WO2024026418A1 - Ciblage d'arn chromr non codant long dans une inflammation médiée par l'interféron chez l'homme - Google Patents
Ciblage d'arn chromr non codant long dans une inflammation médiée par l'interféron chez l'homme Download PDFInfo
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Definitions
- the present disclosure relates generally to approaches for treatment of conditions that are associated with type I interferon induced inflammation by targeting RNA Cholesterol Homeostasis Regulator of Micro-RNA expression RNA (IncRNA CHROMR).
- Human respiratory viruses including influenza and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are major causes of morbidity and mortality worldwide.
- Effective antiviral immunity relies on the activation of conserved innate immune signaling pathways that coordinate the production of type I interferons (IFNcc/p) and the expression of several hundred interferon-stimulated genes (ISGs), which collectively subvert viral entry, replication and pathogenesis (1) .
- IFNcc/p type I interferons
- ISGs interferon-stimulated genes
- IFNa/'P are secreted cytokines that bind IFNa/p receptors (IFNARs) to initiate JAK-STAT signaling and the assembly of the IFN-stimulated gene factor 3 complex (ISGF3), consisting of interferon regulatory factor (IRF)-9 together with a STAT1-STAT2 heterodimer.
- IFNARs IFNa/p receptors
- ISGF3 IFN-stimulated gene factor 3 complex
- IRF interferon regulatory factor
- STAT1-STAT2 heterodimer IFN-stimulated gene factor 3 complex
- This complex transcriptionally activates target genes harboring regulatory IFN-stimulated response elements (ISRE), culminating in the expression of hundreds of ISGs (1, 2) .
- IFN-stimulated response elements ISRE
- constitutive and IFN-induced ISG expression can also be regulated by IRF-1 binding of ISREs (2, 3) .
- IncRNAs non-coding RNAs
- innate immunity 5, 6
- IncRNAs execute their structural and regulatory functions by interacting with DNA, protein or other RNAs in the nucleus or cytoplasm.
- LncRNAs contribute to gene regulation through diverse mechanisms, including through guiding or sequestering chromatin-modifying enzymes and transcriptional complexes in the nucleus; regulating mRNA processing, splicing and translation; and acting as competitive inhibitors of endogenous RNAs (e g., microRNAs) or proteins in the cytoplasm (7, 8) .
- endogenous RNAs e g., microRNAs
- IncRNAs e g., a limited number of IncRNAs have been described to regulate the IFN response by altering the function of viral sensors, production of IFNs, and expression of ISGs.
- IncATV 9 and lncRNA-LSm3b (10) have been shown to interact with the cytosolic double stranded (ds)RNA sensor RIG-I and restrict its function, whereas Lnczc3h7a promotes RIG-I function by enabling its interaction with TRIM25 (11) .
- lnc-ITPRIP-1 binds and enhances the function of the RIG-I-like receptor MDA5 (IFIH1) (12) .
- IncRNAs have been shown to be induced by IFN-I and mediate feedback inhibition of IFN responses, such as Inc-MxA, which negatively regulates IFNP expression by impeding NF-KB and IRF3 binding at its promoter (13 ), and LUCAT1, which binds and sequesters STAT1 in the nucleus to limit IFN signaling (14) .
- BISPR is an example of a IncRNA expressed from a bidirectional promoter that cis-regulates expression of its neighboring gene, BST2 (Tetherin), an ISG that is known to prevent infection (15 > CCR5AS behaves as a decoy for the RNA-binding protein RALY, preventing its binding to and repression of the chemokine receptor CCR5 (16) . Finally, lncRNA-CMPK2 (17) , NRAV (18) , and NRIR (19) have been shown to broadly alter ISG expression, although the exact mechanisms remain unclear.
- CHROMR a primate-specific IncRNA first identified to regulate cellular lipid metabolism (20)
- SARS-CoV-2 a primate-specific IncRNA first identified to regulate cellular lipid metabolism (20)
- Loss-of-function studies identify an important role for CHROMR in the regulation of ISG expression, and restriction of influenza virus replication in macrophages.
- CHROATR-depleted macrophages While activation of NF-KB signaling is intact in CHROATR-depleted macrophages, these cells exhibit reduced expression of an IRF-inducible ISRE luciferase reporter gene indicating a defect in transcriptional activation of IRF signaling and interferon response pathways.
- the disclosure also reveals that CHROMR sequesters the nuclear transcriptional co-repressor IRF2BP2, which acts together with IRF-2 to repress ISG transcription, thereby licensing IRF-dependent signaling and transcription of the ISG network.
- CHROMR expression correlates with systemic lupus erythematosus (SLE) two- score IFN system signature, and knocking down CHROMR expression using antisense oligonucleotides leads to reduced IRF transcriptional activity induced by SLE-relevant agonists Imiquimod.
- SLE systemic lupus erythematosus
- ASO_7/1 CHROMR-targeting 7-Mer designed against the first GG-pair of a G-quadruplex present in CHROMR efficiently decreases IFNP-induced ISG expression without causing CHROMR degradation.
- the disclosure also demonstrates that a CHROMR-targeting 13-Mer (ASO_13/1) antisense oligonucleotide designed against the first two GG-pairs of a G-quadruplex present in CHROMR efficiently decrease IFNP-induced ISG expression without causing CHROMR degradation.
- the disclosure also demonstrates that (7// OA7/ -targeting GapmeR (ASO_Gap/3) designed to cause CHROMR degradation efficiently decreases IFNP-induced ISG expression and decreases CHROMR expression.
- Cffl?OA77?-targeting antisense oligonucleotides are efficient at reducing cytokine secretion in human vascular explants.
- FIG. 1 LncRNA CHROMR is upregulated in SARS-CoV-2 and influenza A infected patients and correlates with transcriptional activation of antiviral gene programs.
- A Experimental design for identification of IncRNAs differentially expressed in whole blood of patients with influenza A virus or SARS-CoV-2 and controls.
- D Violin plot showing the distributions of the Pearson correlation coefficient between indicated IncRNAs and 226 differentially expressed interferon-stimulated genes (ISGs) common to IAV- and CoV-2-infected patients.
- E Robust third-order non-linear fit of the IncRNA x ISG Pearson correlation coefficient displayed as a function of the differential expression of the ISGs.
- FIG. 1 CHROMR deficiency leads to diminished expression of interferon-stimulated genes.
- A Time course of CHROMR expression (FPKM) in human monocyte-derived macrophages infected with influenza A/California/04/09 (H1N1), influenza A/Wyoming/03/03 (H3N2), or mock infected.
- B qPCR analysis of CHROMR in human THP-1 macrophages infected with influenza A virus/WSN/1933 (H1N1, 1000 PFU) or stimulated with the synthetic dsRNA poly(I:C) (1 pg/mL).
- Cutoffs used for visualization -2 ⁇ fold change (FC) > 2; and P-adj ⁇ 0.05.
- E List of most affected canonical pathways identified through Ingenuity Pathway Analysis of (C) ranked by P-adj .
- F Expression of top chemokine genes differentially regulated in CHROMR-depleted and control THP-1 macrophages. Top row: RNA-seq normalized expression counts (CPM) after poly(I:C) (1 pg/mL, 8h), bottom row: immunoassay of protein levels after poly(I:C) (1 pg/mL, 24h).
- CPM RNA-seq normalized expression counts
- Data are mean ⁇ standard error of the mean for 2 (A), 3 (B to F (top), G) independent experiments, or representative of 3 independent experiments (F (bottom)).
- CHROMR is required to restrict influenza virus and activate interferon stimulated gene transcription.
- A Percentage of viral infection in CHROMR- depleted (GapC///?OA7/?-treated) and control (GapCTRL-treated) THP-1 macrophages challenged with influenza A virus/WSN/1933 (H1N1) at increasing plaque forming units (PFU). Percentages were calculated relative to GapCTRL transfection at highest infection rate.
- B Transcription factor binding enrichment scores for interferon stimulated genes (ISG) differentially expressed in CHROATK-depleted and control THP-1 macrophages stimulated with poly(I:C) using the ChIP Enrichment Analysis (ChEA 2016) database gene set library.
- D Volcano plot showing differential H3K27Ac modification in C///?OM/?-de leted and control THP-1 macrophages stimulated with poly(I:C).
- ChlP-seq reads that are gained or lost after CHROMR knockdown are indicated in red and blue, respectively. Dashed line indicates P-adj ⁇ 0.1.
- E Genomic distribution of H3K27Ac marks lost after CHROMR knockdown identified in D, P-adj ⁇ 0.1.
- F List of biological processes identified using the Genomic Regions Enrichment Annotations Tool (GREAT) analysis of H3K27Ac-depleted promoter regions.
- G Metagene plots showing the mean (top) and individual unique positions (bottom) of normalized H3K27Ac read density around the transcription start site (TSS ⁇ 1500 base pairs) of ISGs in THP-1 macrophages transfected with Ga ⁇ CHROMR or GapCTRL.
- H Hypergeometric Optimization of Motif EnRichment (HOMER) analysis of promoter regions depleted of H3K27Ac after CHROMR knockdown showing transcription factors with highest similarity score in motif indicated in bars. Data are mean ⁇ standard error of the mean for 3 independent experiments. P values were calculated using a repeated measures two-way ANOVA with Sidak’s multiple comparison test (A and C) or Binomial test (B, F and H). *P ⁇ 0.05; **P ⁇ 0.01; ***P ⁇ 0.001.
- FIG. 1 CHROMR binds to IRF2BP2 to control interferon-stimulated gene expression.
- A Schematic representation of Chromatin Isolation by RNA Purification (ChIRP) followed by genomic DNA sequencing (ChIRP-Seq) or mass spectrometry (ChIRP - MS) to identify RNA-binding proteins.
- B Distribution of CHROMR binding sites within interferon stimulated gene (ISG) loci (left) and representative ChIRP-seq reads (top: even probe set; middle: odd probe set; bottom: input) at selected ISG promoters (right).
- C Nuclear Cffl?OA77?-binding proteins identified by ChIRP -MS in THP-1 macrophages from 3 independent experiments.
- E qPCR analysis of CHR0MR3 in RNA- immunocomplexes precipitated from THP-1 macrophages using IRF2BP2 or HNRNPLL antibodies, or IgG as a control.
- (J) Integrated model depicting CHROMR binding to IRF2BP2 to sequester the IRF-2 repressor complex from interferon-stimulated response elements (ISRE), facilitating access for activating interferon regulatory factors (e.g., IRF-1).
- E, I Data are relative to IgG control; mean ⁇ standard error of 3 independent experiments. P values were calculated using one-way ANOVA with Dunnetf s multiple comparison test (D and I) or a repeated measures two-way ANOVA with Sidak’s multiple comparison test (E). *P ⁇ 0.05; **P ⁇ 0.01; ***P ⁇ 0.001.
- Fig. 4 panel H. CHROMR gene mutation in the G-quadruplex region between nucleotide 237 and 264. Mutated nucleotides are bolded.
- CHROMR expression levels in whole blood of patients infected with influenza A virus is associated with expression of cholesterol efflux genes and interferon-stimulated genes.
- CPM CHROMR expression
- IAV influenza A virus
- B Pearson correlation matrix showing the 50 ISGs that are most strongly associated with CHROMR in whole blood in lAV-infected patients.
- A) r Pearson correlation coefficient
- B) Individual dot size and color represent Pearson correlation coefficient and absence of dot indicate lack of association. P ⁇ 0.05.
- CHROMR is required for LPS induction of interferon-stimulated gene expression.
- A CHROMR expression (FKPM) in human monocyte-derived macrophages infected with influenza A/Vietnam/1203/2004 (H5N1), or mock infected.
- B-C qPCR analysis of CHROMR in THP-1 macrophages after transfection with CHROMR- targeting (GapCHROMR) and control GapmeRs (GapCTRL) (B) or in THP-1 macrophages stable overexpressing CHROMR or an empty vector control (C).
- Data are mean +/- standard error of the mean for 2 (A) or 3 (D to G, I and J) independent experiments, or representative of 3 independent experiments (B, C and H).
- P values were calculated using a repeated measures two-way ANOVA with Sidak’s multiple comparison test (A), right-tailed Fisher’s exact test (F, I and J), or a two-tailed unpaired Student’s t-test (B, C, G and H).
- FIG. 7 CHROMR regulates ISG expression in response to LPS.
- A List of most affected microRNAs identified through Ingenuity Pathway Analysis of Fig. 2C.
- C Representative whole-well microscopy images of immunofluorescent staining for influenza-A-infected (H1N1, green) THP-1 macrophages transfected with GapCTRL or GapCHROMR and counterstained for nuclear RNA (DAPI, blue). P values were calculated using Binomial test (A-B).
- FIG. 8 CHROMR is enriched in the nucleus and interacts with histones.
- A qPCR analysis of CHROMR variants after cellular fractionation of THP-1 macrophages. ActinB and IncRNA HOTAIR are used as cytoplasmic and nuclear controls, respectively.
- B Enrichment of CHROMR variants in H3 -immunoprecipitates from THP-1 macrophages relative to IgG control. IncRNA NEAT 1 was used as H3 -enriched control.
- C Heatmap showing chromatin interactions at genomic location of CHROMR.
- D Pol II ChlA-PET analysis in K562 indicating chromatin interactions within genomic location indicated in (C) black, connected bars indicate direct interactions.
- F Normalized transcript reads (CPM) of genes present in CHROMR’ s TAD indicated in (D and E) from THP-1 macrophages transfected GapCHROMR or GapCTRL. Data (A, B, F) are mean +/- standard error of the mean for 3 independent experiments. P values were calculated using a repeated measures two-way ANOVA with Sidak’s multiple comparison test (B). ***P ⁇ 0.001; ****P ⁇ 0.0001.
- FIG. 9 Shown is (A) Identification of cytoplasmic CHROMR-binding proteins by ChIRP-MS (Comprehensive identification of RNA-binding proteins by mass spectrometry) in THP-1 macrophages. Mean score of 3 independent experiments. (B) QGRS- mapper analysis of putative Quadruplex forming G-Rich Sequences (QGRS, G-quadruplex) in CHROME3. Putative G-quadruplexes are highlighted in blue. (C) qPCR analysis of CHR0ME3 expression in HEK- 293 T cells transfected with plasmids expressing CHR0ME3, CHROME3-G4mut or control. Data are mean +/- standard error of the mean for 2 independent experiments (C). P values were calculated using a Student’s t-test (C).
- Fig. 9 panel B. Bioinformatic assessment of putative G-quadruplex in CHROMR. Identified GG-pairs are bolded.
- CHROMR expression correlates with SLE two-score IFN system signature and knocking down CHROMR expression by GapmeRs leads to reduced IRF transcriptional activity induced by SLE-relevant agonists Imiquimod.
- c) Relative expression normalized to baseline (Oh 100%
- FIG. 14 CHROMR-targeting antisense oligonucleotides designed against the first GG pair of a G-quadruplex present in CHROMR decrease binding to IRF2BP2.
- IP RNA immunoprecipitation
- RNA- IP experiment showing that CHROMR binds to IRF2BP2 after overexpression of CHROMR and IRF2BP2 in human embryonic kidney (HEK293T) with empty overexpression vector (EV) used as control
- CHROMR-targeting ASO are efficient at reducing cytokine secretion in human vascular explants, a) Human carotid vascular explant model for testing CHROMR-M&O function ex vivo,- b) Heatmap showing row Z-score of secretion levels of selected cytokine / chemokine measured by Luminex-immunoassay from supernatant of vascular explants transfected with control (CTRL-Lv) or CHROMR overexpressing vector (CHROMR-Lv), or c-d) transfected with GapmeRs targeting CHROMR (gapCHROMR) and control (gapCTRL) (c) or the G-quadruplex-targeting 7-Mer ASO (d) and stimulated with TLR3 agonist (poly[I:C]; Ipg/ml) to stimulate an inflammatory response. P-value by RM- 2Way ANOVA with multiple comparison. *P ⁇ 0.05;
- the disclosure includes all polynucleotide sequences described herein. Complementary and anti-parallel polynucleotide sequences are included.
- the disclosure provides agents that are used for prophylaxis or treatment of disorders that are associated with type I interferon induced inflammation.
- the agent comprise an antisense oligonucleotide targeted to CHROMR RNA.
- Representative examples of olignoucleotides that function in the described methods are provided, as are examples of olignoucleotides that also target CHROMR RNA but do not function, or do not function as efficiently, as the oligonucleotides that are used in the described methods.
- a described oligonucleotide comprises or consists of 7-20 nucleotides. Any oligonucleotide described herein can comprise or consist of a described sequence.
- Any antisense oligonucleotide of this disclosure may be referred to herein as “ASO.” Any antisense oligonucleotide described herein may modified or unmodified. As such, the terms “oligonucleotide” and “antisense oligonucleotide” and “ASO” as used herein includes unmodified oligonucleotides and modified oligonucleotides that include modified nucleotides and/or modified nucleotide linkages, including but not necessarily limited to methylation. The nucleotides of the oligonucleotides may be nucleotide analogs.
- Modified nucleotides that can be incorporated into the described antisense oligonucleotides are known in the art, such as those described in Metelev VG, Oretskaya TS. Modified Oligonucleotides: New Structures, New Properties, and New Spheres of Application. Russ J Bioorg Chem.
- nucleotides or nucleotide analogs may be linked by phosphodiester linkages or by a synthetic linkage, i.e., a linkage other than a phosphodiester linkage.
- Non-limiting examples of linkages in the modified oligonucleotide agents that can be used in this disclosure include phosphodiester, alkylphosphonate, phosphorothioate, phosphorodithioate, phosphate ester, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, morpholino, phosphate triester, acetamidate, carboxymethyl ester, or combinations thereof.
- any oligonucleotide described herein may be provided as a GapmeR. Oligonucleotides that comprise DNAZRNA hybrids are included.
- oligonucleotides that are used in the described methods comprise the sequence CCCCCAT, which may also be referred to herein as ASO_7/1.
- an oligonucleotide used in the described methods comprises the sequence GGAGGTCCCCCAT (SEQ ID NO: 2), which may also be referred to herein as ASO 13/1.
- an oligonucleotide used in the described methods comprises the sequence CTCATAAGAAAACTGA (SEQ ID NO: 1), which may also be referred to herein as ASO_Gap/3.
- an oligonucleotide of this disclosure may exhibit one or several functions that are involved in prophylaxis or treatment of disorders that are associated with type I interferon induced inflammation.
- an ASO of this disclosure can inhibit expression of one or more interferon- stimulated genes (ISGs).
- an ASO of this disclosure prevents or inhibits CHROMR from binding to Interferon Regulatory Factor-2 Binding Protein 2 (IRF2BP2).
- IRF2BP2BP2 Interferon Regulatory Factor-2 Binding Protein 2
- an ASO of this disclosure may be functional in a described method and participate in degradation of CHROMR.
- an ASO of this disclosure may be functional in a described method without participating in degradation of CHROMR.
- the described oligonucleotides exert their effects on CHROMR in the nucleus, in contrast to previous descriptions of the function of RNA CHROMR that regulates cholesterol efflux and fatty acid oxidation via microRNA sequestration in the cytoplasm.
- a composition comprising an antisense oligonucleotide of this disclosure is administered to an individual in a therapeutically effective amount.
- therapeutically effective amount refers to an amount of a described agent sufficient to achieve, in a single or multiple doses, the intended purpose of treatment. The amount desired or required may vary depending on the particular oligonucleotide or combination of oligonucleotides used, the mode of administration, patient specifics and the like. Appropriate effective amounts can be determined by one of ordinary skill in the art informed by the instant disclosure using routine experimentation. For example, a therapeutically effective amount, e g., a dose, can be estimated initially either in cell culture assays or in animal models.
- An animal model can also be used to determine a suitable concentration range, and route of administration.
- a precise dosage can be selected by in view of the patient to be treated. Dosage and administration can be adjusted to provide sufficient levels of components to achieve a desired effect. Factors which may be taken into account include the type of condition, the age, weight and gender of the patient, desired duration of treatment, method of administration, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy.
- a therapeutically effective amount is an amount that reduces one or more signs or symptoms of a disease, and/or reduces the severity of the disease. A therapeutically effective amount may also inhibit or prevent the onset of a disease, or a disease relapse.
- the individual in need of a described oligonucleotide has any condition that is associated with type I interferon induced inflammation, including but not necessarily limited to an autoimmune disorder or a type I interferon induced inflammation that is associated with a pathology of the cardiovascular system of the indivdiual.
- type I interferon induced inflammation is associated with or causes a type I interferonopathy.
- type I interferon induced inflammation is associated with a hyperactive type I interferon (IFN) response.
- IFN hyperactive type I interferon
- the individual in need of a described oligonucleotide has an autoimmune disorder that is any of Systemic lupus erythematosus (SLE), psoriasis, type I diabetes, rheumatoid arthritis, Sjbgrens syndrome, dermatomyositis, Aicardi-Goutieres Syndrome, Familial chilblain lupus, STING-associated vasculopathy spastic paraparesis, Singleton-Merten syndrome, Trichohepatoenteric syndrome, infantile encephalopathy, ataxia telangiectasia, Bloom syndrome, common variable immunodeficiency, or proteasome- associated autoinflammatory syndrome.
- SLE Systemic lupus erythematosus
- psoriasis psoriasis
- type I diabetes rheumatoid arthritis
- Sjbgrens syndrome dermatomyositis
- Aicardi-Goutieres Syndrome Familial
- the individual in need of a described oligonucleotide has type I interferon induced inflammation that is associated with pathology of the cardiovascular system, such as comprises heart failure.
- the heart failure has been induced by treating the individual with interferon-0, e.g., of iatrogenic origin, or of unknown origin, or is a sepsis-induced cardiomyopathy.
- the individual does not have a condition associated with cholesterol efflux or high-density lipoprotein (HDL) biogenesis. In embodiments, the individual does not have a disorder that is associated with elevated cholesterol, or cholesterol homeostasis. In embodiments, the individual who is treated with a described oligonucleotide is not also treated with an inhibitor or any other non-coding RNA, including but not necessarily limited to miR-33.
- HDL high-density lipoprotein
- the described oligonucleotides are provided in the form of a pharmaceutical formulation.
- a pharmaceutical formulation can be prepared by mixing the compound(s) with any suitable pharmaceutical additive, buffer, and the like.
- suitable pharmaceutical additive for example, any suitable pharmaceutical additive, buffer, and the like.
- pharmaceutically acceptable carriers, excipients and stabilizers can be found, for example, in Remington: The Science and Practice of Pharmacy (2020) 23rd Edition, Academic Press, the disclosure of which is incorporated herein by reference.
- a described ASO is used with nanoparticles, including but not necessarily limited to liposomal formulations.
- Administration of pharmaceutical formulations comprising the described oligonucleotides of this disclosure can be performed using any suitable route of administration, including but not limited to parenteral, intraperitoneal, and oral administration.
- Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, and subcutaneous administration.
- a single administration is administered and is sufficient for a therapeutic response.
- more than one administration is provided.
- only a single administration is used.
- only one, or only a combination of oligonucleotides described herein are used in a described method.
- a described oligonucleotide or combination of described oligonucleotides may be the only therapeutic agent(s) used in a described method.
- one or more described oligonucleotides may be combined with standard anti-inflammatory agents, such as anti-inflammatory steroids, selective or non- selective non-steroidal anti-inflammatory drugs (NSAIDs), and the like.
- standard anti-inflammatory agents such as anti-inflammatory steroids, selective or non- selective non-steroidal anti-inflammatory drugs (NSAIDs), and the like.
- LncRNA CHROMR associates with the interferon response in patients with COVID-19 and influenza
- CHROMR When compared to other human IncRNAs known to regulate antiviral responses 19 - 22) , CHROMR showed a distribution of correlation coefficients equivalent to BISPR (lncBST2) and significantly higher than NRIR, CCR5AS, LUCAT1 an MALATl (Fig. ID). Of these IncRNAs, only CHROMR showed an equivalent transcriptional response to both viral infections (Fig. 1C). To further visualize the association of CHROMR with ISGs differentially expressed after influenza A or COVID-19 infection, we rank-ordered the ISGs by level of differential expression in influenza A-infected patients and plotted their correlation coefficient with CHROMR.
- RNA-seq data from human monocyte-derived macrophages infected with A/California/04/09 (H1N1), influenza A/Wyoming/03/03 (H3N2) or influenza A/Vietnam/1203/2004 (H5N1) HaLo viruses (retrieved from (23) ).
- H1N1 human monocyte-derived macrophages infected with A/California/04/09
- H3N2 influenza A/Wyoming/03/03
- influenza A/Vietnam/1203/2004 H5N1 HaLo viruses
- transcript levels of several IFN-induced chemokines were reduced in CHROMR depleted macrophages treated with poly(I:C), including members of the CXCL (CXCL10, CXCL1I) and CCL (CCL2) families, which was further validated at the protein level by beadbased immunoassay (Fig. 2F).
- a similar downregulation of ISGs was observed in CHROMR- depleted macrophages treated with bacterial lipopolysaccharide (LPS) (Fig. 6D-H and Extended Data Table 4).
- CHROMR overexpression of CHROMR in THP-1 macrophages increased expression of ISGs, including CXCL 10, IFIT1, IFITM1, IF1TM3, MX1, MX2, OAS1, OAS2, STAT1, and ISG15 (Fig. 2G and Fig. 6C and Extended Data Table 5), as assessed using a qPCR array to profile 84 selected ISGs.
- IRF-1 Interferon Regulatory Factors
- IRF-7 Interferon Regulatory Factors
- STAT Signal Transducers and Activators of Transcription
- THP-1 macrophages were treated with Gw CHROMR or GapCTRL, and challenged with influenza A/WSN/1933 (H1N1) at increasing doses of 100, 500 or 1000 plaque forming units (PFU) per well for multi-cycle replication.
- CHROMR knockdown significantly increased IAV infection levels in G pCHROMR- compared to GapCTRL-treated macrophages, suggesting an important role for CHROMR in restricting IAV infection (Fig. 3A and Fig. 7Q.
- CHROMR associates with chromatin and shapes H3K27Ac at ISG regulatory regions
- CHROMR is known to regulate lipid metabolism by sequestering microRNAs in the cytoplasm f20) , we performed in silico analyses to predict microRNA regulators of the ISGs differentially expressed upon ("7// GA7/ -knockdown (Fig. 7A). miR-21 and miR-184 were identified as putative repressors of genes whose expression was reduced in Ga ⁇ CHROMR- compared to GapCTRL treated macrophages, however, CHROMR lacks binding sites for these microRNAs, suggesting an alternative mechanism of gene regulation. Cell fractionation studies revealed that CHROMR localizes to the nucleus as well as the cytoplasm of macrophages (Extended Data Table 4).
- Chromatin Interaction Analysis by Paired-End Tag Sequencing which combines chromatin immunoprecipitation (ChlP)-based methods, chromatin proximity interaction and chromosome conformation capture (3C) revealed weak interactions between CHROMR and its neighboring genes, including the PRKRA gene that encodes Protein ACTivator of the interferon-induced protein kinase PKR (PACT), which binds dsRNA and activates RIG-I- mediated antiviral signaling (Fig. 8Z) and E).
- PACT Protein ACTivator of the interferon-induced protein kinase PKR
- Fig. 8Z RIG-I- mediated antiviral signaling
- H3K27Ac histone H3 lysine 27 acetylation
- H3K27Ac Classification of the H3K27Ac peak distribution among genomic features showed that the depletion of H3K27Ac marks after CHROMR knockdown occurred mainly in promoter regions (66%), followed by distal intergenic and intronic regions (Fig. 3E).
- GREAT Annotations Tool
- H3K27Ac helps shape active promoters and enhancers by opening chromatin to allow binding of transcriptional regulators.
- HOMER Motif EnRichment
- CHROMR binds IRF-2 binding protein 2
- IRF2BP2 Interferon Regulatory Factor-2 Binding Protein 2
- siRNA-mediated knockdown of endogenous IRF2BP2 or IRF-2 inhibited infection with influenza A/WSN/1933 (H1N1) compared to control siRNA treatment in THP-1 macrophages (Fig. AD).
- the CHROMR and IRF2BP2 interaction was confirmed by RNA immunoprecipitation, which showed that CHROMR was enriched in IRF2BP2 immunoprecipitates compared to IgG controls (Fig. AE).
- RNA fluorescence in situ hybridization for CHROMR with immunofluorescence for IRF2BP2 in THP-1 macrophages and observed nuclear colocalization Fig. 4 ).
- CHROMR is not conserved in common preclinical animal models used to study antiviral immunity, whereas the present disclosure includes analysis of human responses.
- HEK293T and THP-1 cell lines were obtained from ATCC and the NF-KB- SEAP and IRF-Lucia luciferase Reporter Monocytes (THP-l-Dual cells) were obtained from InvivoGen. All cell lines were authenticated using standard ATCC methods (morphology check by microscope, growth curve analysis) and tested monthly for mycoplasma contamination.
- HEK293T were maintained in high-glucose DMEM (Corning) supplemented with 10% fetal bovine serum (FBS, Life Technologies) and 1% penicillin/streptomycin (P/S, Life Technologies).
- THP-1 cells were maintained in RPMI 1640 (ATCC) supplemented with 10% FBS and 1% P/S.
- THP-1 -Dual cells were maintained in RPMI 1640 supplemented 10% FBS, 1% P/S, and 50 pg/mL of Normocin (InvivoGen). THP-l-Dual cells were cultured with selectable marker Zeocin (100 pg/mL, InvivoGen) every other passage to maintain stable integration of inducible reporter constructs. THP-1 cells and THP-l-Dual Cells were differentiated into macrophages in the presence of 100 nM phorbol-12-myristate acetate (PMA, Sigma) for 48-72h.
- PMA phorbol-12-myristate acetate
- Transient knockdown of CHROMR was acquired as follows; PMA- differentiated THP-1 cells or PMA-differentiated THP-l-Dual cells were transfected with 62.5 nM locked nucleic acid GapmeRs (Qiagen) targeting a common region of all CHROMR variants (Ga CHROMR) or Negative Control A (GapCTRL) using Lipofectamine RNAiMax (Life Technologies) as described (20) . Cffl?OA77?3-overexpressing THP-1 cells were created as described (20) , and cultured under selection pressure puromycin (5 pg/mL, Thermo Fisher Scientific) to maintain purity.
- IRF2 and IRF2BP2 were acquired by transfecting 100 nM siRNA directed against IRF2 (Qiagen, GS3660) or IRF2BP 2 (Qiagen, GS359948) using Lipofectamine RNAiMax into THP-1 macrophages, Allstars Negative Control (Qiagen, 1027280) was used control.
- RNA isolation, cell fractionation and qPCR Total RNA was isolated using TRIzol reagent (Invitrogen) and Direct-zol RNA MicroPrep columns (Zymo Research). For cell fractionation experiments RNA was isolated from separate cytoplasmic and nuclear fractions using the PARIS kit (Thermo Fisher Scientific). Upon isolation, RNA was reverse transcribed using i Script cDNA Synthesis kit (Bio-Rad Laboratories) and quantitative PCR analysis was conducted using KAPA SYBR green Supermix (KAPA Biosystems) according to the manufacturer’s instructions and quantified on Quantstudio 3 (Applied Biosystems). Fold change in mRNA expression was calculated using the comparative cycle method (2 -AACt ) normalized to the housekeeping gene GAPDH. A list of primers used in this study can be found in Extended Data Table 6
- THP-1 macrophages or GapmeR-treated THP-1 macrophages with either 100-500 ng/mL lipopolysaccharide (LPS, Invivogen), 1 pg/mL polyinosinic:polycytidylic acid (poly(I:C), Invivogen), influenza A virus/WSN/1933 (H1N1) or vehicle control for indicated time periods. After treatment RNA was isolated and analyzed.
- LPS lipopolysaccharide
- poly(I:C) polyinosinic:polycytidylic acid
- H1N1 influenza A virus/WSN/1933
- RNA-sequencing RNA was isolated from THP-1 macrophages treated with ( 7// OA// -targeting GapmeRs or negative control and subsequently stimulated with 500 ng/mL LPS or 1 pg/rnL poly(LC) (InvivoGen) for indicated times. RNA was used to generate barcoded cDNA libraries using the TruSeq RNA Sample Preparation kit (Illumina). Indexed libraries were pooled and sequenced (paired-end 50 or 100 bp reads) on the Illumina HiSEQ platform. RNA-seq reads were aligned using the STAR Aligner against hg38 annotations. Gene counting was done using featureCounts.
- RNA-seq data are deposited in the GEO under the accession number GSE190413.
- THP-1 macrophages transiently knocked down for CHROMR were infected with 100, 500 or 1000 plaque forming units (PFU, as determined on MDCK cells) of influenza A/WSN/1933 (H1N1) virus.
- the virus inoculate was diluted in DPBS supplemented with calcium and magnesium. Cell growth media was replaced by virus dilution and incubated for Ih at 37°C and 5% CO2. After Ih, the virus was aspirated, RPMI 1640 with 20% FBS was added to the cells, and cells were incubated at 37°C and 5% CO2.
- the cells were fixed with 8% paraformaldehyde (Thermo Fisher Scientific), quenched with 50 mM NH4Q and washed with PBS.
- Cells were stained with a monoclonal mouse anti-NP antibody (Sigma, MAB8251) followed by anti-mouse Alexa 488 secondary antibody (Thermo Fisher Scientific, R37120) and nuclear staining (4',6-diamidino-2-phenylindole (DAPI, Sigma). Cells were washed with PBS leaving the last wash on before imaging. Plates were imaged using the Cell-Insight CX7 high-content screening platform. Images were analyzed and quantified with HCS Navigator software for total and infected cell numbers.
- THP-l-Dual reporter assay THP-l-Dual cells were differentiated towards macrophages using PMA and subsequently transfected with GapmeRs targeted CHROMR or a GapmeR control as described above, 24h post-transfection the THP-l-Dual cells were treated with 1 pg/mL poly(I:C). Supernatants were taken on indicated time points and activation of NF-KB was measured by detecting secreted alkaline phosphatase (SEAP) using Quanti-Blue (InvivoGen); activation of the Interferon Regulatory Factor (IRF) at the ISRE was measured by detecting luciferase levels in the supernatants using Quanti-Luc (InvivoGen). Detected levels of SEAP and luciferase at the start of the experiment (Oh) were set to 100%.
- SEAP secreted alkaline phosphatase
- IRF Interferon Regulatory Factor
- Nuclear pellets were isolated by swelling cross-linked cells in hypotonic lysis buffer (25 mM HEPES pH 7.4, 1.5 mM MgCh, 10 mM KC1, 0.5% NP-40 and 1 mM DTT) supplemented with lx HALT protease inhibitor cocktail (Promega) on ice for 15 min, followed by dounce homogenization. Nuclear pellets were suspended in sonication buffer (50 mM HEPES pH 7.4, 140 mM NaCl, 1 mM EDTA, 1% Triton-X 100, 0.1% sodium deoxycholate, 0.5% SDS, 1 mM DTT and lx protease inhibitor cocktail) and incubated at ice for 10 min.
- hypotonic lysis buffer 25 mM HEPES pH 7.4, 1.5 mM MgCh, 10 mM KC1, 0.5% NP-40 and 1 mM DTT
- lx HALT protease inhibitor cocktail Promega
- Nuclear extracts were sonicated using Bioruptor UCD-200 (Diagenode Inc.) for 10 x 1 min cycles of “30 sec ON / OFF” at the highest voltage setting to generate 200 - 500 bp chromatin fragments.
- chromatin was first processed by agarose gel electrophoresis to confirm DNA shearing to 200 - 500 bp fragments, and the DNA concentration was measured by NanoDrop 2000.
- Equal quantities of sheared chromatin (10 pg per immunoprecipitation) were diluted 1 :5 in sonication buffer to the final volume of 1 mb, and immunoprecipitated overnight with 1 pg antibody targeting human histone H3K27Ac (Active Motif, 39685) or isotype control IgG antibody (Sigma, 12-370) at 4°C overnight.
- Chromatin complexes were captured using 20 pL Dynabeads protein G (Invitrogen) at 4°C for Ih.
- Beads were washed once with sonication buffer (containing 0.1% SDS), two times with high salt buffer (50 mM HEPES pH 7.4, 500 mM NaCl, 1 mM EDTA, 1% Triton-X 100, 0.1% sodium deoxycholate, 0.1% SDS), two times with LiCl buffer (20 mM Tris pH 7.4, 250 mM LiCl, 1 mM EDTA, 0.5% NP-40, 0.1% sodium deoxycholate, 0.05% Tween-20), and once with Tris-EDTA buffer (10 mM Tris pH 7.4, 1 mM EDTA). Each wash was performed at room temperature for 5 min in 1 m volume. Beads were captured using DynaMag magnet (Thermo Fisher Scientific).
- Chromatin immunoprecipitation (ChIP) eluates were reverse cross-linked at 65°C for 4h, digested with proteinase K (Thermo Fisher Scientific, 10 pg/mL) at 55°C for Ih and 2 pL RNase cocktail (Ambion) at 37°C for 30 min.
- Chromatin immunoprecipitation (ChIP) eluates were reverse cross-linked at 65°C for 4h, digested with proteinase K (Thermo Fisher Scientific, 10 pg/mL) at 55°C for Ih and 2 pL RNase cocktail (Ambion) at 37°C for 30 min.
- ChlP-sequencing ChIP purified DNA was cleaned using PCR purification columns (Qiagen) and subjected to Illumina sequencing. Next, the overall quality of the sequenced ChlP-seq libraries was assessed with FastQC (41) . To remove contaminating sequencing adapters and low-quality bases, reads were trimmed using Fastp (4S) . FastQC was run again on the trimmed reads to analyze the global impact of trimming. Reads were then aligned to the human genome (hg38) using Bowtie2 (49) . Alignments were sorted and indexed using Samtools for downstream processes (50) . MACS2 was then used to identify significant peaks (51) . Peaks with a Q-value of less than 0.05 were retained.
- ChlP-seq peak quality and reproducibility Custom scripts and the ChlPQC R package were used to assess ChlP-seq peak quality and reproducibility (52) . Peaks present in all replicates from each condition were retained for differential enrichment analysis. Peaks were annotated using ChlPseeker package from Bioconductor (53) . Peaks that overlapped a 4kb window centered at an annotated transcription start site were annotated as promoter peaks. Differential enrichment analysis was performed using DiffBind package from Bioconductor (54) . Peaks with a false discovery rate (FDR-)adjusted P-value of 0.1 or less were considered differentially enriched between the knockdown and control conditions.
- FDR- false discovery rate
- Chromatin Isolation by RNA Precipitation (ChIRP).
- Cell harvesting, lysis, disruption, and chromatin isolation by RNA purification were performed as previously described (57) with the following modifications: (1) Cells were cross-linked in 3% formaldehyde for 30 min, followed by 0.125 M glycine quenching for 5 min; (2) Hybridization was performed for 16h; (3) For mass spectrometry (MS) experiments, lysates were pre-cleared by incubating with 30 mL washed beads per mL of lysate at 37°C for 30 min with mixing; (4) As a negative control, lysates were pooled and aliquoted into equal amounts and RNA was removed by incubating with RNase A (1 pg/mL, Sigma), and subsequent incubation at 37°C for 30 min prior to hybridization steps.
- MS mass spectrometry
- RNA, DNA, protein isolation was performed as described (57) and further detailed below for ChIRP followed by DNA-seq (ChIRP-seq) or Comprehensive Identification of RNA-binding Proteins by Mass Spectrometry (ChIRP-MS). RNA extraction was performed for validation of IncRNA enrichment. A list of probes used in this study can be found in Extended Data Table 6.
- ChIRP followed by DNA-seq (ChIRP-seq).
- DNA was eluted from hybridized magnetic beads and subjected for Illumina sequencing. In short, beads were washed at room temperature with ChIRP wash buffer (EMD Millipore, #17-10494). Beads were subsequently captured using a DynaMag magnet (Thermo Fisher Scientific) and DNA was eluted by suspending beads in elution buffer (20 mM Tris pH 7.4, 1% SDS, 50 mM NaHCO3, 1 mM EDTA).
- ChIRP eluates were reverse cross-linked at 65°C for 4h, digested with Proteinase K (EMD Millipore) at 55°C followed by incubation with RNase cocktail (Ambion).
- ChIRP purified DNA was cleaned using PCR purification columns (Zymo Research) and subjected to Illumina sequencing. Reads were trimmed using Trimm omatic (58) and mapped to hgl9 using BWA (59) . Peaks were then called for each probe set and replicate using the ‘callpeak’ function from MACS2 (51) relative to the input from the same replicate. Peaks were then imported into the DiffBind package from Bioconductor (54) and differential peaks were called between even and odd probe sets.
- ChIRP-seq data are deposited in the GEO under the accession number GSE190413
- Chromatometry Chromatomeroscopy (ChIRP-MS). Protein was isolated from magnetic beads and analyzed by MS. To elute protein beads were collected on magnetic stand, resuspended in biotin elution buffer (12.5 mM D-biotin (Thermo Fisher Scientific), 7.5 mM HEPES pH 7.5, 75 mM NaCl, 1.5 mM EDTA, 0.15% SDS, 0.075% sarkosyl, and 0.02% sodium deoxy cholate). Trichloroacetic acid (25% of total volume) was added to the clean eluent and proteins were precipitated at 4°C overnight.
- biotin elution buffer 12.5 mM D-biotin (Thermo Fisher Scientific)
- 7.5 mM HEPES pH 7.5, 75 mM NaCl 1.5 mM EDTA
- SDS 0.075% sarkosyl
- 0.02% sodium deoxy cholate sodium deoxy cholate
- Proteins were pelleted at 16,000 g at 4°C for 30 min, washed with cold acetone and pelleted again at 16,000 g at 4°C for 5 min. Proteins were immediately solubilized in desired volumes of Laemmli sample buffer (Invitrogen) and boiled at 95°C for 30 min with occasional mixing to reverse crosslinking. Final protein samples were size- separated in Bis-Tris SDS-PAGE gels (Invitrogen) and submitted for MS analysis by the Proteomics Laboratory at NYU Langone Health. Individual samples were subjected to liquid chromatography (LC) separation with MS using the autosampler of an EASY-nLC 1000 (Thermo Fisher Scientific).
- LC liquid chromatography
- peptides were gradient eluted from the column directly to Q Exactive mass spectrometer using a Ih gradient (Thermo Fisher Scientific).
- High resolution full MS spectra were acquired with a resolution of 70,000, an AGC target of 1 x 10 6 , with a maximum ion time of 120 ms, and scan range of 400 to 1,500 m/z.
- Twenty data-dependent high resolution HCD MS/MS spectra were acquired. All MS/MS spectra were collected using the following instrument parameters: resolution of 17,500, AGC target of 5 x 10 4 , maximum ion time of 120 ms, one microscan, 2 m/z isolation window, fixed first mass of 150 m/z, and NCE of 27.
- RNA Immunoprecipitation Human histone H3, IRF2BP2, and HNRPNLL were immunoprecipitated from PMA-differentiated THP-1 macrophages.
- RNA Fluorescence In situ Hybridization Custom Stellaris® FISH Probes were designed against CHROMR utilizing the Stellaris® FISH Probe Designer (LGC Biosearch Technologies). Formaldehyde-fixed THP-1 macrophages were permeabilized with 70% isopropanol and subsequently simultaneously hybridized with the CHROMR Stellaris® FISH Probe set labeled with Quasar® 670 Dye (LGC Biosearch Technologies) and a rabbit polyclonal antibody against IRF2BP2 (Atlas Antibodies, HPA062269), following the manufacturer’s protocol. IRF2BP2 was visualized using fluorescent goat anti-rabbit secondary antibodies (Thermo Fisher Scientific, A-21206) and DAPI was used to visualize nuclear DNA.
- human IRF2BP2, CHR0MR3 and CHROMR3-G4mv4 were overexpressed in HEK293T cells using plasmids overexpressing a MYC/DDK tagged IRF2BP2 (OriGene Technologies, RC213250) and plasmids overexpressing CHR0MR3 and CHROMR3-G4mv4 using Lipofectamine 2000 (Thermo Fisher Scientific).
- Antibodies directed against MYC/DDK (OriGene Technologies, TA50011) or an isotype matched control antibody (Sigma, 12-370) were used in immunoprecipitations as described above.
- RNAfold part of The Vienna RNA Websuite (64) , was used to predict the minimum free energy secondary structure of CHR0MR3 and the RNA plot was created with RNArtist, developed by Fabrice Jossinet and available at github.com/ljossinet/RNArtist
- Robust third-order polynomial non-linear regression was used to assess distribution of IncRNA x ISG correlation coefficient in function of differential expression in influenza A infection to minimize outlier impact.
- RNA-seq normalized transcript data were logip-transformed to normalize distribution for partial correlation analysis. Partial correlation analysis was used to control for CHROMR expression as a covariate within ISG x ISG associations. Pearson and partial correlation coefficients were compared by Fisher-r-to-Z transformation followed by Z-test.
- top canonical pathways and top upstream regulators are calculated in Ingenuity Pathway Analysis by a right-tailed Fisher’s exact test. Enrichr, GREAT and HOMER use a binomial test to calculate significant enrichment in biological process or motif enrichment, respectively.
- Statistical analyses were performed using GraphPad Prism software, bivariate and partial correlation analyses were performed in R studio. Threshold for statistical significance was P ⁇ 0.05. All quantitative data are presented as mean ⁇ standard error of the mean (sem).
- ASO_7/1 designed against the first GG-pair, was able to decrease ISG expression in the presence of IFNP (Fig. I la). Neither ASOs designed against the neighboring GG-pairs, nor a non-targeting control ASO had any effect on ISG expression.
- the use of ASO_7/1 did not induce changes in CHROMR transcript expression in the presence of absence of IFNP, although IFNP did induce an increase in CHROMR expression (Fig. l ib).
- ASO_13/1 designed against the 1 st and 2 nd GG-pair was also efficient at reducing IFN0-induced ISG expression, while ASOs against the neighboring GG-pairs were not (Fig. 12a).
- RNA-immunoprecipitation in human embryonic kidney (HEK293T) cell (Fig.14a).
- IRF2BP2 IP led to a 30-fold enrichment of CHROMR after overexpression relative to a control empty vector (EV; Fig.14b).
- transfection of CA/ V/A-expressing HEK293T cells with ASO_7/1 (Fig.14c-d) or ASO_13/1 (Fig.l4e-f) reduced the binding of CHROMR to IRF2BP2 by ⁇ 75% compared to a non-targeting control ASOs.
- Fig.15a To demonstrate the role of IncRNA CHROMR in licensing inflammation, we transfected freshly isolated atherosclerotic carotid explants (3mm 2 ) obtained from subjects undergoing carotid endarterectomy with a CHROMR overexpression vector. CHROMR ovexpression resulted in significant production of pro-inflammatory cytokines compared to a control empty overexpression vector (Fig.15b). To test the effect of a reduction in CHROMR expression on inflammation, ASO_Gap/3 was used in the presence of TLR-3 agonist poly(I:C) to induce a type I IFN response, which resulted in a significant reduction in proinflammatory cytokine production compared to its non-targeting control ASOs (Fig.15c). CHROMR’ s G-quadrupl ex-targeting ASO_7/1 had a similar effect under identical conditions (Fig.l5d).
- RNA LUCAT1 is a negative feedback regulator of interferon responses in humans. Nat Commun 11, 6348 (2020).
- SARS-CoV-2 requires cholesterol for viral entry and pathological syncytia formation. Elife 10 (2021).
- Table 2 List of ASO sequences (DNA, 5’-3’) that have been tested for their ability to inhibit interferon-stimulated gene expression. The highlighted ASOs (bold) showed efficacy whether via containing the 5’-CCCCCAT-3’ DNA sequence or by causing degradation of CHROMR (ASO_Gap_3). Abbreviations: Interferon-stimulated gene (ISG).
- Table 4 List of all possible ASO sequences (DNA, 5 ’-3 ’) of 7 to 20 nucleotides in length and containing the 5’-CCCCCAT-3’ DNA sequence that have shown efficacy. These sequences were designed to allow flexibility in designing flapping sequences to enhance specificity. Sequences highlighted (bold) were experimentally shown to be efficient in reducing interferon-stimulated gene expression. Abbreviations: nucleotides (nts) [0089] Extended Data Table 1. Demographics of COVID-19 Whole Blood RNA- Seq cohort
- Extended Data Table 3 Genes differentially expressed in THP-1 macrophages treated with GapCHROMR versus GapCTRL after poly(I:C) stimulation for 8h.
- IER2 1.15 1.59E-12 SERP1NB8 1.03 1.67E-12 ICOSLG -1.21 1.73E-12 PDGFRB 1.54 1.74E-12 CENPF -1.19 1 84E-12 IDP2 -1.71 2.25E-12 TLDC2 -1.14 2.50E-12 FYB -1.96 3.05E-12 TOMM34 1.03 3.16E-12 FILIP IL -1.17 4.70E-12 LDLR 1.71 5.17E-12 MMS22L -1.41 5.57E-12 GBP4 -1.44 6.67E-12 SASH3 -1.29 6.68E-12 LINC00941 1.75 6.81E-12 RHOU -1.47 7.17E-12 RARG 1.09 7.17E-12 CYP27A1 -1.24 7.25E-12 HS3ST3A1 1.26 7.25E-12 GAB2 -1.17 7.68E-12 MGAT4A -1.32 8.01E-12 POLQ -1.54 1.01E-11 SNX2 -1.07
- LDHAL6B 1.12 1.41E-02 MMP10 1.18 1.43E-02 CNN3 1.1 1.46E-02 LOC100288798 -2.41 1.47E-02 AMIGO2 1.28 1.47E-02 HESX1 -2.86 1.52E-02 LOC729683 1.09 1.54E-02 GBP IP 1 -2.31 1.54E-02 LOC202181 -1.14 1.58E-02 HSPA4L -1.09 1.61E-02 ZNF630 -3.42 1.65E-02 CDCA7 -1.05 1.67E-02 PAPPA 1.36 1.68E-02 CDH13 1.17 1.72E-02 HMMR-AS1 -3.09 1.73E-02 DNAH17-AS1 -1.2 1.76E-02 CTGF 1.4 1.80E-02 LOC641367 -1.83 1.81E-02 PTGER3 1.46 1.81E-02 MGC39584 -2.72 1.84E-02 PSMD6-AS2 -1.01 1.
- ARSJ 1.45 4.13E-02 TMOD2 -1.19 4.16E-02 PRICKLE2 1.63 4.16E-02 HSPA6 -1.75 4.24E-02 TGFB3 1.54 4.27E-02 LOC101928766 2.08 4.27E-02 NR4A1 -1.59 4.30E-02 KLLN -1.48 4.30E-02 RAB3B 1.14 4.32E-02
- EPB41L4B 1.52 4.34E-02 ZNF485 -1.52 4.35E-02 FRMD5 -1.13 4.37E-02 CCL20 1.25 4.41E-02 LINC00702 1.71 4.44E-02 FPR3 -1.88 4.45E-02 PDE10A 2.38 4.45E-02 NOXA1 -2.32 4.51E-02 MIR7848 -2.51 4.52E-02
- Extended Data Table 4 Genes differentially expressed in THP-1 macrophages treated with GapCHROMR versus GapCTRL after LPS stimulation for 3h.
- WTAPP1 1.93 1.11E-05 FAM26E -1.08 1.14E-05 NEXN -1.17 1.28E-05 KRBA1 1.13 1.33E-05 CCR7 -1.04 1.47E-05 FRMD3 -1.28 1.95E-05 SRPX -1.53 1.95E-05
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Abstract
L'invention concerne des compositions et des méthodes de prophylaxie ou de traitement d'un trouble associé à une inflammation induite par l'interféron de type I. Les compositions impliquent l'utilisation d'un agent qui inhibe la fonction et/ou réduit le niveau de long régulateur de l'homéostasie du cholestérol à ARN non codant de l'ARN d'expression de micro-ARN (CHROMR ARNlnc) chez l'individu pour ainsi réduire la gravité de l'inflammation induite par l'interféron de type I. Les agents sont fournis sous forme d'oligonucléotides antisens.
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WO2006110688A2 (fr) * | 2005-04-08 | 2006-10-19 | Nastech Pharmaceutical Company Inc. | Arni therapeutique pour infection virale respiratoire |
WO2009024834A2 (fr) * | 2006-12-05 | 2009-02-26 | Rosetta Genomics Ltd | Acides nucléiques impliques dans les infections virales |
US20170327577A1 (en) * | 2014-06-06 | 2017-11-16 | The California Institute For Biomedical Research | Methods of constructing amino terminal immunoglobulin fusion proteins and compositions thereof |
WO2022147209A1 (fr) * | 2020-12-31 | 2022-07-07 | Dyne Therapeutics, Inc. | Complexes de ciblage musculaire et utilisations associées pour le traitement de la dystrophie myotonique |
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WO2006110688A2 (fr) * | 2005-04-08 | 2006-10-19 | Nastech Pharmaceutical Company Inc. | Arni therapeutique pour infection virale respiratoire |
WO2009024834A2 (fr) * | 2006-12-05 | 2009-02-26 | Rosetta Genomics Ltd | Acides nucléiques impliques dans les infections virales |
US20170327577A1 (en) * | 2014-06-06 | 2017-11-16 | The California Institute For Biomedical Research | Methods of constructing amino terminal immunoglobulin fusion proteins and compositions thereof |
WO2022147209A1 (fr) * | 2020-12-31 | 2022-07-07 | Dyne Therapeutics, Inc. | Complexes de ciblage musculaire et utilisations associées pour le traitement de la dystrophie myotonique |
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VAN SOLINGEN COEN, SCACALOSSI KAITLYN R, DE VRIES MAREN, AFONSO MILESSA, FANUCCHI STEPHANIE, KHER RAADHIKA, PELED DANIEL, BURKE AM: "Abstract 247: LNCRNA CHROME Regulates the Interferon Response to Microbial Challenge", ARTERIOSCLEROSIS, THROMBOSIS, AND VASCULAR BIOLOGY, vol. 40, 29 June 2020 (2020-06-29), XP093136257 * |
VAN SOLINGEN COEN, YANNICK CYR, KAITLYN R. SCACALOSSI, MAREN DE VRIES, TESSA J. BARRETT, ANNIKA DE JONG, MORGANE GOURVEST, TRACY Z: "Long noncoding RNA CHROMR regulates antiviral immunity in humans", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, NATIONAL ACADEMY OF SCIENCES, vol. 119, no. 37, 24 August 2021 (2021-08-24), pages 2210321119, XP093136343, ISSN: 0027-8424, DOI: 10.1073/pnas.2210321119 * |
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