{"gene":"SRA1","run_date":"2026-06-10T07:46:41","timeline":{"discoveries":[{"year":1999,"finding":"SRA functions as a non-coding RNA coactivator (not a translated protein) that selectively enhances steroid hormone receptor transactivation via their amino-terminal AF-1 activation function; it resides in distinct ribonucleoprotein complexes, one containing SRC-1. Evidence: SRA functions in presence of cycloheximide and retains activity with multiple translational stop codon mutations.","method":"Transient transfection with cycloheximide treatment, translational stop-codon mutagenesis, biochemical fractionation, co-immunoprecipitation","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (cycloheximide resistance, stop-codon mutagenesis, biochemical fractionation, Co-IP) in original discovery paper, widely replicated","pmids":["10199399"],"is_preprint":false},{"year":2002,"finding":"Distinct RNA structural motifs within the SRA molecule are required for its coactivation function; six RNA motifs important for coactivation were identified by systematic mutagenesis using silent mutations that do not alter encoded amino acid sequence, providing strong evidence SRA acts as an RNA transcript rather than a protein.","method":"Comparative sequence analysis, free energy calculations, site-directed mutagenesis, genetic deletion analysis, transient transfection reporter assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution with systematic mutagenesis, silent mutations confirm RNA-based mechanism, multiple orthogonal approaches","pmids":["12444263"],"is_preprint":false},{"year":2001,"finding":"SRA associates with estrogen receptor alpha (ERα) coactivator complexes containing SRC-1/TIF2 family proteins, CBP/p300, and the RNA-binding DEAD-box proteins p72/p68; p72/p68 interact with both the AD2 domain of SRC-1/TIF2 and the ERα A/B domain, and all co-immunoprecipitate with estrogen-bound ERα in MCF7 cells.","method":"Co-immunoprecipitation from MCF7 cells and HeLa nuclear extracts, co-localization by immunofluorescence, transient transfection reporter assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP from endogenous complex plus functional reporter assays, replicated across multiple labs","pmids":["11250900"],"is_preprint":false},{"year":2003,"finding":"SRA coactivation of ERα AF-1 requires an intact serine 118 (S118) residue; MAPK activation enables ligand-independent coactivation of ERα by SRA through the AF-1 domain in a mechanism independent of AF-2. SRA differentially activates ERα vs. ERβ through their respective AF-1 domains.","method":"Transient transfection reporter assays, site-directed mutagenesis of S118, H-Ras(V12) activation of MAPK pathway","journal":"The Journal of steroid biochemistry and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis plus gain-of-function signaling experiments, single lab","pmids":["12943696"],"is_preprint":false},{"year":2004,"finding":"SLIRP (SRA stem-loop interacting RNA binding protein) binds the functional SRA substructure STR7 via an RNA recognition motif (RRM) and represses nuclear receptor transactivation in a SRA- and RRM-dependent manner; SLIRP modulates the association of SRC-1 with SRA, is recruited to endogenous promoters in a SRA-dependent manner, and recruits NCoR.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, RRM mutagenesis, reporter assays, subcellular fractionation","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, ChIP, mutagenesis, reporter assays) in single rigorous study with clear mechanistic outcome","pmids":["16762838"],"is_preprint":false},{"year":2006,"finding":"RNA helicases p68/p72 and non-coding SRA RNA are coactivators of MyoD and required for skeletal muscle differentiation; p68/p72 promote assembly of TBP, RNA polymerase II, and the Brg-1 ATPase subunit of SWI/SNF at muscle gene promoters and facilitate chromatin remodeling. RNAi against p68/p72 or SRA prevents muscle gene activation and differentiation.","method":"Co-immunoprecipitation with MyoD, RNA interference, chromatin remodeling assays, ChIP, reporter assays","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP demonstrating association, RNAi loss-of-function with defined molecular phenotype (ChIP, chromatin remodeling), multiple orthogonal methods","pmids":["17011493"],"is_preprint":false},{"year":2009,"finding":"SRA RNA functions as a coactivator for steroidogenic factor 1 (SF-1) in steroidogenesis; both SF-1 and Dax-1 bind SRA, and coactivation by Dax-1 is abolished by SRA knockdown. Knockdown of endogenous SRA reduces expression of steroidogenic gene products StAR and melanocortin 2 receptor in adrenal Y1 cells.","method":"Co-immunoprecipitation, siRNA knockdown of endogenous SRA, reporter assays, RT-PCR for steroidogenic genes","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus knockdown with defined transcriptional phenotype, single lab","pmids":["19188450"],"is_preprint":false},{"year":2010,"finding":"SRA and RNA helicase p68 (DDX5) form a complex with CTCF that is essential for insulator function at the IGF2/H19 imprinted control region; SRA/p68 depletion reduces cohesin binding at CTCF sites without affecting CTCF binding itself, increases IGF2 expression, and increases enhancer-promoter interactions. The mechanism involves p68/SRA stabilizing interaction of cohesin with CTCF.","method":"Co-immunoprecipitation, ChIP, siRNA depletion, chromosome conformation assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ChIP demonstrating cohesin loss at CTCF sites, functional insulator assay, multiple orthogonal methods","pmids":["20966046"],"is_preprint":false},{"year":2010,"finding":"SRA non-coding RNA associates with PPARγ and coactivates PPARγ-dependent transcription to promote adipocyte differentiation; SRA overexpression in ST2 mesenchymal precursor cells promotes adipogenesis, while SRA knockdown inhibits 3T3-L1 preadipocyte differentiation. SRA also increases insulin-stimulated glucose uptake, Akt and FOXO1 phosphorylation, and S-phase entry.","method":"Co-immunoprecipitation of SRA with PPARγ, reporter assays, SRA overexpression and siRNA knockdown, differentiation assays, microarray, glucose uptake assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus gain- and loss-of-function with defined cellular phenotypes, single lab","pmids":["21152033"],"is_preprint":false},{"year":2010,"finding":"SRAP (the protein product of SRA1) prevents SRA ncRNA-dependent co-activation of MyoD during myogenic differentiation; the inhibitory effect is mediated through interaction of SRAP with SRA RNA via its RRM-like domain interacting with the SRA functional sub-structure STR7. Ratio of non-coding to coding SRA isoforms increases during normal myogenic differentiation but not in myotonic dystrophy patient cells.","method":"Constructs producing exclusively ncRNA or SRAP, reporter assays, RRM mutagenesis, co-immunoprecipitation, myogenic differentiation assays","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis of RRM domain plus functional reporter assays, single lab with two orthogonal approaches","pmids":["20855289"],"is_preprint":false},{"year":2013,"finding":"RISC proteins PACT, TRBP, and Dicer are SRA-binding nuclear receptor coregulators; they target steroid-responsive promoters, regulate nuclear receptor activity, and associate with SRA and specific pre-microRNAs in both the nucleus and cytoplasm together with Argonaute 2.","method":"Co-immunoprecipitation, ChIP, nuclear receptor reporter assays, subcellular fractionation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ChIP demonstrating binding at endogenous promoters, single lab","pmids":["23550157"],"is_preprint":false},{"year":2013,"finding":"RNA helicase Ddx5 and SRA function as coactivators of Notch signaling; Ddx5 directly interacts with the Notch transcription factor RBP-J and localizes to RBP-J binding sites at Notch target genes. SRA knockdown/overexpression reduces Notch target gene expression accompanied by loss of p300 occupancy and decreased histone acetylation.","method":"Biotinylation-tagging/mass spectrometry, Co-IP confirming Ddx5-RBP-J interaction, ChIP, Ddx5/SRA knockdown and overexpression with RT-PCR readout","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ChIP and loss-of-function, single lab","pmids":["23396200"],"is_preprint":false},{"year":2014,"finding":"SRA1 gene knockout in mice confers resistance to high fat diet-induced obesity, with decreased adipose mass, reduced adipocyte marker gene expression, improved insulin sensitivity (reduced fasting insulin, improved glucose tolerance), and reduced hepatic lipid droplets. SRA is expressed at highest levels in adipose tissue.","method":"Whole-body Sra1 gene knockout mouse model, high-fat diet feeding, metabolic phenotyping (glucose and insulin tolerance tests), gene expression analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout with multiple defined metabolic phenotypes and molecular endpoints, rigorous in vivo model","pmids":["24675075"],"is_preprint":false},{"year":2015,"finding":"SRA associates with both trithorax group (TrxG) and polycomb repressive complex 2 (PRC2) complexes; p68 binding preferentially stabilizes SRA-TrxG but not SRA-PRC2 association. SRA binding sites co-occupied by p68 are enriched for H3K4me3 in human pluripotent stem cells. SRA directly interacts with NANOG and co-localizes with it genome-wide. SRA is required for maintaining pluripotency and reprogramming human fibroblasts.","method":"Co-immunoprecipitation of SRA with TrxG/PRC2, ChIP-seq, RIP-seq, loss-of-function experiments in pluripotent stem cells","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus genome-wide ChIP data plus functional pluripotency assay, single lab","pmids":["26496121"],"is_preprint":false},{"year":2012,"finding":"SRA requires pseudouridylation by Pus1p to stimulate steroid receptor signaling; uridine at position 206 (U206) in SRA hairpin STR5 is a critical pseudouridylation target. SRA binds directly to the N-terminal domain (NTD) of ERα and AR via a novel RNA-binding motif. A synthetic STR5 fragment competitively inhibits Pus1p-dependent pseudouridylation of SRA and inhibits ERα- and AR-dependent transactivation.","method":"In vitro pseudouridylation assay, RNA-protein binding assays with recombinant protein, transient transfection reporter assays, competitive inhibition with synthetic RNA","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro enzymatic assay plus binding assays and functional reporters, single lab","pmids":["22998747"],"is_preprint":false},{"year":2014,"finding":"SRAP (SRA protein) crystal structure reveals a five-helix bundle carboxy-terminal domain similar to yeast spliceosome protein PRP18 rather than an RNA recognition motif; in vitro and cell-based binding experiments found no specific interaction between SRAP and SRA RNA, contradicting the previously proposed model. SRAP depletion had only small (~20%) effects on estrogen-responsive gene expression.","method":"Crystal structure determination of SRAP C-terminal domain, in vitro RNA binding assays with recombinant SRAP, plasmid-expressed SRAP and SRA RNA in cells, siRNA knockdown followed by RNA-seq","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — crystal structure plus multiple binding assays (negative result for SRAP-SRA RNA interaction), single lab; contradicts earlier model","pmids":["24486609"],"is_preprint":false},{"year":2004,"finding":"SRA coactivation of ERα is phosphorylation-independent for the AF-1 A/B domain; SRA selectively enhances ERα but not ERβ AF-1 activity. SRA also enhances ERα AF-2 activity. SRA enhances 4-hydroxytamoxifen agonist activity on ERα but cannot convert tamoxifen to an ERβ agonist.","method":"Transient transfection reporter assays with GAL4-AB fusion constructs, phosphorylation site mutagenesis, tamoxifen treatment","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis plus receptor-isoform comparison in reporter assays, single lab","pmids":["15351741"],"is_preprint":false},{"year":2016,"finding":"LncRNA SRA promotes hepatic steatosis by repressing expression of adipose triglyceride lipase (ATGL); SRA inhibits ATGL promoter activity primarily by inhibiting the inductive effects of transcription factor FoxO1. Loss of SRA in hepatocytes or SRA knockout mice induces ATGL expression and free fatty acid β-oxidation.","method":"SRA knockout mice on high-fat diet, SRA loss/gain-of-function in primary hepatocytes and hepatocyte cell line, ATGL promoter-reporter assays, RT-PCR and immunoblotting","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knockout plus in vitro promoter assay identifying FoxO1 as mechanism, single lab","pmids":["27759039"],"is_preprint":false},{"year":2021,"finding":"SRSF1 promotes inclusion of exon 3 of SRA1 pre-mRNA by directly binding exon 3, increasing expression of the long SRA1-L isoform, which promotes hepatocellular carcinoma invasion through upregulation of CD44. SRA1-S (exon 3-skipped) opposes this effect. RNA immunoprecipitation, CLIP, RNA pulldown, and minigene-MS2 mutation experiments confirmed direct SRSF1-exon3 interaction.","method":"RNA immunoprecipitation (RIP), cross-link immunoprecipitation (CLIP), RNA pulldown, minigene-MS2 mutation assay, siRNA knockdown, invasion assays, in vivo lung metastasis model","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple RNA-binding methods (RIP, CLIP, pulldown, minigene) plus in vivo model, single lab","pmids":["34011971"],"is_preprint":false},{"year":2010,"finding":"Dax1 augments LRH-1-mediated activation of the Oct4 gene in mouse embryonic stem cells in a SRA-dependent manner; Dax1 and LRH-1 co-immunoprecipitate in mES cells and co-localize at the Oct4 promoter. SRA knockdown abolishes Dax1 coactivation of Oct4.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, luciferase reporter assays, SRA knockdown, overexpression/knockdown of Dax1","journal":"Molecular endocrinology (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ChIP plus knockdown, single lab","pmids":["20943815"],"is_preprint":false}],"current_model":"SRA1 encodes both a functional non-coding RNA (SRA) and a protein (SRAP); the SRA ncRNA acts as a molecular scaffold and RNA coactivator that enhances transcription by steroid hormone receptors (ERα, AR, PR, GR) via their AF-1 domains, assembles ribonucleoprotein complexes containing SRC-1, p68/p72 helicases, SLIRP, and RISC components, requires pseudouridylation at U206 by Pus1p for full activity, supports CTCF insulator function by stabilizing cohesin at CTCF sites through p68, co-activates MyoD-driven myogenesis and PPARγ-driven adipogenesis, promotes hepatic steatosis by repressing ATGL via FoxO1, regulates steroidogenesis through SF-1/Dax-1, and participates in Notch and pluripotency pathways; SRAP appears structurally distinct from canonical RNA-binding proteins and its proposed direct binding to SRA RNA has not been confirmed by rigorous experiments."},"narrative":{"mechanistic_narrative":"SRA1 produces a functional non-coding RNA (SRA) that serves as a structured RNA scaffold and transcriptional coactivator, selectively enhancing steroid hormone receptor activity through their amino-terminal AF-1 domains [PMID:10199399, PMID:12943696]. SRA acts as an RNA molecule rather than a protein: it functions under cycloheximide and tolerates translational stop-codon mutations, and discrete RNA secondary-structure motifs—not encoded amino acids—are required for coactivation [PMID:10199399, PMID:12444263]. The active SRA RNA assembles into ribonucleoprotein coactivator complexes built around the SRC-1/TIF2 family, CBP/p300, and the DEAD-box helicases p68/p72, which bridge the receptor A/B domain to coactivators [PMID:11250900]. Its activity is tuned by RNA-binding regulators that dock on defined substructures: SLIRP binds the STR7 element through an RRM and represses receptor transactivation by recruiting NCoR and modulating SRC-1 association [PMID:16762838], while pseudouridylation of U206 within STR5 hairpin by Pus1p is required for full steroid-receptor stimulation, and SRA binds the receptor N-terminal domain through a novel RNA-binding motif [PMID:22998747]. Beyond canonical nuclear receptors, SRA/p68 act as broad transcriptional and architectural cofactors: they coactivate MyoD-driven myogenesis by assembling RNA Pol II and the Brg-1/SWI-SNF remodeler at muscle promoters [PMID:17011493], support PPARγ-driven adipogenesis [PMID:21152033], coactivate SF-1/Dax-1-dependent steroidogenesis [PMID:19188450], and stabilize cohesin at CTCF sites to maintain insulator function at the IGF2/H19 locus [PMID:20966046]. SRA also associates with TrxG and PRC2 chromatin complexes and with NANOG to maintain pluripotency [PMID:26496121]. In vivo, whole-body Sra1 knockout confers resistance to high-fat-diet obesity with improved insulin sensitivity, and SRA promotes hepatic steatosis by repressing ATGL via FoxO1 [PMID:24675075, PMID:27759039]. The SRA1 locus additionally encodes a protein, SRAP, whose C-terminal domain adopts a five-helix bundle resembling the spliceosomal protein PRP18 rather than an RRM; its proposed direct binding to SRA RNA was not reproduced in structural and binding experiments [PMID:24486609].","teleology":[{"year":1999,"claim":"Established the foundational and counterintuitive principle that SRA acts as an RNA, not a protein, defining a new class of non-coding RNA coactivator selective for steroid receptor AF-1 function.","evidence":"Transfection under cycloheximide, stop-codon mutagenesis, biochemical fractionation and Co-IP showing SRA in SRC-1-containing RNP complexes","pmids":["10199399"],"confidence":"High","gaps":["Did not define the RNA structural determinants of activity","Did not resolve receptor-binding interface"]},{"year":2001,"claim":"Identified the protein composition of the SRA-associated ERα coactivator complex, placing SRA within an SRC-1/p300/p68-p72 assembly bridged to the receptor.","evidence":"Reciprocal Co-IP from MCF7 cells and HeLa extracts, immunofluorescence co-localization, reporter assays","pmids":["11250900"],"confidence":"High","gaps":["Did not establish whether helicase binding is RNA-dependent","Stoichiometry of the complex unresolved"]},{"year":2002,"claim":"Provided definitive structural evidence that SRA acts through RNA motifs by showing silent mutations that preserve amino-acid sequence but disrupt RNA structure abolish coactivation.","evidence":"Comparative sequence/free-energy analysis, silent and deletion mutagenesis, reporter assays","pmids":["12444263"],"confidence":"High","gaps":["Functional roles of individual motifs not fully assigned","No high-resolution RNA structure"]},{"year":2003,"claim":"Connected SRA coactivation to MAPK signaling by showing it requires ERα Ser118 and enables ligand-independent AF-1 activation.","evidence":"S118 mutagenesis with H-Ras(V12)-driven MAPK activation in reporter assays","pmids":["12943696"],"confidence":"Medium","gaps":["Single lab","Mechanism linking phosphorylation to SRA recruitment unresolved"]},{"year":2004,"claim":"Refined receptor selectivity and phosphorylation-dependence, showing SRA enhances ERα (not ERβ) AF-1 independent of phosphorylation and modulates tamoxifen agonism.","evidence":"GAL4-AB fusion reporter assays, phospho-site mutagenesis, tamoxifen treatment","pmids":["15351741"],"confidence":"Medium","gaps":["Apparent tension with S118-dependence not reconciled","Single lab"]},{"year":2006,"claim":"Resolved how SRA inhibitory regulation works mechanistically, identifying SLIRP as an RRM protein binding the STR7 substructure to repress receptor activity and recruit NCoR.","evidence":"Co-IP, ChIP, RRM mutagenesis, reporter assays and fractionation","pmids":["16762838"],"confidence":"High","gaps":["How SLIRP and SRC-1 compete on SRA not fully resolved","In vivo relevance not tested"]},{"year":2006,"claim":"Extended SRA/p68-p72 beyond nuclear receptors to lineage-specifying transcription, showing they coactivate MyoD and are required for chromatin remodeling and Pol II/Brg-1 recruitment at muscle genes.","evidence":"Co-IP with MyoD, RNAi loss-of-function, chromatin remodeling assays and ChIP","pmids":["17011493"],"confidence":"High","gaps":["Direct SRA-MyoD contact not defined","Role of SRA RNA structure here untested"]},{"year":2009,"claim":"Demonstrated SRA functions in steroidogenesis as a coactivator for SF-1 and Dax-1, linking it to control of steroidogenic gene expression.","evidence":"Co-IP, siRNA knockdown of endogenous SRA, reporter and RT-PCR readouts in Y1 cells","pmids":["19188450"],"confidence":"Medium","gaps":["Single lab","Whether SF-1 binds SRA directly unresolved"]},{"year":2010,"claim":"Revealed an architectural, non-transcription-factor role: SRA/p68 stabilize cohesin at CTCF sites to enforce insulator function at the IGF2/H19 locus.","evidence":"Co-IP, ChIP showing cohesin loss without CTCF loss, chromosome conformation assays under siRNA depletion","pmids":["20966046"],"confidence":"High","gaps":["Molecular basis of cohesin stabilization unresolved","Genome-wide generality not addressed"]},{"year":2010,"claim":"Linked SRA to adipogenesis and glucose metabolism by showing it associates with and coactivates PPARγ and promotes preadipocyte differentiation.","evidence":"Co-IP with PPARγ, gain/loss-of-function differentiation assays, microarray, glucose uptake assays","pmids":["21152033"],"confidence":"Medium","gaps":["Single lab","Direct vs indirect PPARγ engagement unresolved"]},{"year":2010,"claim":"Defined the SRAP protein as an antagonist of SRA function in myogenesis, proposing SRAP binds the STR7 substructure via an RRM-like domain to inhibit MyoD coactivation.","evidence":"ncRNA-only vs SRAP-only constructs, RRM mutagenesis, Co-IP, myogenic differentiation assays","pmids":["20855289"],"confidence":"Medium","gaps":["Proposed SRAP-SRA binding later contradicted (#15)","Single lab"]},{"year":2010,"claim":"Connected SRA to pluripotency gene regulation by showing Dax1 augments LRH-1-driven Oct4 activation in an SRA-dependent manner.","evidence":"Co-IP, ChIP at the Oct4 promoter, SRA knockdown in mES cells","pmids":["20943815"],"confidence":"Medium","gaps":["Single lab","Direct SRA-Dax1/LRH-1 contacts not mapped"]},{"year":2012,"claim":"Identified a post-transcriptional RNA modification requirement, showing Pus1p-dependent pseudouridylation at U206 (STR5) is needed for steroid-receptor stimulation and that SRA binds the receptor NTD via a novel motif.","evidence":"In vitro pseudouridylation and RNA-protein binding assays, reporter assays, competitive inhibition with synthetic STR5","pmids":["22998747"],"confidence":"Medium","gaps":["Single lab","In vivo requirement of pseudouridylation untested"]},{"year":2013,"claim":"Broadened SRA's coactivator partnerships to RISC machinery, showing Dicer/TRBP/PACT bind SRA and act as nuclear receptor coregulators at steroid-responsive promoters.","evidence":"Co-IP, ChIP, reporter assays, subcellular fractionation with Ago2 and pre-miRNA association","pmids":["23550157"],"confidence":"Medium","gaps":["Single lab","Functional consequence of pre-miRNA co-association unclear"]},{"year":2013,"claim":"Extended SRA/Ddx5 coactivation to Notch signaling via the RBP-J transcription factor, linking SRA to p300 recruitment and histone acetylation at Notch targets.","evidence":"BioID/MS, Co-IP of Ddx5-RBP-J, ChIP, SRA knockdown/overexpression with RT-PCR","pmids":["23396200"],"confidence":"Medium","gaps":["Single lab","Whether SRA contacts RBP-J directly unknown"]},{"year":2014,"claim":"Provided definitive in vivo metabolic function by showing Sra1 knockout mice resist diet-induced obesity with improved insulin sensitivity and reduced hepatic lipid.","evidence":"Whole-body knockout mouse, high-fat diet, metabolic phenotyping and gene expression analysis","pmids":["24675075"],"confidence":"High","gaps":["Did not separate ncRNA from SRAP contributions in vivo","Tissue-specific mechanisms not dissected"]},{"year":2014,"claim":"Challenged the SRAP-as-RNA-binding-protein model by solving the SRAP C-terminal structure (PRP18-like five-helix bundle) and failing to detect specific SRAP-SRA RNA binding.","evidence":"Crystal structure, in vitro and cell-based RNA binding assays (negative), siRNA knockdown with RNA-seq","pmids":["24486609"],"confidence":"Medium","gaps":["Direct contradiction with #9 unresolved","True molecular function of SRAP undefined"]},{"year":2015,"claim":"Placed SRA at the chromatin-state interface, showing it associates with both TrxG and PRC2, binds NANOG genome-wide, and is required for pluripotency and reprogramming.","evidence":"Co-IP, ChIP-seq, RIP-seq, loss-of-function in human pluripotent stem cells","pmids":["26496121"],"confidence":"Medium","gaps":["Single lab","How SRA selects TrxG vs PRC2 outcomes unresolved"]},{"year":2016,"claim":"Defined a hepatic disease mechanism, showing SRA promotes steatosis by repressing ATGL through inhibition of FoxO1-driven ATGL induction.","evidence":"Knockout mice on high-fat diet, hepatocyte gain/loss-of-function, ATGL promoter-reporter assays","pmids":["27759039"],"confidence":"Medium","gaps":["Single lab","Direct SRA-FoxO1 relationship not structurally defined"]},{"year":2021,"claim":"Revealed isoform-specific cancer relevance, showing SRSF1-driven exon 3 inclusion produces SRA1-L that promotes hepatocellular carcinoma invasion via CD44.","evidence":"RIP, CLIP, RNA pulldown, minigene-MS2 mutation, invasion and in vivo metastasis assays","pmids":["34011971"],"confidence":"Medium","gaps":["Single lab","Whether the invasion effect is ncRNA- or SRAP-mediated unresolved"]},{"year":null,"claim":"The molecular function of the SRAP protein and its relationship to the SRA ncRNA remain unresolved, as does how a single structured RNA is partitioned among its many coactivator and architectural complexes.","evidence":"","pmids":[],"confidence":"Medium","gaps":["SRAP biochemical activity undefined and its proposed SRA-RNA binding contradicted","No high-resolution structure of active SRA RNP","Determinants directing SRA among receptor, chromatin, and insulator complexes unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,4,14]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2,5,8]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2,7]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,4,7]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[2,10]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2,5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,6,11]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[7,13]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[8,12,17]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5,8,13]}],"complexes":["SRC-1/p300 nuclear receptor coactivator complex","CTCF-cohesin insulator complex","TrxG chromatin complex","PRC2"],"partners":["DDX5","DDX17","SLIRP","SRC-1","CTCF","PPARG","NANOG","RBPJ"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H7N4","full_name":"Splicing factor, arginine/serine-rich 19","aliases":["SR-related C-terminal domain-associated factor 1","SR-related and CTD-associated factor 1","SR-related-CTD-associated factor","SCAF","Serine arginine-rich pre-mRNA splicing factor SR-A1","SR-A1"],"length_aa":1312,"mass_kda":139.3,"function":"May function in pre-mRNA splicing","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9H7N4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SRA1","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SRA1","total_profiled":1310},"omim":[{"mim_id":"617264","title":"SR-RELATED C-TERMINAL DOMAIN-ASSOCIATED FACTOR 1; SCAF1","url":"https://www.omim.org/entry/617264"},{"mim_id":"610211","title":"SRA STEM LOOP-INTERACTING RNA-BINDING PROTEIN; SLIRP","url":"https://www.omim.org/entry/610211"},{"mim_id":"608469","title":"DEAD-BOX HELICASE 17; 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development.","date":"2018","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29899856","citation_count":32,"is_preprint":false},{"pmid":"18922854","id":"PMC_18922854","title":"Human protein S inhibits the uptake of AcLDL and expression of SR-A through Mer receptor tyrosine kinase in human macrophages.","date":"2008","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/18922854","citation_count":32,"is_preprint":false},{"pmid":"20338659","id":"PMC_20338659","title":"The scavenger receptors SRA-1 and SREC-I cooperate with TLR2 in the recognition of the hepatitis C virus non-structural protein 3 by dendritic cells.","date":"2010","source":"Journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/20338659","citation_count":32,"is_preprint":false},{"pmid":"28472786","id":"PMC_28472786","title":"Roles of the Exogenous H2S-Mediated SR-A Signaling Pathway in Renal Ischemia/ Reperfusion Injury in Regulating Endoplasmic Reticulum Stress-Induced Autophagy in a Rat Model.","date":"2017","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/28472786","citation_count":31,"is_preprint":false},{"pmid":"31106680","id":"PMC_31106680","title":"LncRNA-SRA1 Suppresses Osteosarcoma Cell Proliferation While Promoting Cell Apoptosis.","date":"2019","source":"Technology in cancer research & treatment","url":"https://pubmed.ncbi.nlm.nih.gov/31106680","citation_count":28,"is_preprint":false},{"pmid":"21507355","id":"PMC_21507355","title":"Recruitment of Dnmt1 roles of the SRA protein Np95 (Uhrf1) and other factors.","date":"2011","source":"Progress in molecular biology and translational science","url":"https://pubmed.ncbi.nlm.nih.gov/21507355","citation_count":28,"is_preprint":false},{"pmid":"26967566","id":"PMC_26967566","title":"Genetic variants in lncRNA SRA and risk of breast cancer.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26967566","citation_count":28,"is_preprint":false},{"pmid":"18380007","id":"PMC_18380007","title":"The RNA coregulator SRA, its binding proteins and nuclear receptor signaling activity.","date":"2008","source":"IUBMB life","url":"https://pubmed.ncbi.nlm.nih.gov/18380007","citation_count":26,"is_preprint":false},{"pmid":"34011971","id":"PMC_34011971","title":"SRSF1 promotes the inclusion of exon 3 of SRA1 and the invasion of hepatocellular carcinoma cells by interacting with exon 3 of SRA1pre-mRNA.","date":"2021","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/34011971","citation_count":26,"is_preprint":false},{"pmid":"15521633","id":"PMC_15521633","title":"Human infectivity trait in Trypanosoma brucei: stability, heritability and relationship to sra expression.","date":"2004","source":"Parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/15521633","citation_count":26,"is_preprint":false},{"pmid":"21736734","id":"PMC_21736734","title":"SR-A ligand and M-CSF dynamically regulate SR-A expression and function in primary macrophages via p38 MAPK activation.","date":"2011","source":"BMC immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21736734","citation_count":26,"is_preprint":false},{"pmid":"23123599","id":"PMC_23123599","title":"SR-A deficiency reduces myocardial ischemia/reperfusion injury; involvement of increased microRNA-125b expression in macrophages.","date":"2012","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/23123599","citation_count":26,"is_preprint":false},{"pmid":"22083206","id":"PMC_22083206","title":"Suppression of antigen-specific CD4+ T cell activation by SRA/CD204 through reducing the immunostimulatory capability of antigen-presenting cell.","date":"2011","source":"Journal of molecular medicine (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/22083206","citation_count":25,"is_preprint":false},{"pmid":"25564526","id":"PMC_25564526","title":"Recognition and cleavage of 5-methylcytosine DNA by bacterial SRA-HNH proteins.","date":"2015","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/25564526","citation_count":24,"is_preprint":false},{"pmid":"24486609","id":"PMC_24486609","title":"Structure and function of steroid receptor RNA activator protein, the proposed partner of SRA noncoding RNA.","date":"2014","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/24486609","citation_count":23,"is_preprint":false},{"pmid":"21795641","id":"PMC_21795641","title":"Inflammatory stress exacerbates lipid-mediated renal injury in ApoE/CD36/SRA triple knockout mice.","date":"2011","source":"American journal of physiology. Renal physiology","url":"https://pubmed.ncbi.nlm.nih.gov/21795641","citation_count":23,"is_preprint":false},{"pmid":"28085012","id":"PMC_28085012","title":"Decreased expression of LncRNA SRA1 in hepatocellular carcinoma and its clinical significance.","date":"2017","source":"Cancer biomarkers : section A of Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/28085012","citation_count":22,"is_preprint":false},{"pmid":"15351741","id":"PMC_15351741","title":"SRA coactivation of estrogen receptor-alpha is phosphorylation-independent, and enhances 4-hydroxytamoxifen agonist activity.","date":"2004","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/15351741","citation_count":22,"is_preprint":false},{"pmid":"22998747","id":"PMC_22998747","title":"A small RNA derived from RNA coactivator SRA blocks steroid receptor signaling via inhibition of Pus1p-mediated pseudouridylation of SRA: evidence of a novel RNA binding domain in the N-terminus of steroid receptors.","date":"2012","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22998747","citation_count":20,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":48741,"output_tokens":5209,"usd":0.112179,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13760,"output_tokens":5755,"usd":0.106338,"stage2_stop_reason":"end_turn"},"total_usd":0.218517,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"SRA functions as a non-coding RNA coactivator (not a translated protein) that selectively enhances steroid hormone receptor transactivation via their amino-terminal AF-1 activation function; it resides in distinct ribonucleoprotein complexes, one containing SRC-1. Evidence: SRA functions in presence of cycloheximide and retains activity with multiple translational stop codon mutations.\",\n      \"method\": \"Transient transfection with cycloheximide treatment, translational stop-codon mutagenesis, biochemical fractionation, co-immunoprecipitation\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (cycloheximide resistance, stop-codon mutagenesis, biochemical fractionation, Co-IP) in original discovery paper, widely replicated\",\n      \"pmids\": [\"10199399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Distinct RNA structural motifs within the SRA molecule are required for its coactivation function; six RNA motifs important for coactivation were identified by systematic mutagenesis using silent mutations that do not alter encoded amino acid sequence, providing strong evidence SRA acts as an RNA transcript rather than a protein.\",\n      \"method\": \"Comparative sequence analysis, free energy calculations, site-directed mutagenesis, genetic deletion analysis, transient transfection reporter assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution with systematic mutagenesis, silent mutations confirm RNA-based mechanism, multiple orthogonal approaches\",\n      \"pmids\": [\"12444263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"SRA associates with estrogen receptor alpha (ERα) coactivator complexes containing SRC-1/TIF2 family proteins, CBP/p300, and the RNA-binding DEAD-box proteins p72/p68; p72/p68 interact with both the AD2 domain of SRC-1/TIF2 and the ERα A/B domain, and all co-immunoprecipitate with estrogen-bound ERα in MCF7 cells.\",\n      \"method\": \"Co-immunoprecipitation from MCF7 cells and HeLa nuclear extracts, co-localization by immunofluorescence, transient transfection reporter assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP from endogenous complex plus functional reporter assays, replicated across multiple labs\",\n      \"pmids\": [\"11250900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SRA coactivation of ERα AF-1 requires an intact serine 118 (S118) residue; MAPK activation enables ligand-independent coactivation of ERα by SRA through the AF-1 domain in a mechanism independent of AF-2. SRA differentially activates ERα vs. ERβ through their respective AF-1 domains.\",\n      \"method\": \"Transient transfection reporter assays, site-directed mutagenesis of S118, H-Ras(V12) activation of MAPK pathway\",\n      \"journal\": \"The Journal of steroid biochemistry and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis plus gain-of-function signaling experiments, single lab\",\n      \"pmids\": [\"12943696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SLIRP (SRA stem-loop interacting RNA binding protein) binds the functional SRA substructure STR7 via an RNA recognition motif (RRM) and represses nuclear receptor transactivation in a SRA- and RRM-dependent manner; SLIRP modulates the association of SRC-1 with SRA, is recruited to endogenous promoters in a SRA-dependent manner, and recruits NCoR.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, RRM mutagenesis, reporter assays, subcellular fractionation\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, ChIP, mutagenesis, reporter assays) in single rigorous study with clear mechanistic outcome\",\n      \"pmids\": [\"16762838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"RNA helicases p68/p72 and non-coding SRA RNA are coactivators of MyoD and required for skeletal muscle differentiation; p68/p72 promote assembly of TBP, RNA polymerase II, and the Brg-1 ATPase subunit of SWI/SNF at muscle gene promoters and facilitate chromatin remodeling. RNAi against p68/p72 or SRA prevents muscle gene activation and differentiation.\",\n      \"method\": \"Co-immunoprecipitation with MyoD, RNA interference, chromatin remodeling assays, ChIP, reporter assays\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP demonstrating association, RNAi loss-of-function with defined molecular phenotype (ChIP, chromatin remodeling), multiple orthogonal methods\",\n      \"pmids\": [\"17011493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SRA RNA functions as a coactivator for steroidogenic factor 1 (SF-1) in steroidogenesis; both SF-1 and Dax-1 bind SRA, and coactivation by Dax-1 is abolished by SRA knockdown. Knockdown of endogenous SRA reduces expression of steroidogenic gene products StAR and melanocortin 2 receptor in adrenal Y1 cells.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown of endogenous SRA, reporter assays, RT-PCR for steroidogenic genes\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus knockdown with defined transcriptional phenotype, single lab\",\n      \"pmids\": [\"19188450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SRA and RNA helicase p68 (DDX5) form a complex with CTCF that is essential for insulator function at the IGF2/H19 imprinted control region; SRA/p68 depletion reduces cohesin binding at CTCF sites without affecting CTCF binding itself, increases IGF2 expression, and increases enhancer-promoter interactions. The mechanism involves p68/SRA stabilizing interaction of cohesin with CTCF.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, siRNA depletion, chromosome conformation assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ChIP demonstrating cohesin loss at CTCF sites, functional insulator assay, multiple orthogonal methods\",\n      \"pmids\": [\"20966046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SRA non-coding RNA associates with PPARγ and coactivates PPARγ-dependent transcription to promote adipocyte differentiation; SRA overexpression in ST2 mesenchymal precursor cells promotes adipogenesis, while SRA knockdown inhibits 3T3-L1 preadipocyte differentiation. SRA also increases insulin-stimulated glucose uptake, Akt and FOXO1 phosphorylation, and S-phase entry.\",\n      \"method\": \"Co-immunoprecipitation of SRA with PPARγ, reporter assays, SRA overexpression and siRNA knockdown, differentiation assays, microarray, glucose uptake assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus gain- and loss-of-function with defined cellular phenotypes, single lab\",\n      \"pmids\": [\"21152033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SRAP (the protein product of SRA1) prevents SRA ncRNA-dependent co-activation of MyoD during myogenic differentiation; the inhibitory effect is mediated through interaction of SRAP with SRA RNA via its RRM-like domain interacting with the SRA functional sub-structure STR7. Ratio of non-coding to coding SRA isoforms increases during normal myogenic differentiation but not in myotonic dystrophy patient cells.\",\n      \"method\": \"Constructs producing exclusively ncRNA or SRAP, reporter assays, RRM mutagenesis, co-immunoprecipitation, myogenic differentiation assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of RRM domain plus functional reporter assays, single lab with two orthogonal approaches\",\n      \"pmids\": [\"20855289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RISC proteins PACT, TRBP, and Dicer are SRA-binding nuclear receptor coregulators; they target steroid-responsive promoters, regulate nuclear receptor activity, and associate with SRA and specific pre-microRNAs in both the nucleus and cytoplasm together with Argonaute 2.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, nuclear receptor reporter assays, subcellular fractionation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ChIP demonstrating binding at endogenous promoters, single lab\",\n      \"pmids\": [\"23550157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RNA helicase Ddx5 and SRA function as coactivators of Notch signaling; Ddx5 directly interacts with the Notch transcription factor RBP-J and localizes to RBP-J binding sites at Notch target genes. SRA knockdown/overexpression reduces Notch target gene expression accompanied by loss of p300 occupancy and decreased histone acetylation.\",\n      \"method\": \"Biotinylation-tagging/mass spectrometry, Co-IP confirming Ddx5-RBP-J interaction, ChIP, Ddx5/SRA knockdown and overexpression with RT-PCR readout\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ChIP and loss-of-function, single lab\",\n      \"pmids\": [\"23396200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SRA1 gene knockout in mice confers resistance to high fat diet-induced obesity, with decreased adipose mass, reduced adipocyte marker gene expression, improved insulin sensitivity (reduced fasting insulin, improved glucose tolerance), and reduced hepatic lipid droplets. SRA is expressed at highest levels in adipose tissue.\",\n      \"method\": \"Whole-body Sra1 gene knockout mouse model, high-fat diet feeding, metabolic phenotyping (glucose and insulin tolerance tests), gene expression analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout with multiple defined metabolic phenotypes and molecular endpoints, rigorous in vivo model\",\n      \"pmids\": [\"24675075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SRA associates with both trithorax group (TrxG) and polycomb repressive complex 2 (PRC2) complexes; p68 binding preferentially stabilizes SRA-TrxG but not SRA-PRC2 association. SRA binding sites co-occupied by p68 are enriched for H3K4me3 in human pluripotent stem cells. SRA directly interacts with NANOG and co-localizes with it genome-wide. SRA is required for maintaining pluripotency and reprogramming human fibroblasts.\",\n      \"method\": \"Co-immunoprecipitation of SRA with TrxG/PRC2, ChIP-seq, RIP-seq, loss-of-function experiments in pluripotent stem cells\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus genome-wide ChIP data plus functional pluripotency assay, single lab\",\n      \"pmids\": [\"26496121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SRA requires pseudouridylation by Pus1p to stimulate steroid receptor signaling; uridine at position 206 (U206) in SRA hairpin STR5 is a critical pseudouridylation target. SRA binds directly to the N-terminal domain (NTD) of ERα and AR via a novel RNA-binding motif. A synthetic STR5 fragment competitively inhibits Pus1p-dependent pseudouridylation of SRA and inhibits ERα- and AR-dependent transactivation.\",\n      \"method\": \"In vitro pseudouridylation assay, RNA-protein binding assays with recombinant protein, transient transfection reporter assays, competitive inhibition with synthetic RNA\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro enzymatic assay plus binding assays and functional reporters, single lab\",\n      \"pmids\": [\"22998747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SRAP (SRA protein) crystal structure reveals a five-helix bundle carboxy-terminal domain similar to yeast spliceosome protein PRP18 rather than an RNA recognition motif; in vitro and cell-based binding experiments found no specific interaction between SRAP and SRA RNA, contradicting the previously proposed model. SRAP depletion had only small (~20%) effects on estrogen-responsive gene expression.\",\n      \"method\": \"Crystal structure determination of SRAP C-terminal domain, in vitro RNA binding assays with recombinant SRAP, plasmid-expressed SRAP and SRA RNA in cells, siRNA knockdown followed by RNA-seq\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus multiple binding assays (negative result for SRAP-SRA RNA interaction), single lab; contradicts earlier model\",\n      \"pmids\": [\"24486609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SRA coactivation of ERα is phosphorylation-independent for the AF-1 A/B domain; SRA selectively enhances ERα but not ERβ AF-1 activity. SRA also enhances ERα AF-2 activity. SRA enhances 4-hydroxytamoxifen agonist activity on ERα but cannot convert tamoxifen to an ERβ agonist.\",\n      \"method\": \"Transient transfection reporter assays with GAL4-AB fusion constructs, phosphorylation site mutagenesis, tamoxifen treatment\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis plus receptor-isoform comparison in reporter assays, single lab\",\n      \"pmids\": [\"15351741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"LncRNA SRA promotes hepatic steatosis by repressing expression of adipose triglyceride lipase (ATGL); SRA inhibits ATGL promoter activity primarily by inhibiting the inductive effects of transcription factor FoxO1. Loss of SRA in hepatocytes or SRA knockout mice induces ATGL expression and free fatty acid β-oxidation.\",\n      \"method\": \"SRA knockout mice on high-fat diet, SRA loss/gain-of-function in primary hepatocytes and hepatocyte cell line, ATGL promoter-reporter assays, RT-PCR and immunoblotting\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockout plus in vitro promoter assay identifying FoxO1 as mechanism, single lab\",\n      \"pmids\": [\"27759039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SRSF1 promotes inclusion of exon 3 of SRA1 pre-mRNA by directly binding exon 3, increasing expression of the long SRA1-L isoform, which promotes hepatocellular carcinoma invasion through upregulation of CD44. SRA1-S (exon 3-skipped) opposes this effect. RNA immunoprecipitation, CLIP, RNA pulldown, and minigene-MS2 mutation experiments confirmed direct SRSF1-exon3 interaction.\",\n      \"method\": \"RNA immunoprecipitation (RIP), cross-link immunoprecipitation (CLIP), RNA pulldown, minigene-MS2 mutation assay, siRNA knockdown, invasion assays, in vivo lung metastasis model\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple RNA-binding methods (RIP, CLIP, pulldown, minigene) plus in vivo model, single lab\",\n      \"pmids\": [\"34011971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Dax1 augments LRH-1-mediated activation of the Oct4 gene in mouse embryonic stem cells in a SRA-dependent manner; Dax1 and LRH-1 co-immunoprecipitate in mES cells and co-localize at the Oct4 promoter. SRA knockdown abolishes Dax1 coactivation of Oct4.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, luciferase reporter assays, SRA knockdown, overexpression/knockdown of Dax1\",\n      \"journal\": \"Molecular endocrinology (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ChIP plus knockdown, single lab\",\n      \"pmids\": [\"20943815\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SRA1 encodes both a functional non-coding RNA (SRA) and a protein (SRAP); the SRA ncRNA acts as a molecular scaffold and RNA coactivator that enhances transcription by steroid hormone receptors (ERα, AR, PR, GR) via their AF-1 domains, assembles ribonucleoprotein complexes containing SRC-1, p68/p72 helicases, SLIRP, and RISC components, requires pseudouridylation at U206 by Pus1p for full activity, supports CTCF insulator function by stabilizing cohesin at CTCF sites through p68, co-activates MyoD-driven myogenesis and PPARγ-driven adipogenesis, promotes hepatic steatosis by repressing ATGL via FoxO1, regulates steroidogenesis through SF-1/Dax-1, and participates in Notch and pluripotency pathways; SRAP appears structurally distinct from canonical RNA-binding proteins and its proposed direct binding to SRA RNA has not been confirmed by rigorous experiments.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SRA1 produces a functional non-coding RNA (SRA) that serves as a structured RNA scaffold and transcriptional coactivator, selectively enhancing steroid hormone receptor activity through their amino-terminal AF-1 domains [#0, #3]. SRA acts as an RNA molecule rather than a protein: it functions under cycloheximide and tolerates translational stop-codon mutations, and discrete RNA secondary-structure motifs—not encoded amino acids—are required for coactivation [#0, #1]. The active SRA RNA assembles into ribonucleoprotein coactivator complexes built around the SRC-1/TIF2 family, CBP/p300, and the DEAD-box helicases p68/p72, which bridge the receptor A/B domain to coactivators [#2]. Its activity is tuned by RNA-binding regulators that dock on defined substructures: SLIRP binds the STR7 element through an RRM and represses receptor transactivation by recruiting NCoR and modulating SRC-1 association [#4], while pseudouridylation of U206 within STR5 hairpin by Pus1p is required for full steroid-receptor stimulation, and SRA binds the receptor N-terminal domain through a novel RNA-binding motif [#14]. Beyond canonical nuclear receptors, SRA/p68 act as broad transcriptional and architectural cofactors: they coactivate MyoD-driven myogenesis by assembling RNA Pol II and the Brg-1/SWI-SNF remodeler at muscle promoters [#5], support PPARγ-driven adipogenesis [#8], coactivate SF-1/Dax-1-dependent steroidogenesis [#6], and stabilize cohesin at CTCF sites to maintain insulator function at the IGF2/H19 locus [#7]. SRA also associates with TrxG and PRC2 chromatin complexes and with NANOG to maintain pluripotency [#13]. In vivo, whole-body Sra1 knockout confers resistance to high-fat-diet obesity with improved insulin sensitivity, and SRA promotes hepatic steatosis by repressing ATGL via FoxO1 [#12, #17]. The SRA1 locus additionally encodes a protein, SRAP, whose C-terminal domain adopts a five-helix bundle resembling the spliceosomal protein PRP18 rather than an RRM; its proposed direct binding to SRA RNA was not reproduced in structural and binding experiments [#15].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established the foundational and counterintuitive principle that SRA acts as an RNA, not a protein, defining a new class of non-coding RNA coactivator selective for steroid receptor AF-1 function.\",\n      \"evidence\": \"Transfection under cycloheximide, stop-codon mutagenesis, biochemical fractionation and Co-IP showing SRA in SRC-1-containing RNP complexes\",\n      \"pmids\": [\"10199399\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the RNA structural determinants of activity\", \"Did not resolve receptor-binding interface\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identified the protein composition of the SRA-associated ERα coactivator complex, placing SRA within an SRC-1/p300/p68-p72 assembly bridged to the receptor.\",\n      \"evidence\": \"Reciprocal Co-IP from MCF7 cells and HeLa extracts, immunofluorescence co-localization, reporter assays\",\n      \"pmids\": [\"11250900\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish whether helicase binding is RNA-dependent\", \"Stoichiometry of the complex unresolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Provided definitive structural evidence that SRA acts through RNA motifs by showing silent mutations that preserve amino-acid sequence but disrupt RNA structure abolish coactivation.\",\n      \"evidence\": \"Comparative sequence/free-energy analysis, silent and deletion mutagenesis, reporter assays\",\n      \"pmids\": [\"12444263\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional roles of individual motifs not fully assigned\", \"No high-resolution RNA structure\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Connected SRA coactivation to MAPK signaling by showing it requires ERα Ser118 and enables ligand-independent AF-1 activation.\",\n      \"evidence\": \"S118 mutagenesis with H-Ras(V12)-driven MAPK activation in reporter assays\",\n      \"pmids\": [\"12943696\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanism linking phosphorylation to SRA recruitment unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Refined receptor selectivity and phosphorylation-dependence, showing SRA enhances ERα (not ERβ) AF-1 independent of phosphorylation and modulates tamoxifen agonism.\",\n      \"evidence\": \"GAL4-AB fusion reporter assays, phospho-site mutagenesis, tamoxifen treatment\",\n      \"pmids\": [\"15351741\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Apparent tension with S118-dependence not reconciled\", \"Single lab\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Resolved how SRA inhibitory regulation works mechanistically, identifying SLIRP as an RRM protein binding the STR7 substructure to repress receptor activity and recruit NCoR.\",\n      \"evidence\": \"Co-IP, ChIP, RRM mutagenesis, reporter assays and fractionation\",\n      \"pmids\": [\"16762838\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SLIRP and SRC-1 compete on SRA not fully resolved\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Extended SRA/p68-p72 beyond nuclear receptors to lineage-specifying transcription, showing they coactivate MyoD and are required for chromatin remodeling and Pol II/Brg-1 recruitment at muscle genes.\",\n      \"evidence\": \"Co-IP with MyoD, RNAi loss-of-function, chromatin remodeling assays and ChIP\",\n      \"pmids\": [\"17011493\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct SRA-MyoD contact not defined\", \"Role of SRA RNA structure here untested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated SRA functions in steroidogenesis as a coactivator for SF-1 and Dax-1, linking it to control of steroidogenic gene expression.\",\n      \"evidence\": \"Co-IP, siRNA knockdown of endogenous SRA, reporter and RT-PCR readouts in Y1 cells\",\n      \"pmids\": [\"19188450\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Whether SF-1 binds SRA directly unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Revealed an architectural, non-transcription-factor role: SRA/p68 stabilize cohesin at CTCF sites to enforce insulator function at the IGF2/H19 locus.\",\n      \"evidence\": \"Co-IP, ChIP showing cohesin loss without CTCF loss, chromosome conformation assays under siRNA depletion\",\n      \"pmids\": [\"20966046\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of cohesin stabilization unresolved\", \"Genome-wide generality not addressed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Linked SRA to adipogenesis and glucose metabolism by showing it associates with and coactivates PPARγ and promotes preadipocyte differentiation.\",\n      \"evidence\": \"Co-IP with PPARγ, gain/loss-of-function differentiation assays, microarray, glucose uptake assays\",\n      \"pmids\": [\"21152033\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct vs indirect PPARγ engagement unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the SRAP protein as an antagonist of SRA function in myogenesis, proposing SRAP binds the STR7 substructure via an RRM-like domain to inhibit MyoD coactivation.\",\n      \"evidence\": \"ncRNA-only vs SRAP-only constructs, RRM mutagenesis, Co-IP, myogenic differentiation assays\",\n      \"pmids\": [\"20855289\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Proposed SRAP-SRA binding later contradicted (#15)\", \"Single lab\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected SRA to pluripotency gene regulation by showing Dax1 augments LRH-1-driven Oct4 activation in an SRA-dependent manner.\",\n      \"evidence\": \"Co-IP, ChIP at the Oct4 promoter, SRA knockdown in mES cells\",\n      \"pmids\": [\"20943815\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct SRA-Dax1/LRH-1 contacts not mapped\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified a post-transcriptional RNA modification requirement, showing Pus1p-dependent pseudouridylation at U206 (STR5) is needed for steroid-receptor stimulation and that SRA binds the receptor NTD via a novel motif.\",\n      \"evidence\": \"In vitro pseudouridylation and RNA-protein binding assays, reporter assays, competitive inhibition with synthetic STR5\",\n      \"pmids\": [\"22998747\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"In vivo requirement of pseudouridylation untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Broadened SRA's coactivator partnerships to RISC machinery, showing Dicer/TRBP/PACT bind SRA and act as nuclear receptor coregulators at steroid-responsive promoters.\",\n      \"evidence\": \"Co-IP, ChIP, reporter assays, subcellular fractionation with Ago2 and pre-miRNA association\",\n      \"pmids\": [\"23550157\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Functional consequence of pre-miRNA co-association unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended SRA/Ddx5 coactivation to Notch signaling via the RBP-J transcription factor, linking SRA to p300 recruitment and histone acetylation at Notch targets.\",\n      \"evidence\": \"BioID/MS, Co-IP of Ddx5-RBP-J, ChIP, SRA knockdown/overexpression with RT-PCR\",\n      \"pmids\": [\"23396200\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Whether SRA contacts RBP-J directly unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Provided definitive in vivo metabolic function by showing Sra1 knockout mice resist diet-induced obesity with improved insulin sensitivity and reduced hepatic lipid.\",\n      \"evidence\": \"Whole-body knockout mouse, high-fat diet, metabolic phenotyping and gene expression analysis\",\n      \"pmids\": [\"24675075\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not separate ncRNA from SRAP contributions in vivo\", \"Tissue-specific mechanisms not dissected\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Challenged the SRAP-as-RNA-binding-protein model by solving the SRAP C-terminal structure (PRP18-like five-helix bundle) and failing to detect specific SRAP-SRA RNA binding.\",\n      \"evidence\": \"Crystal structure, in vitro and cell-based RNA binding assays (negative), siRNA knockdown with RNA-seq\",\n      \"pmids\": [\"24486609\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct contradiction with #9 unresolved\", \"True molecular function of SRAP undefined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placed SRA at the chromatin-state interface, showing it associates with both TrxG and PRC2, binds NANOG genome-wide, and is required for pluripotency and reprogramming.\",\n      \"evidence\": \"Co-IP, ChIP-seq, RIP-seq, loss-of-function in human pluripotent stem cells\",\n      \"pmids\": [\"26496121\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"How SRA selects TrxG vs PRC2 outcomes unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined a hepatic disease mechanism, showing SRA promotes steatosis by repressing ATGL through inhibition of FoxO1-driven ATGL induction.\",\n      \"evidence\": \"Knockout mice on high-fat diet, hepatocyte gain/loss-of-function, ATGL promoter-reporter assays\",\n      \"pmids\": [\"27759039\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct SRA-FoxO1 relationship not structurally defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed isoform-specific cancer relevance, showing SRSF1-driven exon 3 inclusion produces SRA1-L that promotes hepatocellular carcinoma invasion via CD44.\",\n      \"evidence\": \"RIP, CLIP, RNA pulldown, minigene-MS2 mutation, invasion and in vivo metastasis assays\",\n      \"pmids\": [\"34011971\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Whether the invasion effect is ncRNA- or SRAP-mediated unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular function of the SRAP protein and its relationship to the SRA ncRNA remain unresolved, as does how a single structured RNA is partitioned among its many coactivator and architectural complexes.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SRAP biochemical activity undefined and its proposed SRA-RNA binding contradicted\", \"No high-resolution structure of active SRA RNP\", \"Determinants directing SRA among receptor, chromatin, and insulator complexes unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 4, 14]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 5, 8]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 4, 7]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [2, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 6, 11]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [7, 13]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [8, 12, 17]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 8, 13]}\n    ],\n    \"complexes\": [\n      \"SRC-1/p300 nuclear receptor coactivator complex\",\n      \"CTCF-cohesin insulator complex\",\n      \"TrxG chromatin complex\",\n      \"PRC2\"\n    ],\n    \"partners\": [\n      \"DDX5\",\n      \"DDX17\",\n      \"SLIRP\",\n      \"SRC-1\",\n      \"CTCF\",\n      \"PPARG\",\n      \"NANOG\",\n      \"RBPJ\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":8,"faith_total":8,"faith_pct":100.0}}