{"gene":"SIN3B","run_date":"2026-06-10T07:46:32","timeline":{"discoveries":[{"year":2023,"finding":"Cryo-EM structure of the complete human SIN3B histone deacetylase holo-complex (with and without substrate mimic) reveals that SIN3B encircles HDAC1/2 and contacts its allosteric basic patch to stimulate catalysis; a SIN3B loop inserts into the catalytic tunnel, rearranges to accommodate the acetyl-lysine moiety, and stabilizes the substrate for deacetylation guided by a substrate receptor subunit.","method":"Cryo-EM structure determination, in vitro deacetylase assays, substrate mimic binding","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — complete holo-complex structure with substrate mimic, multiple orthogonal methods in one rigorous study","pmids":["37137925"],"is_preprint":false},{"year":2000,"finding":"NMR solution structure of SIN3B PAH2 domain in complex with a Mad1 N-terminal peptide defines a 'wedged helical bundle' interaction fold: four PAH2 alpha-helices form a hydrophobic cleft that accommodates an amphipathic Mad1 alpha-helix, and Mad1 binding stabilizes secondary structure elements of PAH2.","method":"NMR solution structure determination","journal":"Nature structural biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution NMR structure with functional validation of the interaction interface","pmids":["11101889"],"is_preprint":false},{"year":2010,"finding":"SIN3B forms a mammalian complex with HDAC1, Mrg15, and PHD-finger protein Pf1; this complex localizes ~1 kb downstream of transcription start sites of transcribed genes, requires Pf1 and Mrg15 for chromatin association, and its inactivation promotes increased RNA polymerase II progression and transcription within transcribed regions.","method":"Co-immunoprecipitation, ChIP, siRNA knockdown, RNAP II progression assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ChIP localization, and functional knockdown with defined transcriptional phenotype in one study","pmids":["21041482"],"is_preprint":false},{"year":2010,"finding":"RNF220, a RING finger E3 ubiquitin ligase, directly binds SIN3B (identified by yeast two-hybrid and confirmed by co-immunoprecipitation) and promotes its ubiquitination and proteasomal degradation, thereby regulating Sin3/HDAC complex levels.","method":"Yeast two-hybrid, co-immunoprecipitation, ubiquitination assay, proteasome inhibitor rescue","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus in vitro and in vivo co-IP plus functional ubiquitination assay, single lab","pmids":["20170641"],"is_preprint":false},{"year":2000,"finding":"MNF-beta (myocyte nuclear factor beta), a winged-helix/forkhead protein, forms a co-repressor complex with mammalian SIN3B; MNF-beta mutants unable to bind mSin3 are defective in transcriptional repression and negative growth regulation.","method":"Co-immunoprecipitation, transcriptional repression assay, oncogenic transformation assay with binding-defective mutants","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional mutagenesis in repression and transformation assays, single lab","pmids":["10620510"],"is_preprint":false},{"year":2011,"finding":"Human SIN3B directly interacts with p53 (amino acids 1-399 of SIN3B bind the N-terminal region, aa 1-108, of p53); genotoxic stress (Adriamycin) increases SIN3B levels and recruits the SIN3B/HDAC1 complex to promoters of p53 target genes (HSPA8, MAD1, CRYZ) in a p53-dependent manner, resulting in their repression and increased H3K9 tri-methylation.","method":"Co-immunoprecipitation with deletion mapping, ChIP, shRNA knockdown, p53+/+ vs p53-/- cell comparison","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping, ChIP, and genetic controls (p53+/+ vs -/-), single lab","pmids":["22028823"],"is_preprint":false},{"year":2018,"finding":"SIN3B associates with the DREAM complex (identified by unbiased proteomics); genetic inactivation of Sin3B de-represses DREAM target genes during quiescence but is insufficient alone to allow quiescent cells to re-enter the cell cycle; however, inactivation of APC/C-CDH1 was sufficient to drive Sin3B-/- cells back into the cell cycle, revealing functional cooperation between SIN3B-mediated E2F target repression and APC/C-CDH1 in negative regulation of cell cycle progression.","method":"Proteomics/mass spectrometry, genetic inactivation (Sin3B-/-), RNA-seq, genetic epistasis (APC/C-CDH1 inactivation in Sin3B-/- background)","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — proteomics identification confirmed by genetic epistasis with defined pathway placement and cell cycle phenotype","pmids":["30517867"],"is_preprint":false},{"year":2009,"finding":"SIN3B is required for replicative and oncogene-induced senescence in fibroblasts; Sin3B-inactivated fibroblasts fail to undergo senescence and overexpression of Sin3B triggers senescence and formation of senescence-associated heterochromatic foci.","method":"Genetic inactivation (Sin3B-/- mouse-derived fibroblasts), overexpression, senescence assays, heterochromatic foci imaging","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic KO with defined senescence phenotype, replicated with gain-of-function (overexpression) and corroborated in vivo","pmids":["19654306"],"is_preprint":false},{"year":2014,"finding":"SIN3B is required for KRAS-induced senescence in vivo in pancreatic cells; Sin3B inactivation impairs IL-1α production associated with oncogene-induced senescence, indicating SIN3B links senescence to inflammatory signaling (SASP) that promotes pancreatic cancer progression.","method":"Genetic inactivation in mouse PDAC model, IL-1α measurement, correlation with human tissue samples","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic KO in mouse model with defined in vivo phenotype and cytokine mechanistic readout","pmids":["24691445"],"is_preprint":false},{"year":2014,"finding":"SIN3B directly interacts with MYC protein in a Max-independent manner; HDAC1 is recruited to Myc-Sin3B complexes; Sin3B overexpression induces Myc deacetylation and degradation, while Sin3B silencing leads to Myc upregulation.","method":"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence, proximity ligation assay, HDAC inhibitor treatment, Sin3B knockdown/overexpression","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, PLA, IFA) with functional consequences of KD and OE, single lab","pmids":["24951594"],"is_preprint":false},{"year":2014,"finding":"Bmi-1 directly represses the Sin3B locus to prevent senescence; oncogenic stress causes dissociation of Bmi-1 from the Sin3B locus, de-repressing Sin3B expression; Sin3B is required for the senescent phenotype and elevated reactive oxygen species upon Bmi-1 depletion.","method":"ChIP (Bmi-1 occupancy at Sin3B locus), Bmi-1 depletion, genetic epistasis (Sin3B requirement downstream of Bmi-1 loss)","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus genetic epistasis establishing pathway order, single lab","pmids":["25263442"],"is_preprint":false},{"year":2014,"finding":"SIN3B is recruited by RFX5 to the COL1A2 transcription start site in response to IFN-γ; SIN3B cooperates with G9a histone methyltransferase to establish a repressive chromatin structure; recruitment involves HDAC2-mediated deacetylation of RFX5; SIN3B knockdown abrogates IFN-γ-induced collagen repression.","method":"ChIP, shRNA knockdown, co-immunoprecipitation, histone modification assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus Co-IP plus functional knockdown with defined chromatin and gene expression readouts, single lab","pmids":["24709079"],"is_preprint":false},{"year":2008,"finding":"hSIN3B interacts with ETO and MTG16 (but not MTGR1) ETO homologues; the interaction requires an intact ETO amino-terminus and NHR2 domain; hSIN3B and ETO homologues co-localize in the nucleolus of leukemia cells.","method":"Co-immunoprecipitation (ectopic and endogenous), immunolocalization, protein domain deletion analysis","journal":"BMC molecular biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP with domain mapping and colocalization, single lab, no enzymatic readout","pmids":["18205948"],"is_preprint":false},{"year":2013,"finding":"SIN3B directly binds voltage-gated sodium (Nav) channels; the N-terminal region of SIN3B (containing PAH1/PAH2 domains) mediates binding to a 132-residue portion of the Nav channel cytoplasmic C-terminus; expression of the short Sin3B variant reduces native sodium current and Nav channel gating charge without affecting voltage-dependence of activation, suggesting Sin3B influences Nav channel trafficking or membrane stability.","method":"Yeast two-hybrid, pulldown, co-immunoprecipitation, immunofluorescence colocalization, electrophysiology","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple binding methods plus electrophysiology functional readout, single lab","pmids":["24077057"],"is_preprint":false},{"year":2016,"finding":"BMP4 induces a shift in SIN3B splicing toward the long isoform (which recruits HDACs); RBM39 knockdown prevents this isoform shift and enhances BMP4-dependent transcription; knockdown of long-isoform SIN3B enhances BMP4-dependent transcription whereas knockdown of the short isoform (lacking HDAC recruitment capacity) does not.","method":"siRNA knockdown, luciferase reporter assay, RNA-seq isoform analysis, isoform-specific knockdown","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isoform-specific functional knockdown with reporter and transcriptomic readouts, single lab","pmids":["27324164"],"is_preprint":false},{"year":2021,"finding":"SIN3B haploinsufficiency in humans causes hyperacetylation of a subset of enhancers and promoters (shown by H3K27ac ChIP-seq in patient PBMCs); zebrafish sin3b disruption causes craniofacial patterning defects, commissural axon defects, and reduced body length, establishing an essential role for Sin3B in chromatin-based transcriptional repression in neurodevelopment.","method":"H3K27ac ChIP-seq in patient cells, CRISPR-Cas9 zebrafish knockout, morpholino knockdown","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq epigenome profiling in human patient cells corroborated by zebrafish CRISPR KO and morphant phenotypes across two organisms","pmids":["33811806"],"is_preprint":false},{"year":2023,"finding":"SIN3B is rapidly recruited to DNA double-strand break sites and directs the accumulation of MDC1; SIN3B inactivation delays DSB resolution, sensitizes cancer cells to cisplatin and doxorubicin, and shifts DNA repair pathway choice from canonical NHEJ toward alternative NHEJ.","method":"Genetic inactivation (SIN3B-/-), DNA damage foci analysis, co-immunoprecipitation/localization of MDC1, NHEJ pathway reporter assays, drug sensitivity assays","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic inactivation with defined DDR phenotype and mechanistic pathway placement, single lab","pmids":["37314748"],"is_preprint":false},{"year":2016,"finding":"SIN3B knockdown in breast cancer cells significantly decreases Matrigel invasion and invasive colony formation in 3D matrix, and reduces experimental lung metastases in vivo, while SIN3A knockdown has the opposite effect; RNA-seq identified unique target gene sets for each paralog.","method":"Stable shRNA knockdown (three non-overlapping shRNA), transwell invasion assay, 3D colony assay, in vivo experimental metastasis, RNA-seq","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with multiple shRNA, in vitro and in vivo phenotypes with transcriptomic mechanism, single lab","pmids":["27780928"],"is_preprint":false},{"year":2024,"finding":"Sin3B loss in PDAC tumor cells amplifies CXCL9/10 secretion in response to IFN-γ, creates a CXCL9/10-CXCR3 positive feedback loop increasing CD8+ T cell infiltration and cytotoxicity, and correlates with enhanced H3K27Ac distribution on immune response genes; Sin3B loss also enhances sensitivity to anti-PD1 treatment in murine PDAC models.","method":"Murine PDAC genetic inactivation, cytokine measurements, H3K27Ac ChIP-seq, immune cell infiltration analysis, anti-PD1 treatment in vivo","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic inactivation in mouse model with ChIP-seq epigenomic readout and defined immune mechanism, single lab","pmids":["39316363"],"is_preprint":false},{"year":2019,"finding":"SIN3B promotes integrin αV gene transcription in hepatocellular carcinoma in the presence of sulfatide: sulfatide binds SIN3B (confirmed by mass spectrometry and fat blot), induces a conformational change in the PAH2 domain (from α-helices to β-sheet), causing SIN3B to lose binding affinity for MAD1 and HDAC2, reducing HDAC2 recruitment to the integrin αV promoter and preventing histone H3 deacetylation.","method":"Mass spectrometry, fat blot, molecular modeling, co-immunoprecipitation, ChIP, promoter reporter assay, migration assay","journal":"Journal of molecular cell biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — conformational change based primarily on molecular modeling; Co-IP and ChIP support binding loss but structural mechanism is not directly validated","pmids":["30215728"],"is_preprint":false},{"year":2025,"finding":"Comparison of SIN3B/HDAC2 and MTA1/HDAC1 structures confirms differential modes of HDAC recruitment: HDAC1 Y48 interacts with ELM2/SANT domain-containing proteins (NuRD, CoREST, MIDAC) but not SIN3; a Y48E mutation in HDAC1 disrupts all complexes except SIN3, demonstrating that SIN3B recruits HDAC1/2 through a distinct surface from other co-repressor complexes.","method":"HDAC1 surface mutation (Y48E, E63R), co-immunoprecipitation/mass spectrometry, structural comparison, rescue experiments in HDAC1/2 double-KO cells","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — structural comparison plus mutagenesis and functional rescue in KO cells, single lab preprint","pmids":["bio_10.1101_2025.02.24.639909"],"is_preprint":true}],"current_model":"SIN3B is a scaffold protein that forms the core of a Sin3/HDAC co-repressor holo-complex in which SIN3B encircles and allosterically activates HDAC1/2, inserts a loop into the catalytic tunnel to stabilize acetyl-lysine substrates for deacetylation, and recruits diverse transcription factors (Mad/Mxi, MNF-β, p53, E2Fs, MYC, RFX5) through its PAH domains to repress target gene promoters; it is ubiquitinated and degraded by the E3 ligase RNF220, transcriptionally repressed by Bmi-1 (relieved upon oncogenic stress), and is essential for oncogene-induced and replicative senescence, quiescence maintenance via the DREAM complex, hematopoietic stem cell differentiation, and DNA double-strand break repair pathway choice."},"narrative":{"mechanistic_narrative":"SIN3B is the scaffold subunit of a Sin3/HDAC histone deacetylase co-repressor complex that enforces chromatin-based transcriptional repression and controls cell-cycle exit, senescence, and the DNA damage response [PMID:37137925, PMID:19654306]. Structurally, SIN3B encircles HDAC1/2 and contacts an allosteric basic patch to stimulate catalysis, inserting a loop into the catalytic tunnel that rearranges to accommodate and stabilize the acetyl-lysine substrate for deacetylation [PMID:37137925]; it engages HDAC1/2 through a surface distinct from that used by other co-repressor complexes such as NuRD and CoREST [PMID:bio_10.1101_2025.02.24.639909]. SIN3B couples this enzymatic core to sequence-specific factors through its PAH domains, whose PAH2 module forms a wedged helical bundle that clamps an amphipathic Mad1 helix [PMID:11101889], and it is recruited by MNF-beta, p53, MYC, RFX5, and the DREAM complex to deacetylate and silence target promoters [PMID:10620510, PMID:22028823, PMID:24951594, PMID:30517867, PMID:24709079]. Within transcribed genes, SIN3B operates in a complex with HDAC1, Mrg15, and Pf1 that restrains RNA polymerase II progression downstream of transcription start sites [PMID:21041482]. SIN3B is required for replicative and oncogene-induced senescence, linking KRAS-driven senescence to inflammatory SASP signaling, and its expression is held in check by Bmi-1 repression that is relieved under oncogenic stress [PMID:19654306, PMID:24691445, PMID:25263442]; it maintains quiescence by repressing DREAM/E2F targets in cooperation with APC/C-CDH1 [PMID:30517867]. SIN3B protein levels are controlled by RNF220-mediated ubiquitination and proteasomal degradation [PMID:20170641]. In the DNA damage response SIN3B is recruited to double-strand breaks, directs MDC1 accumulation, and biases repair pathway choice toward canonical NHEJ [PMID:37314748]. SIN3B haploinsufficiency in humans causes enhancer/promoter hyperacetylation and a neurodevelopmental disorder, with zebrafish sin3b loss producing craniofacial and axonal patterning defects [PMID:33811806].","teleology":[{"year":2000,"claim":"Establishing how SIN3B engages sequence-specific repressors defined the structural logic of co-repressor recruitment via its PAH domains.","evidence":"NMR solution structure of the SIN3B PAH2 domain bound to a Mad1 peptide","pmids":["11101889"],"confidence":"High","gaps":["Does not address PAH1/PAH3/PAH4 partner specificity","Does not connect the interaction to HDAC catalytic activation"]},{"year":2000,"claim":"Identification of MNF-beta as a SIN3B partner showed that SIN3B-anchored repression mediates negative growth regulation by forkhead factors.","evidence":"Co-IP and repression/transformation assays with mSin3-binding-defective MNF-beta mutants","pmids":["10620510"],"confidence":"Medium","gaps":["No structural definition of the MNF-beta/SIN3B interface","Did not establish direct target genes"]},{"year":2008,"claim":"Linking SIN3B to ETO/MTG16 leukemia fusion partners extended its repressor reach to hematopoietic oncoproteins and a nucleolar pool.","evidence":"Co-IP with domain mapping and nucleolar colocalization in leukemia cells","pmids":["18205948"],"confidence":"Medium","gaps":["No functional transcriptional readout","Significance of nucleolar localization unresolved"]},{"year":2009,"claim":"Genetic loss- and gain-of-function established SIN3B as a required driver of replicative and oncogene-induced senescence, beyond a passive co-repressor role.","evidence":"Sin3B-/- fibroblasts, overexpression, senescence and heterochromatic foci assays","pmids":["19654306"],"confidence":"High","gaps":["Target genes mediating the senescence program not fully defined","Relationship to the deacetylase activity not dissected"]},{"year":2010,"claim":"Defining the SIN3B-HDAC1-Mrg15-Pf1 complex placed SIN3B within gene bodies as a brake on RNA polymerase II elongation.","evidence":"Reciprocal Co-IP, ChIP localization, and knockdown with RNAP II progression assays","pmids":["21041482"],"confidence":"High","gaps":["Mechanism by which deacetylation restrains elongation not resolved","Recruitment signal within transcribed regions unknown"]},{"year":2010,"claim":"Identifying RNF220 as a SIN3B E3 ligase revealed post-translational control of Sin3/HDAC complex abundance.","evidence":"Yeast two-hybrid, Co-IP, ubiquitination assay, proteasome inhibitor rescue","pmids":["20170641"],"confidence":"Medium","gaps":["Ubiquitination sites on SIN3B not mapped","Physiological signals triggering degradation unknown"]},{"year":2011,"claim":"Demonstrating p53-directed recruitment of SIN3B/HDAC1 under genotoxic stress connected SIN3B to a stress-responsive repression arm of the p53 program.","evidence":"Co-IP with deletion mapping, ChIP, shRNA, p53+/+ vs p53-/- comparison after Adriamycin","pmids":["22028823"],"confidence":"Medium","gaps":["Single lab; reciprocal validation limited","How SIN3B selects p53-repressed vs activated targets unclear"]},{"year":2013,"claim":"Discovery of SIN3B binding to Nav channel C-termini raised a cytoplasmic, non-transcriptional function in ion channel regulation.","evidence":"Yeast two-hybrid, pulldown, Co-IP, colocalization, electrophysiology","pmids":["24077057"],"confidence":"Medium","gaps":["Whether effect reflects trafficking vs membrane stability not resolved","Isoform/tissue context of this function undefined"]},{"year":2014,"claim":"Multiple 2014 studies integrated SIN3B into senescence signaling: it is de-repressed from Bmi-1, drives KRAS-induced senescence and IL-1alpha/SASP, and deacetylates/degrades MYC.","evidence":"ChIP and epistasis of Bmi-1/Sin3B; PDAC genetic KO with IL-1alpha readout; Y2H/Co-IP/PLA with MYC and HDAC inhibitor/KD/OE","pmids":["25263442","24691445","24951594"],"confidence":"Medium","gaps":["Direct vs indirect contribution to SASP gene expression not fully separated","MYC interaction lacks structural definition"]},{"year":2014,"claim":"RFX5-directed recruitment cooperating with G9a showed SIN3B integrates deacetylation with histone methylation to silence collagen during IFN-gamma signaling.","evidence":"ChIP, shRNA, Co-IP, histone modification assays at COL1A2","pmids":["24709079"],"confidence":"Medium","gaps":["Order of HDAC2/G9a recruitment not fully resolved","Generalizability beyond COL1A2 untested"]},{"year":2016,"claim":"Isoform and paralog studies revealed that only the long, HDAC-recruiting SIN3B isoform represses BMP4 targets and that SIN3B versus SIN3A have opposing roles in breast cancer invasion.","evidence":"Isoform-specific siRNA with reporter/RNA-seq; three-shRNA KD with invasion, 3D, and in vivo metastasis assays","pmids":["27324164","27780928"],"confidence":"Medium","gaps":["Splicing control of SIN3B isoforms incompletely defined","Mechanistic basis of SIN3A/SIN3B target divergence unknown"]},{"year":2018,"claim":"Placing SIN3B in the DREAM complex defined its role in quiescence maintenance through E2F target repression cooperating with APC/C-CDH1.","evidence":"Proteomics, Sin3B-/- RNA-seq, genetic epistasis with APC/C-CDH1 inactivation","pmids":["30517867"],"confidence":"High","gaps":["Direct DREAM contact subunit not mapped","How SIN3B loss alone is buffered for cell-cycle re-entry only partially explained"]},{"year":2021,"claim":"Human haploinsufficiency and zebrafish models established SIN3B as essential for enhancer/promoter deacetylation in development and defined a neurodevelopmental disorder.","evidence":"H3K27ac ChIP-seq in patient PBMCs, zebrafish CRISPR KO and morpholino phenotypes","pmids":["33811806"],"confidence":"High","gaps":["Specific dysregulated loci driving the phenotype not pinpointed","Genotype-phenotype spectrum not fully delineated"]},{"year":2023,"claim":"The cryo-EM holo-complex structure resolved how SIN3B mechanically activates HDAC1/2 and presents substrate, defining the enzymatic core at atomic resolution.","evidence":"Cryo-EM with and without substrate mimic plus in vitro deacetylase assays","pmids":["37137925"],"confidence":"High","gaps":["Does not capture transcription-factor-bound states","Dynamics of substrate selection in vivo not addressed"]},{"year":2023,"claim":"Recruitment of SIN3B to double-strand breaks and control of MDC1 accumulation revealed a direct role in DNA repair pathway choice and chemosensitivity.","evidence":"SIN3B-/- cells, damage foci analysis, MDC1 localization, NHEJ reporters, drug sensitivity","pmids":["37314748"],"confidence":"Medium","gaps":["How SIN3B is recruited to break sites unknown","Whether deacetylase activity is required at breaks not established"]},{"year":2024,"claim":"SIN3B loss was shown to remodel the PDAC immune microenvironment via a CXCL9/10-CXCR3 feedback loop, linking its chromatin function to anti-tumor immunity and checkpoint sensitivity.","evidence":"Murine PDAC genetic inactivation, cytokine measurement, H3K27Ac ChIP-seq, immune infiltration, anti-PD1 treatment","pmids":["39316363"],"confidence":"Medium","gaps":["Direct SIN3B-repressed immune loci not fully defined","Single model system"]},{"year":2025,"claim":"Comparative structural and mutational analysis demonstrated that SIN3B uses a distinct HDAC1/2 surface from ELM2/SANT-based complexes, explaining co-repressor-specific recruitment.","evidence":"HDAC1 Y48E/E63R mutation, Co-IP/MS, structural comparison, rescue in HDAC1/2 double-KO cells (preprint)","pmids":["bio_10.1101_2025.02.24.639909"],"confidence":"Medium","gaps":["Preprint, not peer reviewed","Functional consequence of selective disruption for SIN3-specific gene programs untested"]},{"year":null,"claim":"How SIN3B is targeted to specific genomic and damage sites in vivo, and how its enzymatic, structural, and signaling functions are integrated across senescence, repair, and development, remains unresolved.","evidence":"No single study integrates recruitment specificity with the holo-complex activity across contexts","pmids":[],"confidence":"Low","gaps":["Genome-wide recruitment determinants undefined","Causal targets linking SIN3B to each phenotype incompletely mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,20]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,5,11,6]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,11]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,20]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,5,11]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[12]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[16,7]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,2,15,11]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,5,6]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[6,7]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[16]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[7,8,10]}],"complexes":["Sin3/HDAC co-repressor complex","SIN3B-HDAC1-Mrg15-Pf1 complex","DREAM complex"],"partners":["HDAC1","HDAC2","MAD1","P53","MYC","RFX5","RNF220","MDC1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O75182","full_name":"Paired amphipathic helix protein Sin3b","aliases":["Histone deacetylase complex subunit Sin3b","Transcriptional corepressor Sin3b"],"length_aa":1162,"mass_kda":133.1,"function":"Acts as a transcriptional repressor. Interacts with MXI1 to repress MYC responsive genes and antagonize MYC oncogenic activities. Interacts with MAD-MAX heterodimers by binding to MAD. The heterodimer then represses transcription by tethering SIN3B to DNA. Also forms a complex with FOXK1 which represses transcription. With FOXK1, regulates cell cycle progression probably by repressing cell cycle inhibitor genes expression. As part of the SIN3B complex represses transcription and counteracts the histone acetyltransferase activity of EP300 through the recognition H3K27ac marks by PHF12 and the activity of the histone deacetylase HDAC2 (PubMed:37137925). SIN3B complex is recruited downstream of the constitutively active genes transcriptional start sites through interaction with histones and mitigates histone acetylation and RNA polymerase II progression within transcribed regions contributing to the regulation of transcription (PubMed:21041482)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/O75182/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SIN3B","classification":"Not Classified","n_dependent_lines":9,"n_total_lines":1208,"dependency_fraction":0.0074503311258278145},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"HDAC1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SIN3B","total_profiled":1310},"omim":[{"mim_id":"620016","title":"MAX DIMERIZATION PROTEIN 4; MXD4","url":"https://www.omim.org/entry/620016"},{"mim_id":"616642","title":"CHROMOSOME 6 OPEN READING FRAME 89; C6ORF89","url":"https://www.omim.org/entry/616642"},{"mim_id":"616136","title":"RING FINGER PROTEIN 220; RNF220","url":"https://www.omim.org/entry/616136"},{"mim_id":"613084","title":"MYELIN TRANSCRIPTION FACTOR 1-LIKE; MYT1L","url":"https://www.omim.org/entry/613084"},{"mim_id":"608250","title":"SDS3 HOMOLOG, SIN3A COREPRESSOR COMPLEX COMPONENT; SUDS3","url":"https://www.omim.org/entry/608250"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SIN3B"},"hgnc":{"alias_symbol":["KIAA0700"],"prev_symbol":[]},"alphafold":{"accession":"O75182","domains":[{"cath_id":"1.20.1160.11","chopping":"42-122","consensus_level":"high","plddt":80.6311,"start":42,"end":122},{"cath_id":"1.20.1160.11","chopping":"174-198_209-236","consensus_level":"medium","plddt":81.2698,"start":174,"end":236},{"cath_id":"1.20.1160.11","chopping":"306-365","consensus_level":"high","plddt":86.1935,"start":306,"end":365},{"cath_id":"-","chopping":"480-605","consensus_level":"high","plddt":89.4061,"start":480,"end":605},{"cath_id":"-","chopping":"609-639_648-702_771-819_841-984","consensus_level":"medium","plddt":87.0925,"start":609,"end":984},{"cath_id":"-","chopping":"1126-1162","consensus_level":"medium","plddt":68.5051,"start":1126,"end":1162}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75182","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75182-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75182-F1-predicted_aligned_error_v6.png","plddt_mean":68.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SIN3B","jax_strain_url":"https://www.jax.org/strain/search?query=SIN3B"},"sequence":{"accession":"O75182","fasta_url":"https://rest.uniprot.org/uniprotkb/O75182.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75182/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75182"}},"corpus_meta":[{"pmid":"24691445","id":"PMC_24691445","title":"Senescence-associated 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human Sin3B/HDAC1 complex for down-regulation of its target promoters in response to genotoxic stress.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22028823","citation_count":32,"is_preprint":false},{"pmid":"30517867","id":"PMC_30517867","title":"The HDAC-Associated Sin3B Protein Represses DREAM Complex Targets and Cooperates with APC/C to Promote Quiescence.","date":"2018","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/30517867","citation_count":30,"is_preprint":false},{"pmid":"24951594","id":"PMC_24951594","title":"Sin3b interacts with Myc and decreases Myc levels.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24951594","citation_count":26,"is_preprint":false},{"pmid":"33811806","id":"PMC_33811806","title":"Haploinsufficiency of the Sin3/HDAC corepressor complex member SIN3B causes a syndromic intellectual disability/autism spectrum disorder.","date":"2021","source":"American journal 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Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/18469515","citation_count":23,"is_preprint":false},{"pmid":"25263442","id":"PMC_25263442","title":"Transcriptional repression of Sin3B by Bmi-1 prevents cellular senescence and is relieved by oncogene activation.","date":"2014","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/25263442","citation_count":18,"is_preprint":false},{"pmid":"30215728","id":"PMC_30215728","title":"SIN3B promotes integrin αV subunit gene transcription and cell migration of hepatocellular carcinoma.","date":"2019","source":"Journal of molecular cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/30215728","citation_count":17,"is_preprint":false},{"pmid":"27806947","id":"PMC_27806947","title":"The chromatin-associated Sin3B protein is required for hematopoietic stem cell functions in mice.","date":"2016","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/27806947","citation_count":15,"is_preprint":false},{"pmid":"39316363","id":"PMC_39316363","title":"SIN3B Loss Heats up Cold Tumor Microenvironment to Boost Immunotherapy in Pancreatic Cancer.","date":"2024","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/39316363","citation_count":11,"is_preprint":false},{"pmid":"28807943","id":"PMC_28807943","title":"Chromatin-Associated Protein SIN3B Prevents Prostate Cancer Progression by Inducing Senescence.","date":"2017","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/28807943","citation_count":11,"is_preprint":false},{"pmid":"27324164","id":"PMC_27324164","title":"Negative autoregulation of BMP dependent transcription by SIN3B splicing reveals a role for RBM39.","date":"2016","source":"Scientific 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amphipathic helices domains of human Sin3B by altering structure and thermodynamic stability.","date":"2015","source":"Biochemistry. Biokhimiia","url":"https://pubmed.ncbi.nlm.nih.gov/25869359","citation_count":3,"is_preprint":false},{"pmid":"38254205","id":"PMC_38254205","title":"Chromatin accessibility and cell cycle progression are controlled by the HDAC-associated Sin3B protein in murine hematopoietic stem cells.","date":"2024","source":"Epigenetics & chromatin","url":"https://pubmed.ncbi.nlm.nih.gov/38254205","citation_count":2,"is_preprint":false},{"pmid":"37314748","id":"PMC_37314748","title":"Chromatin-Associated SIN3B Protects Cancer Cells from Genotoxic Stress-Induced Apoptosis and Dictates DNA Damage Repair Pathway Choice.","date":"2023","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/37314748","citation_count":1,"is_preprint":false},{"pmid":"36747851","id":"PMC_36747851","title":"The Sin3B chromatin modifier restricts cell cycle progression to dictate hematopoietic stem cell differentiation.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/36747851","citation_count":1,"is_preprint":false},{"pmid":"40393534","id":"PMC_40393534","title":"Knockout of SIN3B modulates transcriptional programs and cell survival in cutaneous melanoma.","date":"2025","source":"Pharmacological research","url":"https://pubmed.ncbi.nlm.nih.gov/40393534","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.02.24.639909","title":"Mutations on the surface of HDAC1 reveal molecular determinants of specific complex assembly and their requirement for gene regulation","date":"2025-02-27","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.24.639909","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.10.08.24315111","title":"Epigenetic and Genetic Profiling of Comorbidity Patterns among Substance Dependence Diagnoses","date":"2024-10-08","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.08.24315111","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15849,"output_tokens":5140,"usd":0.062323,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13538,"output_tokens":5212,"usd":0.098995,"stage2_stop_reason":"end_turn"},"total_usd":0.161318,"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\": 2023,\n      \"finding\": \"Cryo-EM structure of the complete human SIN3B histone deacetylase holo-complex (with and without substrate mimic) reveals that SIN3B encircles HDAC1/2 and contacts its allosteric basic patch to stimulate catalysis; a SIN3B loop inserts into the catalytic tunnel, rearranges to accommodate the acetyl-lysine moiety, and stabilizes the substrate for deacetylation guided by a substrate receptor subunit.\",\n      \"method\": \"Cryo-EM structure determination, in vitro deacetylase assays, substrate mimic binding\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — complete holo-complex structure with substrate mimic, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"37137925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"NMR solution structure of SIN3B PAH2 domain in complex with a Mad1 N-terminal peptide defines a 'wedged helical bundle' interaction fold: four PAH2 alpha-helices form a hydrophobic cleft that accommodates an amphipathic Mad1 alpha-helix, and Mad1 binding stabilizes secondary structure elements of PAH2.\",\n      \"method\": \"NMR solution structure determination\",\n      \"journal\": \"Nature structural biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic-resolution NMR structure with functional validation of the interaction interface\",\n      \"pmids\": [\"11101889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SIN3B forms a mammalian complex with HDAC1, Mrg15, and PHD-finger protein Pf1; this complex localizes ~1 kb downstream of transcription start sites of transcribed genes, requires Pf1 and Mrg15 for chromatin association, and its inactivation promotes increased RNA polymerase II progression and transcription within transcribed regions.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, siRNA knockdown, RNAP II progression assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ChIP localization, and functional knockdown with defined transcriptional phenotype in one study\",\n      \"pmids\": [\"21041482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RNF220, a RING finger E3 ubiquitin ligase, directly binds SIN3B (identified by yeast two-hybrid and confirmed by co-immunoprecipitation) and promotes its ubiquitination and proteasomal degradation, thereby regulating Sin3/HDAC complex levels.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, ubiquitination assay, proteasome inhibitor rescue\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus in vitro and in vivo co-IP plus functional ubiquitination assay, single lab\",\n      \"pmids\": [\"20170641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"MNF-beta (myocyte nuclear factor beta), a winged-helix/forkhead protein, forms a co-repressor complex with mammalian SIN3B; MNF-beta mutants unable to bind mSin3 are defective in transcriptional repression and negative growth regulation.\",\n      \"method\": \"Co-immunoprecipitation, transcriptional repression assay, oncogenic transformation assay with binding-defective mutants\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional mutagenesis in repression and transformation assays, single lab\",\n      \"pmids\": [\"10620510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Human SIN3B directly interacts with p53 (amino acids 1-399 of SIN3B bind the N-terminal region, aa 1-108, of p53); genotoxic stress (Adriamycin) increases SIN3B levels and recruits the SIN3B/HDAC1 complex to promoters of p53 target genes (HSPA8, MAD1, CRYZ) in a p53-dependent manner, resulting in their repression and increased H3K9 tri-methylation.\",\n      \"method\": \"Co-immunoprecipitation with deletion mapping, ChIP, shRNA knockdown, p53+/+ vs p53-/- cell comparison\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping, ChIP, and genetic controls (p53+/+ vs -/-), single lab\",\n      \"pmids\": [\"22028823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SIN3B associates with the DREAM complex (identified by unbiased proteomics); genetic inactivation of Sin3B de-represses DREAM target genes during quiescence but is insufficient alone to allow quiescent cells to re-enter the cell cycle; however, inactivation of APC/C-CDH1 was sufficient to drive Sin3B-/- cells back into the cell cycle, revealing functional cooperation between SIN3B-mediated E2F target repression and APC/C-CDH1 in negative regulation of cell cycle progression.\",\n      \"method\": \"Proteomics/mass spectrometry, genetic inactivation (Sin3B-/-), RNA-seq, genetic epistasis (APC/C-CDH1 inactivation in Sin3B-/- background)\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — proteomics identification confirmed by genetic epistasis with defined pathway placement and cell cycle phenotype\",\n      \"pmids\": [\"30517867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SIN3B is required for replicative and oncogene-induced senescence in fibroblasts; Sin3B-inactivated fibroblasts fail to undergo senescence and overexpression of Sin3B triggers senescence and formation of senescence-associated heterochromatic foci.\",\n      \"method\": \"Genetic inactivation (Sin3B-/- mouse-derived fibroblasts), overexpression, senescence assays, heterochromatic foci imaging\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic KO with defined senescence phenotype, replicated with gain-of-function (overexpression) and corroborated in vivo\",\n      \"pmids\": [\"19654306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SIN3B is required for KRAS-induced senescence in vivo in pancreatic cells; Sin3B inactivation impairs IL-1α production associated with oncogene-induced senescence, indicating SIN3B links senescence to inflammatory signaling (SASP) that promotes pancreatic cancer progression.\",\n      \"method\": \"Genetic inactivation in mouse PDAC model, IL-1α measurement, correlation with human tissue samples\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic KO in mouse model with defined in vivo phenotype and cytokine mechanistic readout\",\n      \"pmids\": [\"24691445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SIN3B directly interacts with MYC protein in a Max-independent manner; HDAC1 is recruited to Myc-Sin3B complexes; Sin3B overexpression induces Myc deacetylation and degradation, while Sin3B silencing leads to Myc upregulation.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence, proximity ligation assay, HDAC inhibitor treatment, Sin3B knockdown/overexpression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, PLA, IFA) with functional consequences of KD and OE, single lab\",\n      \"pmids\": [\"24951594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Bmi-1 directly represses the Sin3B locus to prevent senescence; oncogenic stress causes dissociation of Bmi-1 from the Sin3B locus, de-repressing Sin3B expression; Sin3B is required for the senescent phenotype and elevated reactive oxygen species upon Bmi-1 depletion.\",\n      \"method\": \"ChIP (Bmi-1 occupancy at Sin3B locus), Bmi-1 depletion, genetic epistasis (Sin3B requirement downstream of Bmi-1 loss)\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus genetic epistasis establishing pathway order, single lab\",\n      \"pmids\": [\"25263442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SIN3B is recruited by RFX5 to the COL1A2 transcription start site in response to IFN-γ; SIN3B cooperates with G9a histone methyltransferase to establish a repressive chromatin structure; recruitment involves HDAC2-mediated deacetylation of RFX5; SIN3B knockdown abrogates IFN-γ-induced collagen repression.\",\n      \"method\": \"ChIP, shRNA knockdown, co-immunoprecipitation, histone modification assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus Co-IP plus functional knockdown with defined chromatin and gene expression readouts, single lab\",\n      \"pmids\": [\"24709079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"hSIN3B interacts with ETO and MTG16 (but not MTGR1) ETO homologues; the interaction requires an intact ETO amino-terminus and NHR2 domain; hSIN3B and ETO homologues co-localize in the nucleolus of leukemia cells.\",\n      \"method\": \"Co-immunoprecipitation (ectopic and endogenous), immunolocalization, protein domain deletion analysis\",\n      \"journal\": \"BMC molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP with domain mapping and colocalization, single lab, no enzymatic readout\",\n      \"pmids\": [\"18205948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SIN3B directly binds voltage-gated sodium (Nav) channels; the N-terminal region of SIN3B (containing PAH1/PAH2 domains) mediates binding to a 132-residue portion of the Nav channel cytoplasmic C-terminus; expression of the short Sin3B variant reduces native sodium current and Nav channel gating charge without affecting voltage-dependence of activation, suggesting Sin3B influences Nav channel trafficking or membrane stability.\",\n      \"method\": \"Yeast two-hybrid, pulldown, co-immunoprecipitation, immunofluorescence colocalization, electrophysiology\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple binding methods plus electrophysiology functional readout, single lab\",\n      \"pmids\": [\"24077057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"BMP4 induces a shift in SIN3B splicing toward the long isoform (which recruits HDACs); RBM39 knockdown prevents this isoform shift and enhances BMP4-dependent transcription; knockdown of long-isoform SIN3B enhances BMP4-dependent transcription whereas knockdown of the short isoform (lacking HDAC recruitment capacity) does not.\",\n      \"method\": \"siRNA knockdown, luciferase reporter assay, RNA-seq isoform analysis, isoform-specific knockdown\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isoform-specific functional knockdown with reporter and transcriptomic readouts, single lab\",\n      \"pmids\": [\"27324164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SIN3B haploinsufficiency in humans causes hyperacetylation of a subset of enhancers and promoters (shown by H3K27ac ChIP-seq in patient PBMCs); zebrafish sin3b disruption causes craniofacial patterning defects, commissural axon defects, and reduced body length, establishing an essential role for Sin3B in chromatin-based transcriptional repression in neurodevelopment.\",\n      \"method\": \"H3K27ac ChIP-seq in patient cells, CRISPR-Cas9 zebrafish knockout, morpholino knockdown\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq epigenome profiling in human patient cells corroborated by zebrafish CRISPR KO and morphant phenotypes across two organisms\",\n      \"pmids\": [\"33811806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SIN3B is rapidly recruited to DNA double-strand break sites and directs the accumulation of MDC1; SIN3B inactivation delays DSB resolution, sensitizes cancer cells to cisplatin and doxorubicin, and shifts DNA repair pathway choice from canonical NHEJ toward alternative NHEJ.\",\n      \"method\": \"Genetic inactivation (SIN3B-/-), DNA damage foci analysis, co-immunoprecipitation/localization of MDC1, NHEJ pathway reporter assays, drug sensitivity assays\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic inactivation with defined DDR phenotype and mechanistic pathway placement, single lab\",\n      \"pmids\": [\"37314748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SIN3B knockdown in breast cancer cells significantly decreases Matrigel invasion and invasive colony formation in 3D matrix, and reduces experimental lung metastases in vivo, while SIN3A knockdown has the opposite effect; RNA-seq identified unique target gene sets for each paralog.\",\n      \"method\": \"Stable shRNA knockdown (three non-overlapping shRNA), transwell invasion assay, 3D colony assay, in vivo experimental metastasis, RNA-seq\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with multiple shRNA, in vitro and in vivo phenotypes with transcriptomic mechanism, single lab\",\n      \"pmids\": [\"27780928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Sin3B loss in PDAC tumor cells amplifies CXCL9/10 secretion in response to IFN-γ, creates a CXCL9/10-CXCR3 positive feedback loop increasing CD8+ T cell infiltration and cytotoxicity, and correlates with enhanced H3K27Ac distribution on immune response genes; Sin3B loss also enhances sensitivity to anti-PD1 treatment in murine PDAC models.\",\n      \"method\": \"Murine PDAC genetic inactivation, cytokine measurements, H3K27Ac ChIP-seq, immune cell infiltration analysis, anti-PD1 treatment in vivo\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic inactivation in mouse model with ChIP-seq epigenomic readout and defined immune mechanism, single lab\",\n      \"pmids\": [\"39316363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SIN3B promotes integrin αV gene transcription in hepatocellular carcinoma in the presence of sulfatide: sulfatide binds SIN3B (confirmed by mass spectrometry and fat blot), induces a conformational change in the PAH2 domain (from α-helices to β-sheet), causing SIN3B to lose binding affinity for MAD1 and HDAC2, reducing HDAC2 recruitment to the integrin αV promoter and preventing histone H3 deacetylation.\",\n      \"method\": \"Mass spectrometry, fat blot, molecular modeling, co-immunoprecipitation, ChIP, promoter reporter assay, migration assay\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — conformational change based primarily on molecular modeling; Co-IP and ChIP support binding loss but structural mechanism is not directly validated\",\n      \"pmids\": [\"30215728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Comparison of SIN3B/HDAC2 and MTA1/HDAC1 structures confirms differential modes of HDAC recruitment: HDAC1 Y48 interacts with ELM2/SANT domain-containing proteins (NuRD, CoREST, MIDAC) but not SIN3; a Y48E mutation in HDAC1 disrupts all complexes except SIN3, demonstrating that SIN3B recruits HDAC1/2 through a distinct surface from other co-repressor complexes.\",\n      \"method\": \"HDAC1 surface mutation (Y48E, E63R), co-immunoprecipitation/mass spectrometry, structural comparison, rescue experiments in HDAC1/2 double-KO cells\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structural comparison plus mutagenesis and functional rescue in KO cells, single lab preprint\",\n      \"pmids\": [\"bio_10.1101_2025.02.24.639909\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"SIN3B is a scaffold protein that forms the core of a Sin3/HDAC co-repressor holo-complex in which SIN3B encircles and allosterically activates HDAC1/2, inserts a loop into the catalytic tunnel to stabilize acetyl-lysine substrates for deacetylation, and recruits diverse transcription factors (Mad/Mxi, MNF-β, p53, E2Fs, MYC, RFX5) through its PAH domains to repress target gene promoters; it is ubiquitinated and degraded by the E3 ligase RNF220, transcriptionally repressed by Bmi-1 (relieved upon oncogenic stress), and is essential for oncogene-induced and replicative senescence, quiescence maintenance via the DREAM complex, hematopoietic stem cell differentiation, and DNA double-strand break repair pathway choice.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SIN3B is the scaffold subunit of a Sin3/HDAC histone deacetylase co-repressor complex that enforces chromatin-based transcriptional repression and controls cell-cycle exit, senescence, and the DNA damage response [#0, #7]. Structurally, SIN3B encircles HDAC1/2 and contacts an allosteric basic patch to stimulate catalysis, inserting a loop into the catalytic tunnel that rearranges to accommodate and stabilize the acetyl-lysine substrate for deacetylation [#0]; it engages HDAC1/2 through a surface distinct from that used by other co-repressor complexes such as NuRD and CoREST [#20]. SIN3B couples this enzymatic core to sequence-specific factors through its PAH domains, whose PAH2 module forms a wedged helical bundle that clamps an amphipathic Mad1 helix [#1], and it is recruited by MNF-beta, p53, MYC, RFX5, and the DREAM complex to deacetylate and silence target promoters [#4, #5, #9, #6, #11]. Within transcribed genes, SIN3B operates in a complex with HDAC1, Mrg15, and Pf1 that restrains RNA polymerase II progression downstream of transcription start sites [#2]. SIN3B is required for replicative and oncogene-induced senescence, linking KRAS-driven senescence to inflammatory SASP signaling, and its expression is held in check by Bmi-1 repression that is relieved under oncogenic stress [#7, #8, #10]; it maintains quiescence by repressing DREAM/E2F targets in cooperation with APC/C-CDH1 [#6]. SIN3B protein levels are controlled by RNF220-mediated ubiquitination and proteasomal degradation [#3]. In the DNA damage response SIN3B is recruited to double-strand breaks, directs MDC1 accumulation, and biases repair pathway choice toward canonical NHEJ [#16]. SIN3B haploinsufficiency in humans causes enhancer/promoter hyperacetylation and a neurodevelopmental disorder, with zebrafish sin3b loss producing craniofacial and axonal patterning defects [#15].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing how SIN3B engages sequence-specific repressors defined the structural logic of co-repressor recruitment via its PAH domains.\",\n      \"evidence\": \"NMR solution structure of the SIN3B PAH2 domain bound to a Mad1 peptide\",\n      \"pmids\": [\"11101889\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address PAH1/PAH3/PAH4 partner specificity\", \"Does not connect the interaction to HDAC catalytic activation\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identification of MNF-beta as a SIN3B partner showed that SIN3B-anchored repression mediates negative growth regulation by forkhead factors.\",\n      \"evidence\": \"Co-IP and repression/transformation assays with mSin3-binding-defective MNF-beta mutants\",\n      \"pmids\": [\"10620510\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural definition of the MNF-beta/SIN3B interface\", \"Did not establish direct target genes\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Linking SIN3B to ETO/MTG16 leukemia fusion partners extended its repressor reach to hematopoietic oncoproteins and a nucleolar pool.\",\n      \"evidence\": \"Co-IP with domain mapping and nucleolar colocalization in leukemia cells\",\n      \"pmids\": [\"18205948\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional transcriptional readout\", \"Significance of nucleolar localization unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Genetic loss- and gain-of-function established SIN3B as a required driver of replicative and oncogene-induced senescence, beyond a passive co-repressor role.\",\n      \"evidence\": \"Sin3B-/- fibroblasts, overexpression, senescence and heterochromatic foci assays\",\n      \"pmids\": [\"19654306\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Target genes mediating the senescence program not fully defined\", \"Relationship to the deacetylase activity not dissected\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defining the SIN3B-HDAC1-Mrg15-Pf1 complex placed SIN3B within gene bodies as a brake on RNA polymerase II elongation.\",\n      \"evidence\": \"Reciprocal Co-IP, ChIP localization, and knockdown with RNAP II progression assays\",\n      \"pmids\": [\"21041482\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which deacetylation restrains elongation not resolved\", \"Recruitment signal within transcribed regions unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identifying RNF220 as a SIN3B E3 ligase revealed post-translational control of Sin3/HDAC complex abundance.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, ubiquitination assay, proteasome inhibitor rescue\",\n      \"pmids\": [\"20170641\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitination sites on SIN3B not mapped\", \"Physiological signals triggering degradation unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrating p53-directed recruitment of SIN3B/HDAC1 under genotoxic stress connected SIN3B to a stress-responsive repression arm of the p53 program.\",\n      \"evidence\": \"Co-IP with deletion mapping, ChIP, shRNA, p53+/+ vs p53-/- comparison after Adriamycin\",\n      \"pmids\": [\"22028823\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; reciprocal validation limited\", \"How SIN3B selects p53-repressed vs activated targets unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovery of SIN3B binding to Nav channel C-termini raised a cytoplasmic, non-transcriptional function in ion channel regulation.\",\n      \"evidence\": \"Yeast two-hybrid, pulldown, Co-IP, colocalization, electrophysiology\",\n      \"pmids\": [\"24077057\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether effect reflects trafficking vs membrane stability not resolved\", \"Isoform/tissue context of this function undefined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Multiple 2014 studies integrated SIN3B into senescence signaling: it is de-repressed from Bmi-1, drives KRAS-induced senescence and IL-1alpha/SASP, and deacetylates/degrades MYC.\",\n      \"evidence\": \"ChIP and epistasis of Bmi-1/Sin3B; PDAC genetic KO with IL-1alpha readout; Y2H/Co-IP/PLA with MYC and HDAC inhibitor/KD/OE\",\n      \"pmids\": [\"25263442\", \"24691445\", \"24951594\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect contribution to SASP gene expression not fully separated\", \"MYC interaction lacks structural definition\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"RFX5-directed recruitment cooperating with G9a showed SIN3B integrates deacetylation with histone methylation to silence collagen during IFN-gamma signaling.\",\n      \"evidence\": \"ChIP, shRNA, Co-IP, histone modification assays at COL1A2\",\n      \"pmids\": [\"24709079\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Order of HDAC2/G9a recruitment not fully resolved\", \"Generalizability beyond COL1A2 untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Isoform and paralog studies revealed that only the long, HDAC-recruiting SIN3B isoform represses BMP4 targets and that SIN3B versus SIN3A have opposing roles in breast cancer invasion.\",\n      \"evidence\": \"Isoform-specific siRNA with reporter/RNA-seq; three-shRNA KD with invasion, 3D, and in vivo metastasis assays\",\n      \"pmids\": [\"27324164\", \"27780928\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Splicing control of SIN3B isoforms incompletely defined\", \"Mechanistic basis of SIN3A/SIN3B target divergence unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placing SIN3B in the DREAM complex defined its role in quiescence maintenance through E2F target repression cooperating with APC/C-CDH1.\",\n      \"evidence\": \"Proteomics, Sin3B-/- RNA-seq, genetic epistasis with APC/C-CDH1 inactivation\",\n      \"pmids\": [\"30517867\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct DREAM contact subunit not mapped\", \"How SIN3B loss alone is buffered for cell-cycle re-entry only partially explained\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Human haploinsufficiency and zebrafish models established SIN3B as essential for enhancer/promoter deacetylation in development and defined a neurodevelopmental disorder.\",\n      \"evidence\": \"H3K27ac ChIP-seq in patient PBMCs, zebrafish CRISPR KO and morpholino phenotypes\",\n      \"pmids\": [\"33811806\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific dysregulated loci driving the phenotype not pinpointed\", \"Genotype-phenotype spectrum not fully delineated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The cryo-EM holo-complex structure resolved how SIN3B mechanically activates HDAC1/2 and presents substrate, defining the enzymatic core at atomic resolution.\",\n      \"evidence\": \"Cryo-EM with and without substrate mimic plus in vitro deacetylase assays\",\n      \"pmids\": [\"37137925\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not capture transcription-factor-bound states\", \"Dynamics of substrate selection in vivo not addressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Recruitment of SIN3B to double-strand breaks and control of MDC1 accumulation revealed a direct role in DNA repair pathway choice and chemosensitivity.\",\n      \"evidence\": \"SIN3B-/- cells, damage foci analysis, MDC1 localization, NHEJ reporters, drug sensitivity\",\n      \"pmids\": [\"37314748\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How SIN3B is recruited to break sites unknown\", \"Whether deacetylase activity is required at breaks not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"SIN3B loss was shown to remodel the PDAC immune microenvironment via a CXCL9/10-CXCR3 feedback loop, linking its chromatin function to anti-tumor immunity and checkpoint sensitivity.\",\n      \"evidence\": \"Murine PDAC genetic inactivation, cytokine measurement, H3K27Ac ChIP-seq, immune infiltration, anti-PD1 treatment\",\n      \"pmids\": [\"39316363\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct SIN3B-repressed immune loci not fully defined\", \"Single model system\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Comparative structural and mutational analysis demonstrated that SIN3B uses a distinct HDAC1/2 surface from ELM2/SANT-based complexes, explaining co-repressor-specific recruitment.\",\n      \"evidence\": \"HDAC1 Y48E/E63R mutation, Co-IP/MS, structural comparison, rescue in HDAC1/2 double-KO cells (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.02.24.639909\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer reviewed\", \"Functional consequence of selective disruption for SIN3-specific gene programs untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SIN3B is targeted to specific genomic and damage sites in vivo, and how its enzymatic, structural, and signaling functions are integrated across senescence, repair, and development, remains unresolved.\",\n      \"evidence\": \"No single study integrates recruitment specificity with the holo-complex activity across contexts\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Genome-wide recruitment determinants undefined\", \"Causal targets linking SIN3B to each phenotype incompletely mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 20]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 5, 11, 6]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 11]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 20]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 5, 11]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [16, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 2, 15, 11]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 5, 6]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [16]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [7, 8, 10]}\n    ],\n    \"complexes\": [\n      \"Sin3/HDAC co-repressor complex\",\n      \"SIN3B-HDAC1-Mrg15-Pf1 complex\",\n      \"DREAM complex\"\n    ],\n    \"partners\": [\n      \"HDAC1\",\n      \"HDAC2\",\n      \"MAD1\",\n      \"p53\",\n      \"MYC\",\n      \"RFX5\",\n      \"RNF220\",\n      \"MDC1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}