includes the sequence SEQ ID NO : 9 ATGAAAATGT.

25. Recombinant DNA molecule according to claim 24, characterised in that between the sequences SEQ ID NO:
1 and SEQ ID NO: 9 there are 515 to 525 base pairs.

26. Recombinant DNA molecule according to one of claims 2 to 25, characterised in that upstream of SEQ ID NO: 1 there is additionally a CAAT box.

27. Recombinant DNA molecule according to claim 26, characterised in that the CAAT box includes the sequence SEQ ID NO: 10 CCAAT.

28. Recombinant DNA molecule according to claim 27, characterised in that between the sequences SEQ ID NO:
1 and SEQ ID NO: 10 there axe 550 to 570 base pairs.

29. Recombinant DNA molecule according to one of claims 2 to 28, characterised in that upstream of SEQ ID NO: 1 there is additionally a CAAT box.

30. Recombinant DNA molecule according to claim 29, characterised in that the CAAT box includes the sequence SEQ ID N0: 11 ATTGG.

31. Recombinant DNA molecule according to claim 30, characterised in that between the sequences SEQ ID NO:
1 and SEQ ID NO: 11 there are 670 to 680 base pairs.

32. Recombinant DNA molecule according to one of claims 2 to 31, characterised in that upstream of SEQ ID NO: 1 there is additionally a CAAT box.

33. Recombinant DNA molecule according to claim 32, characterised in that the CAAT box includes the sequence SEQ ID NO: 12 ATTGG.

34. Recombinant DNA molecule according to claim 33, characterised in that between the sequences SEQ ID NO:
1 and SEQ ID NO: 12 there are 730 to 740 base pairs.

35. Recombinant DNA molecule according to one of claims 2 to 34, characterised in that upstream of SEQ ID NO: 1 there is additionally a binding site for an upstream binding stimulating factor.

36. Recombinant DNA molecule according to claim 35, characterised in that the binding site for an upstream binding stimulating factor includes the sequence SEQ
ID NO: 13 CCACGTGC.

37. Recombinant DNA molecule according to claim 36, characterised in that between the sequences SEQ ID NO:
1 and SEQ ID NO: 13 there are 845 to 855 base pairs.

39. Recombinant DNA molecule which contains the DNA
sequence of the UCP-3 promoter active in muscle cells but does not contain a functional sequence of the UCP-3 promoter active in fat cells.

39. Recombinant DNA molecule according to claim 38, which contains the sequences SEQ ID NO: 3 TATAAGA and SEQ ID
NO: 4 CAATCC but does not contain the sequences SEQ ID
NO: 1 TATATTAAA and SEQ ID NO: 2 CACCTC.

40 Recombinant DNA molecule according to claim 39 r which contains the sequences SEQ ID NO: 3 TATAAGA and SEQ ID
NO: 4 CAATCC and derivatives of the sequences SEQ ID
NO: 1 TATATTAAA and SEQ ID NO: 2 CACCTC formed by point mutations, as a result of which the sequences SEQ ID NO: 1 and SEQ ID NO: 2 lose their function in the transcription.

41. Recombinant DNA molecule according to claim 39, which contains the sequences SEQ ID NO: 3 TATAAGA and SEQ ID
NO: 4 CAATCC and derivatives of the sequences SEQ ID
NO: 1 TATATTAAA and SEQ ID NO: 2 CACCTC formed by deletions, as a result of which the sequences SEQ ID
NO: 1 and SEQ ID NO: 2 lose their function in the transcription.

42. Recombinant DNA molecule according to claim 39, which contains the sequences SEQ ID NO: 3 TATAAGA and SEQ ID
NO: 4 CAATCC and derivatives of the sequences SEQ ID
NO: 1 TATATTAAA and SEQ ID NO: 2 CACCTC formed by combinations of point mutations and deletions, as a result of which the sequences SEQ ID NO: 1 and SEQ ID
NO: 2 lose their function in the transcription.

43. Recombinant DNA molecule according to one of claims 39 to 42, characterised in that between the sequences SEQ
ID NO: 3 and SEQ ID NO: 4 there are 45 to 70 base pairs.

44. Recombinant DNA molecule according to one of claims 39 to 43, characterised in that between the sequences SEQ
ID NO: 3 and SEQ ID NO: 4 there are 52 to 58 base pairs.

45. Recombinant DNA molecule according to one of claims 39 to 44, characterised in that between the sequences SEQ
ID NO: 3 and SEQ ID NO: 4 there are 55 base pairs.

46. Recombinant DNA molecule according to one of claims 39 to 45, characterised in that upstream of SEQ ID NO. 3 there is additionally an RXR/PPAR element.

47. Recombinant DNA molecule according co claim 46, characterised in that the RXR/PPAR element include the sequence SEQ ID NO: 5 TGACCTTTGACT.

48. Recombinant DNA molecule according to one of claims 39 to 47, characterised in that upstream of SEQ ID NO: 3 there is additionally an Alu sequence.

49.Recombinant DNA molecule according to one of claims 39 to 48, characterised in that upstream of SEQ ID N0: 3 there is additionally an E2A element.

5d.Recomtaiz~ant DNA molecule a.ecording to claim 49, characterised in that the 82A elemeo.t sncludee the Bequ~nc~ SBQ ID NOa 6 CAGATG.

51.Recomb~.nant DNA mo? ecul.e according to one of claims 39 to 50, character~.~ed in that upstream of S$Q ID NO:3 there is add~.tionally arl $ box.

52.Recombinant DNA molecule according to cla~.m 51, characterised in that the E bax ineluciea the sequeace SSQ ID N0: 7 CACTTG.

53.Recombinant DNA molecule according to one of claims 39 to 52, cha.racteried ire that upatream of SEQ ID No:3 there ~.s additionally ar. F bo~c.

54.Recombinant DNA mo~.ecule according to claim 53, characterised in that the E box includes the sequenee SEQ ID NO : 8 CATrI*hG .

55.Recombinant DNA molecule according to one of claims 39 to 54, Characterised in that upstream of S$Q ID N0:3 there is a.dd~.tionally an octamer sequence.

56.Recombinant DN14 molecule according to claim 55 characterised in that the octamex sequence includes the sequenee SFQ ID NO. 9 ATGAAAATGT.

57.Recocnbi.z~ant DICTA molecule accarding of claims 39 to 56, charaCteri9ed in that upstream of SEQ ID N0:3 there ig addi,tional~.y a CHAT hox.

58.Recombinant DNA molecule accordi:~g to claim 57, characterised in th't the CART box includes the a~quex~ce SEQ TD N0: io CCAA~'.

59.Reco~c~binant pNA molecule accord~.n~g to or claims one 39 to 58 , characterised in that upstream ofi SEg ID N0:

there is additionally a CART box.

&0.gecombinant DNA molecule according to claim 59, characterised in that the CART box ireludes the sequence SEQ III NQ: .1 ATTGG.

61. ReeornbinanG DNA molecule a,ccoxdi.ng to one of cl.aime 39 to 60 , characterised is that up9tream of SEQ TD N0: 3 there is additionally a CART bo~c.

62. Recombinant DNA molaeu~,e according to claim 61, characterised in that the CHAT box includes the ~equex~ae 8EQ TD N0: 1z ATTGG.

63. Recombinarit DNA molecule accox~dirg to one of claims 39 to 52 , characterised is that upstream of S8Q ID v0: 3 there zs additional,ly a ha.nd~.ng site for an upstream binding etimulat~.ng factor.

64. Recombinant DNA molecule according to claim 63, characterised in that the binding sits for an upstream binding stimulating f~.ctor iacludee the sequence SEQ
ID NO: 13 CCACGTGC.

66. Recombinant DN~1 molecule which contains the sequence SEQ ID N0: 1.4.

66. Recombinant DNA mod.°cule Which contains a aeguEnce which hybridises atith the sequence SEQ ID NO 14 under etringerit conditions.

67. Recombinant DN'A mo~.ecule which contains a functional derivs~.tive of a DNA molecule according to one o~
clairng 1 to 66, characterised in that these functional derivatives have the ability to mediate the transcription of a gene.

6B. Recombinant DNA molecule according to claim 67, characterised in that the functional derivatives have been produced by deletions.

69. Recombinant DNA molecules according to claim 6~, characGerieed in that the functional derivati.~res have been produced by point mutations.

7D. Recombinant DNA molecule according to cJ.aim 67, eharaeterieed in that the functional deriv<° ~ r_ :Fns :~a-v been produced by com3~znation~ of point mutations and deietiona.

71. Recombinant DNA molecule according to one of claims 1 to 70, characterised in that the DNA,molecule contains an additional gene which is functionally linked.

72 Recombinant DNA molecule according to Claim 71, characterised in that the additional gene is the gene of the uncoupling protein 3.

73. Recombinant DNA molecule according to claim 71, characterised in that the additional gene is a reporter gene.

74. Recombinant DNA molecule according to claim 73, characterised in that the reporter gene is the luciferase gene or green fluorescent protein,

75. Recombinant DNA molecule which contains the sequence SEQ ID NO 15.

76. Recombinant DNA molecule which contains a sequence which hybridises with the sequence SEQ ID NO 15 under stringent conditions.

77. A cell which contains a recombinant DNA molecule according to one of claims 1 to 76.

78. Use of a recombinant DNA molecule according to one of claims 1 to 76 for the transcription of a gene.

79. Use of a recombinant DNA molecule according to one of claims 1 to 76 for finding substances which are able to influence transcription.

80. Use of a cell according to claim 77 for finding substances which are able to influence transcription.

81. Process for finding substances which are able to influence transcription, characterised in that a recombinant DNA molecule according to one of claims 1 to 76 or a cell according to claim 77 is used.

82. Process according to claim 81, characterised is that it is a cell-free or cell-based process.

83. Process according to claim 82, characterised in that the transcription rate is measured in the presence of a test substance.

84. Process according to claim 83, characterised in that the transcription rate is measured in the presence of a test substance in a cell-free in-vitro system which contains at least cell extract, ribonucleotides and a recombinant DNA molecule according to one of claims 1 to 72.

85. Process according to claim 83, characterised in that the quantity, activity, luminescence or fluorescence of a reporter protein produced in the presence of a test substance is measured.

86. Process according to claim 85, characterised in that in the presence of a test substance RNA ie transcribed in vitro, then translated in vitro and the amount of reporter protein produced is determined.

87. Process according to claim 85, characterised in that the amount of a reporter protin produced by a cell according to claim 73 in the presence of a test substance is measured.

89. Process according to one of claims 85 to 87, characterised in that the reporter protein is luciferase or green fluorescent protein.

89. Process for finding a modulator of the UCP3 promoter, characterised is that a) a host cell according to claim 77 is cultivated in the presence of a test substance, b) the transcription rate of the UCP3 promoter is measured, c) the transcription rate thus obtained is compared with the transcription rate which was obtained in the absence o~ the test substance.

90. Process according to one of claims 81 to 89, characterised in that it is carried out in a High Throughput Screening (HTS) format.

91. Use of a recombinant DNA molecule according to one of claims 1 to 76 for finding factors or substances which bind to the DNA molecule.

92. Use according to claim 91 characterised in that the recombinant DNA molecule is bound to a carrier, contacted with a mixture of various substances or factors, subjected to one or more washing steps and the bound substances or factors are identified.

93. Process for identifying substances or factors which bind to a recombinant DNA molecule according to one of claims 1 to 76, characterised in that:
- the recombinant DNA molecules are bound to a carrier, - contacted with a mixture of various substances, - subjected to one or more washing steps, - the bound factors axe identified.