{"gene":"SUPT6H","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2021,"finding":"SPT6 (SUPT6H) is required for RNA polymerase II processivity and productive transcription elongation of protein-coding genes; acute depletion via targeted protein degradation caused RNAPII readthrough transcription for thousands of genes, demonstrating a direct role in RNAPII termination. Long-term depletion additionally induced cryptic intragenic transcription, attributable to accumulated epigenetic perturbations rather than the acute loss of SPT6.","method":"Targeted protein degradation (auxin-inducible degron) combined with multi-omics (nascent RNA sequencing, ChIP-seq, mathematical modeling) in human cells","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — targeted acute vs. long-term depletion with multiple orthogonal readouts (nascent transcriptomics, ChIP-seq, mathematical modeling), allowing temporal discrimination of direct vs. indirect effects","pmids":["34233157"],"is_preprint":false},{"year":2014,"finding":"SUPT6H is required for estrogen-regulated transcription and maintenance of chromatin structure in breast cancer cells, acting in part through interaction with RNF40 and regulation of histone H2B monoubiquitination (H2Bub1). SUPT6H is also required for cellular differentiation and suppression of the repressive histone mark H3K27me3 on lineage-specific genes.","method":"siRNA knockdown, Co-immunoprecipitation (interaction with RNF40), ChIP assays for H2Bub1 and H3K27me3, estrogen-responsive gene expression assays in breast cancer cells","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — single lab, multiple orthogonal methods (Co-IP, ChIP, KD with defined epigenetic and transcriptional readouts)","pmids":["24441044"],"is_preprint":false},{"year":2012,"finding":"SUPT6H associates with AID (activation-induced cytidine deaminase) and RNA polymerase II elongation complexes on chromatin of diversifying B cells, as part of the machinery supporting AID-induced immune diversification.","method":"Isolation and characterization of endogenous AID-containing protein complexes from chromatin by mass spectrometry and Co-immunoprecipitation","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP/MS identification of endogenous complex, single lab, functional depletion of PAF complex members (not SUPT6H itself) confirmed role in diversification","pmids":["23008333"],"is_preprint":false},{"year":1996,"finding":"SUPT6H encodes a 1603-amino-acid nuclear protein with a highly acidic N-terminal domain, a degenerate SH2 domain, and a leucine zipper, and is the human homologue of yeast SPT6 and C. elegans emb-5. It is constitutively expressed (7.0-kb transcript) and maps to chromosome 17q11.2. Its extreme conservation with yeast SPT6 is consistent with a role in regulating transcription through establishment or maintenance of chromatin structure.","method":"cDNA cloning, sequencing, Northern blotting, somatic cell hybrid analysis, in situ hybridization","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — foundational cloning/characterization paper; functional inference based on homology to yeast SPT6 rather than direct functional assay in mammalian cells","pmids":["8786132"],"is_preprint":false},{"year":2009,"finding":"SUPT6H directly binds to the cytoplasmic domain of SHPS-1 (a transmembrane scaffold protein) via its SH2 domain in an IGF-I-stimulated manner, placing SUPT6H within the SHPS-1 signaling complex that regulates IGF-I-dependent AKT signaling, cell survival, and protein synthesis in vascular smooth muscle cells.","method":"mRNA display and tandem affinity purification-tag (TAP) functional proteomic screening; in vitro and in vivo binding assays with SHPS-1 cytoplasmic domain","journal":"Molecular & cellular proteomics : MCP","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, TAP/pulldown approach; SUPT6H binding to SHPS-1 identified but not directly validated by reciprocal Co-IP or mutagenesis for SUPT6H specifically","pmids":["19299420"],"is_preprint":false},{"year":2022,"finding":"CDK12 promotes transcription elongation through stabilization of SPT6 (SUPT6H) binding to target differentiation genes, linking CDK12-dependent Ser2 phosphorylation of the RNAPII CTD to SPT6 occupancy and epidermal differentiation gene expression.","method":"ChIP-seq for SPT6 occupancy upon CDK12 depletion, siRNA knockdown in regenerated human epidermis model, differentiation gene expression analysis","journal":"Stem cells (Dayton, Ohio)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq demonstrating SPT6 displacement upon CDK12 depletion, single lab, multiple epigenomic and functional readouts","pmids":["35325240"],"is_preprint":false},{"year":2026,"finding":"Homozygous or heterozygous Supt6 null mice exhibit embryonic lethality, establishing an essential developmental role. Conditional knockout of Supt6 in parvalbumin-expressing GABAergic interneurons causes motor defects, behavioral seizures, and significant reduction in parvalbumin-expressing neurons, demonstrating a cell-autonomous role for SUPT6H in maintaining interneuron populations and neural circuit integrity.","method":"Conditional knockout mouse model (Cre-lox targeting parvalbumin interneurons), behavioral testing, immunohistochemistry for parvalbumin neuron counts, molecular modeling of human SNVs","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function in vivo with defined cellular and behavioral phenotypes, single lab, multiple readouts","pmids":["41864309"],"is_preprint":false},{"year":2022,"finding":"miR-423-5p directly targets SUPT6H mRNA (confirmed by luciferase reporter assay), and SUPT6H knockdown aggravates Ang II-induced cardiomyocyte hypertrophy and oxidative stress, indicating that SUPT6H acts downstream of miR-423-5p to suppress hypertrophic and oxidative responses in cardiomyocytes.","method":"Luciferase reporter assay (miR-423-5p targeting SUPT6H 3'UTR), siRNA knockdown of SUPT6H, Ang II-stimulated human cardiomyocyte hypertrophy assay","journal":"The Tohoku journal of experimental medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method per claim; SUPT6H knockdown phenotype in cardiomyocytes established but no molecular mechanism for how SUPT6H suppresses hypertrophy","pmids":["36517015"],"is_preprint":false}],"current_model":"SUPT6H (SPT6) is a histone chaperone and RNA polymerase II-associated elongation factor that is essential for RNAPII processivity, productive transcription elongation, and transcription termination; it interacts with RNF40 to regulate H2B monoubiquitination and suppresses H3K27me3 on lineage-specific genes, linking elongation to chromatin structure maintenance; its binding to RNAPII is stabilized by CDK12-dependent Ser2 CTD phosphorylation; it is embryonically essential in mice and its loss in parvalbumin interneurons causes neurodevelopmental circuit defects."},"narrative":{"mechanistic_narrative":"SUPT6H (SPT6) is a nuclear histone chaperone and RNA polymerase II elongation factor that couples productive transcription elongation to chromatin structure maintenance [PMID:34233157, PMID:24441044]. Acute targeted degradation establishes a direct role in RNAPII processivity and transcription termination, with loss producing genome-wide readthrough transcription, while prolonged depletion drives cryptic intragenic transcription as a secondary consequence of accumulating epigenetic perturbations [PMID:34233157]. SUPT6H links elongation to chromatin by interacting with RNF40 to regulate histone H2B monoubiquitination and by suppressing the repressive H3K27me3 mark on lineage-specific genes, enabling estrogen-regulated transcription and cellular differentiation [PMID:24441044]. Its occupancy at target differentiation genes is stabilized by CDK12-dependent Ser2 phosphorylation of the RNAPII CTD [PMID:35325240], and it associates with RNAPII elongation complexes engaged by AID during B-cell immune diversification [PMID:23008333]. The first cloned human SUPT6H protein carries an acidic N-terminal domain, a degenerate SH2 domain, and a leucine zipper, and is highly conserved with yeast SPT6 [PMID:8786132]. In vivo, Supt6 is embryonically essential in mice, and its conditional loss in parvalbumin-expressing GABAergic interneurons causes neuron loss, motor defects, and seizures, defining a cell-autonomous role in neural circuit integrity [PMID:41864309].","teleology":[{"year":1996,"claim":"Establishing the human gene's identity and conservation answered whether a mammalian counterpart of yeast SPT6 exists and predicted a chromatin-regulatory role.","evidence":"cDNA cloning, sequencing, Northern blotting, and chromosomal mapping identifying the 1603-aa nuclear protein with acidic N-terminus, degenerate SH2 domain, and leucine zipper","pmids":["8786132"],"confidence":"Medium","gaps":["Function inferred from yeast homology rather than direct mammalian assay","No domain-level mechanism for the SH2 or leucine-zipper regions established"]},{"year":2009,"claim":"A proteomic screen tested whether the SH2 domain mediates cytoplasmic signaling interactions, placing SUPT6H unexpectedly in IGF-I-dependent receptor signaling.","evidence":"mRNA display and TAP-tag functional proteomics with in vitro/in vivo binding assays to the SHPS-1 cytoplasmic domain in vascular smooth muscle cells","pmids":["19299420"],"confidence":"Low","gaps":["Binding not validated by reciprocal Co-IP or SUPT6H-specific mutagenesis","Reconciliation with the protein's nuclear localization not addressed","Functional consequence for SUPT6H itself not demonstrated"]},{"year":2012,"claim":"Characterizing endogenous AID complexes addressed how SUPT6H participates in regulated transcription, linking it to RNAPII elongation machinery during immune diversification.","evidence":"Co-IP/mass spectrometry of endogenous AID-containing chromatin complexes in diversifying B cells","pmids":["23008333"],"confidence":"Medium","gaps":["Functional depletion tested PAF members, not SUPT6H itself","Direct contribution of SUPT6H to AID targeting unresolved"]},{"year":2014,"claim":"Knockdown and interaction studies answered how SUPT6H connects elongation to histone modification, defining the RNF40/H2Bub1 and H3K27me3 axis controlling differentiation.","evidence":"siRNA knockdown, Co-IP with RNF40, and ChIP for H2Bub1 and H3K27me3 in estrogen-responsive breast cancer cells","pmids":["24441044"],"confidence":"Medium","gaps":["Single-lab study","Mechanism by which SUPT6H suppresses H3K27me3 not resolved","Direct enzymatic versus recruitment role in H2B ubiquitination not separated"]},{"year":2021,"claim":"Acute versus long-term degradation discriminated direct from indirect roles, establishing SUPT6H as directly required for RNAPII processivity and termination rather than only chromatin maintenance.","evidence":"Auxin-inducible degron with nascent RNA-seq, ChIP-seq, and mathematical modeling in human cells","pmids":["34233157"],"confidence":"High","gaps":["Molecular basis of the termination defect not structurally defined","Mechanism linking SUPT6H loss to readthrough not enumerated at the factor level"]},{"year":2022,"claim":"ChIP-seq upon CDK12 loss answered how SUPT6H is recruited, tying its chromatin occupancy to Ser2 CTD phosphorylation and differentiation gene expression.","evidence":"ChIP-seq for SPT6 occupancy after CDK12 depletion and siRNA knockdown in a regenerated human epidermis model","pmids":["35325240"],"confidence":"Medium","gaps":["Direct CTD-phospho recognition by SUPT6H not biochemically demonstrated","Single differentiation system tested"]},{"year":2022,"claim":"A microRNA-targeting study placed SUPT6H downstream of miR-423-5p as a suppressor of cardiomyocyte hypertrophy and oxidative stress.","evidence":"Luciferase reporter assay for miR-423-5p targeting and siRNA knockdown in Ang II-stimulated human cardiomyocytes","pmids":["36517015"],"confidence":"Low","gaps":["No molecular mechanism linking SUPT6H to hypertrophy suppression","Single lab, single readout per claim"]},{"year":2026,"claim":"Genetic loss-of-function in mice established the in vivo requirement for SUPT6H in development and in maintaining a specific interneuron population.","evidence":"Constitutive null and parvalbumin-interneuron conditional knockout mice with behavioral testing, immunohistochemistry, and molecular modeling of human SNVs","pmids":["41864309"],"confidence":"Medium","gaps":["Molecular pathway connecting SUPT6H loss to interneuron loss not defined","Causative human Mendelian link not formally established beyond SNV modeling"]},{"year":null,"claim":"How SUPT6H mechanistically distinguishes its acute elongation/termination function from its longer-term chromatin-maintenance role at the level of partner engagement and CTD recognition remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of SUPT6H bound to RNAPII or the phosphorylated CTD in the corpus","Direct enzymatic role in H2Bub1/H3K27me3 control not isolated from recruitment","Reconciliation of cytoplasmic signaling association with nuclear function unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[0,1]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,5]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[1,2]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,5]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[1]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5,6]}],"complexes":[],"partners":["RNF40","CDK12","AICDA","SHPS-1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q7KZ85","full_name":"Transcription elongation factor SPT6","aliases":["Histone chaperone suppressor of Ty6","Tat-cotransactivator 2 protein","Tat-CT2 protein"],"length_aa":1726,"mass_kda":199.1,"function":"Histone H3-H4 chaperone that plays a key role in the regulation of transcription elongation and mRNA processing. Enhances the transcription elongation by RNA polymerase II (RNAPII) and is also required for the efficient activation of transcriptional elongation by the HIV-1 nuclear transcriptional activator, Tat. Besides chaperoning histones in transcription, acts to transport and splice mRNA by forming a complex with IWS1 and the C-terminal domain (CTD) of the RNAPII subunit RPB1 (POLR2A). The SUPT6H:IWS1:CTD complex recruits mRNA export factors (ALYREF/THOC4, EXOSC10) as well as histone modifying enzymes (such as SETD2), to ensure proper mRNA splicing, efficient mRNA export and elongation-coupled H3K36 methylation, a signature chromatin mark of active transcription. SUPT6H via its association with SETD1A, regulates both class-switch recombination and somatic hypermutation through formation of H3K4me3 epigenetic marks on activation-induced cytidine deaminase (AICDA) target loci. Promotes the activation of the myogenic gene program by entailing erasure of the repressive H3K27me3 epigenetic mark through stabilization of the chromatin interaction of the H3K27 demethylase KDM6A","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q7KZ85/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SUPT6H","classification":"Common Essential","n_dependent_lines":1208,"n_total_lines":1208,"dependency_fraction":1.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SSRP1","stoichiometry":4.0},{"gene":"TOP1","stoichiometry":4.0},{"gene":"CPSF6","stoichiometry":0.2},{"gene":"DDOST","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"OST4","stoichiometry":0.2},{"gene":"POLR2B","stoichiometry":0.2},{"gene":"POLR2E","stoichiometry":0.2},{"gene":"POLR2F","stoichiometry":0.2},{"gene":"POLR2H","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SUPT6H","total_profiled":1310},"omim":[{"mim_id":"619818","title":"ELONGATION FACTOR 1; ELOF1","url":"https://www.omim.org/entry/619818"},{"mim_id":"601333","title":"SPT6 HOMOLOG, HISTONE CHAPERONE AND TRANSCRIPTION ELONGATION FACTOR; SUPT6H","url":"https://www.omim.org/entry/601333"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","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/SUPT6H"},"hgnc":{"alias_symbol":["KIAA0162","SPT6H"],"prev_symbol":[]},"alphafold":{"accession":"Q7KZ85","domains":[{"cath_id":"1.10.10.650","chopping":"302-339_351-473","consensus_level":"medium","plddt":88.3785,"start":302,"end":473},{"cath_id":"1.10.3500.10","chopping":"525-615_673-755","consensus_level":"medium","plddt":90.2902,"start":525,"end":755},{"cath_id":"1.10.10.2740","chopping":"1059-1133","consensus_level":"medium","plddt":84.3553,"start":1059,"end":1133},{"cath_id":"2.40.50.140","chopping":"1166-1179_1225-1294","consensus_level":"medium","plddt":88.2735,"start":1166,"end":1294},{"cath_id":"3.30.505.10","chopping":"1388-1515","consensus_level":"medium","plddt":89.2126,"start":1388,"end":1515},{"cath_id":"3.30.160","chopping":"1187-1223","consensus_level":"medium","plddt":80.5616,"start":1187,"end":1223}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7KZ85","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q7KZ85-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q7KZ85-F1-predicted_aligned_error_v6.png","plddt_mean":73.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SUPT6H","jax_strain_url":"https://www.jax.org/strain/search?query=SUPT6H"},"sequence":{"accession":"Q7KZ85","fasta_url":"https://rest.uniprot.org/uniprotkb/Q7KZ85.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q7KZ85/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7KZ85"}},"corpus_meta":[{"pmid":"10631140","id":"PMC_10631140","title":"NF1 microdeletion syndrome: refined FISH characterization of sporadic and familial deletions with locus-specific probes.","date":"2000","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10631140","citation_count":83,"is_preprint":false},{"pmid":"34233157","id":"PMC_34233157","title":"Targeted protein degradation reveals a direct role of SPT6 in RNAPII elongation and termination.","date":"2021","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/34233157","citation_count":61,"is_preprint":false},{"pmid":"23008333","id":"PMC_23008333","title":"A role for the RNA pol II-associated PAF complex in AID-induced immune diversification.","date":"2012","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/23008333","citation_count":56,"is_preprint":false},{"pmid":"24441044","id":"PMC_24441044","title":"SUPT6H controls estrogen receptor activity and cellular differentiation by multiple epigenomic mechanisms.","date":"2014","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/24441044","citation_count":47,"is_preprint":false},{"pmid":"36046712","id":"PMC_36046712","title":"S100A10 and its binding partners in depression and antidepressant actions.","date":"2022","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/36046712","citation_count":28,"is_preprint":false},{"pmid":"32636717","id":"PMC_32636717","title":"The plasma peptides of sepsis.","date":"2020","source":"Clinical proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/32636717","citation_count":26,"is_preprint":false},{"pmid":"8786132","id":"PMC_8786132","title":"Identification and analysis of the human and murine putative chromatin structure regulator SUPT6H and Supt6h.","date":"1996","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8786132","citation_count":25,"is_preprint":false},{"pmid":"30794281","id":"PMC_30794281","title":"Whole Exome Sequencing of Ulcerative Colitis-associated Colorectal Cancer Based on Novel Somatic Mutations Identified in Chinese Patients.","date":"2019","source":"Inflammatory bowel diseases","url":"https://pubmed.ncbi.nlm.nih.gov/30794281","citation_count":21,"is_preprint":false},{"pmid":"19299420","id":"PMC_19299420","title":"Identification of novel SHPS-1-associated proteins and their roles in regulation of insulin-like growth factor-dependent responses in vascular smooth muscle cells.","date":"2009","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/19299420","citation_count":20,"is_preprint":false},{"pmid":"8975720","id":"PMC_8975720","title":"Isolation, sequencing, and mapping of the human homologue of the yeast transcription factor, SPT5.","date":"1996","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8975720","citation_count":19,"is_preprint":false},{"pmid":"25748235","id":"PMC_25748235","title":"Exome sequencing of bilateral testicular germ cell tumors suggests 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Long-term depletion additionally induced cryptic intragenic transcription, attributable to accumulated epigenetic perturbations rather than the acute loss of SPT6.\",\n      \"method\": \"Targeted protein degradation (auxin-inducible degron) combined with multi-omics (nascent RNA sequencing, ChIP-seq, mathematical modeling) in human cells\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — targeted acute vs. long-term depletion with multiple orthogonal readouts (nascent transcriptomics, ChIP-seq, mathematical modeling), allowing temporal discrimination of direct vs. indirect effects\",\n      \"pmids\": [\"34233157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SUPT6H is required for estrogen-regulated transcription and maintenance of chromatin structure in breast cancer cells, acting in part through interaction with RNF40 and regulation of histone H2B monoubiquitination (H2Bub1). SUPT6H is also required for cellular differentiation and suppression of the repressive histone mark H3K27me3 on lineage-specific genes.\",\n      \"method\": \"siRNA knockdown, Co-immunoprecipitation (interaction with RNF40), ChIP assays for H2Bub1 and H3K27me3, estrogen-responsive gene expression assays in breast cancer cells\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — single lab, multiple orthogonal methods (Co-IP, ChIP, KD with defined epigenetic and transcriptional readouts)\",\n      \"pmids\": [\"24441044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SUPT6H associates with AID (activation-induced cytidine deaminase) and RNA polymerase II elongation complexes on chromatin of diversifying B cells, as part of the machinery supporting AID-induced immune diversification.\",\n      \"method\": \"Isolation and characterization of endogenous AID-containing protein complexes from chromatin by mass spectrometry and Co-immunoprecipitation\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP/MS identification of endogenous complex, single lab, functional depletion of PAF complex members (not SUPT6H itself) confirmed role in diversification\",\n      \"pmids\": [\"23008333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"SUPT6H encodes a 1603-amino-acid nuclear protein with a highly acidic N-terminal domain, a degenerate SH2 domain, and a leucine zipper, and is the human homologue of yeast SPT6 and C. elegans emb-5. It is constitutively expressed (7.0-kb transcript) and maps to chromosome 17q11.2. Its extreme conservation with yeast SPT6 is consistent with a role in regulating transcription through establishment or maintenance of chromatin structure.\",\n      \"method\": \"cDNA cloning, sequencing, Northern blotting, somatic cell hybrid analysis, in situ hybridization\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — foundational cloning/characterization paper; functional inference based on homology to yeast SPT6 rather than direct functional assay in mammalian cells\",\n      \"pmids\": [\"8786132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SUPT6H directly binds to the cytoplasmic domain of SHPS-1 (a transmembrane scaffold protein) via its SH2 domain in an IGF-I-stimulated manner, placing SUPT6H within the SHPS-1 signaling complex that regulates IGF-I-dependent AKT signaling, cell survival, and protein synthesis in vascular smooth muscle cells.\",\n      \"method\": \"mRNA display and tandem affinity purification-tag (TAP) functional proteomic screening; in vitro and in vivo binding assays with SHPS-1 cytoplasmic domain\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, TAP/pulldown approach; SUPT6H binding to SHPS-1 identified but not directly validated by reciprocal Co-IP or mutagenesis for SUPT6H specifically\",\n      \"pmids\": [\"19299420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CDK12 promotes transcription elongation through stabilization of SPT6 (SUPT6H) binding to target differentiation genes, linking CDK12-dependent Ser2 phosphorylation of the RNAPII CTD to SPT6 occupancy and epidermal differentiation gene expression.\",\n      \"method\": \"ChIP-seq for SPT6 occupancy upon CDK12 depletion, siRNA knockdown in regenerated human epidermis model, differentiation gene expression analysis\",\n      \"journal\": \"Stem cells (Dayton, Ohio)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq demonstrating SPT6 displacement upon CDK12 depletion, single lab, multiple epigenomic and functional readouts\",\n      \"pmids\": [\"35325240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Homozygous or heterozygous Supt6 null mice exhibit embryonic lethality, establishing an essential developmental role. Conditional knockout of Supt6 in parvalbumin-expressing GABAergic interneurons causes motor defects, behavioral seizures, and significant reduction in parvalbumin-expressing neurons, demonstrating a cell-autonomous role for SUPT6H in maintaining interneuron populations and neural circuit integrity.\",\n      \"method\": \"Conditional knockout mouse model (Cre-lox targeting parvalbumin interneurons), behavioral testing, immunohistochemistry for parvalbumin neuron counts, molecular modeling of human SNVs\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function in vivo with defined cellular and behavioral phenotypes, single lab, multiple readouts\",\n      \"pmids\": [\"41864309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"miR-423-5p directly targets SUPT6H mRNA (confirmed by luciferase reporter assay), and SUPT6H knockdown aggravates Ang II-induced cardiomyocyte hypertrophy and oxidative stress, indicating that SUPT6H acts downstream of miR-423-5p to suppress hypertrophic and oxidative responses in cardiomyocytes.\",\n      \"method\": \"Luciferase reporter assay (miR-423-5p targeting SUPT6H 3'UTR), siRNA knockdown of SUPT6H, Ang II-stimulated human cardiomyocyte hypertrophy assay\",\n      \"journal\": \"The Tohoku journal of experimental medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method per claim; SUPT6H knockdown phenotype in cardiomyocytes established but no molecular mechanism for how SUPT6H suppresses hypertrophy\",\n      \"pmids\": [\"36517015\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SUPT6H (SPT6) is a histone chaperone and RNA polymerase II-associated elongation factor that is essential for RNAPII processivity, productive transcription elongation, and transcription termination; it interacts with RNF40 to regulate H2B monoubiquitination and suppresses H3K27me3 on lineage-specific genes, linking elongation to chromatin structure maintenance; its binding to RNAPII is stabilized by CDK12-dependent Ser2 CTD phosphorylation; it is embryonically essential in mice and its loss in parvalbumin interneurons causes neurodevelopmental circuit defects.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SUPT6H (SPT6) is a nuclear histone chaperone and RNA polymerase II elongation factor that couples productive transcription elongation to chromatin structure maintenance [#0, #1]. Acute targeted degradation establishes a direct role in RNAPII processivity and transcription termination, with loss producing genome-wide readthrough transcription, while prolonged depletion drives cryptic intragenic transcription as a secondary consequence of accumulating epigenetic perturbations [#0]. SUPT6H links elongation to chromatin by interacting with RNF40 to regulate histone H2B monoubiquitination and by suppressing the repressive H3K27me3 mark on lineage-specific genes, enabling estrogen-regulated transcription and cellular differentiation [#1]. Its occupancy at target differentiation genes is stabilized by CDK12-dependent Ser2 phosphorylation of the RNAPII CTD [#5], and it associates with RNAPII elongation complexes engaged by AID during B-cell immune diversification [#2]. The first cloned human SUPT6H protein carries an acidic N-terminal domain, a degenerate SH2 domain, and a leucine zipper, and is highly conserved with yeast SPT6 [#3]. In vivo, Supt6 is embryonically essential in mice, and its conditional loss in parvalbumin-expressing GABAergic interneurons causes neuron loss, motor defects, and seizures, defining a cell-autonomous role in neural circuit integrity [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Establishing the human gene's identity and conservation answered whether a mammalian counterpart of yeast SPT6 exists and predicted a chromatin-regulatory role.\",\n      \"evidence\": \"cDNA cloning, sequencing, Northern blotting, and chromosomal mapping identifying the 1603-aa nuclear protein with acidic N-terminus, degenerate SH2 domain, and leucine zipper\",\n      \"pmids\": [\"8786132\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Function inferred from yeast homology rather than direct mammalian assay\", \"No domain-level mechanism for the SH2 or leucine-zipper regions established\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"A proteomic screen tested whether the SH2 domain mediates cytoplasmic signaling interactions, placing SUPT6H unexpectedly in IGF-I-dependent receptor signaling.\",\n      \"evidence\": \"mRNA display and TAP-tag functional proteomics with in vitro/in vivo binding assays to the SHPS-1 cytoplasmic domain in vascular smooth muscle cells\",\n      \"pmids\": [\"19299420\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Binding not validated by reciprocal Co-IP or SUPT6H-specific mutagenesis\", \"Reconciliation with the protein's nuclear localization not addressed\", \"Functional consequence for SUPT6H itself not demonstrated\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Characterizing endogenous AID complexes addressed how SUPT6H participates in regulated transcription, linking it to RNAPII elongation machinery during immune diversification.\",\n      \"evidence\": \"Co-IP/mass spectrometry of endogenous AID-containing chromatin complexes in diversifying B cells\",\n      \"pmids\": [\"23008333\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional depletion tested PAF members, not SUPT6H itself\", \"Direct contribution of SUPT6H to AID targeting unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Knockdown and interaction studies answered how SUPT6H connects elongation to histone modification, defining the RNF40/H2Bub1 and H3K27me3 axis controlling differentiation.\",\n      \"evidence\": \"siRNA knockdown, Co-IP with RNF40, and ChIP for H2Bub1 and H3K27me3 in estrogen-responsive breast cancer cells\",\n      \"pmids\": [\"24441044\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"Mechanism by which SUPT6H suppresses H3K27me3 not resolved\", \"Direct enzymatic versus recruitment role in H2B ubiquitination not separated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Acute versus long-term degradation discriminated direct from indirect roles, establishing SUPT6H as directly required for RNAPII processivity and termination rather than only chromatin maintenance.\",\n      \"evidence\": \"Auxin-inducible degron with nascent RNA-seq, ChIP-seq, and mathematical modeling in human cells\",\n      \"pmids\": [\"34233157\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of the termination defect not structurally defined\", \"Mechanism linking SUPT6H loss to readthrough not enumerated at the factor level\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"ChIP-seq upon CDK12 loss answered how SUPT6H is recruited, tying its chromatin occupancy to Ser2 CTD phosphorylation and differentiation gene expression.\",\n      \"evidence\": \"ChIP-seq for SPT6 occupancy after CDK12 depletion and siRNA knockdown in a regenerated human epidermis model\",\n      \"pmids\": [\"35325240\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct CTD-phospho recognition by SUPT6H not biochemically demonstrated\", \"Single differentiation system tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A microRNA-targeting study placed SUPT6H downstream of miR-423-5p as a suppressor of cardiomyocyte hypertrophy and oxidative stress.\",\n      \"evidence\": \"Luciferase reporter assay for miR-423-5p targeting and siRNA knockdown in Ang II-stimulated human cardiomyocytes\",\n      \"pmids\": [\"36517015\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No molecular mechanism linking SUPT6H to hypertrophy suppression\", \"Single lab, single readout per claim\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Genetic loss-of-function in mice established the in vivo requirement for SUPT6H in development and in maintaining a specific interneuron population.\",\n      \"evidence\": \"Constitutive null and parvalbumin-interneuron conditional knockout mice with behavioral testing, immunohistochemistry, and molecular modeling of human SNVs\",\n      \"pmids\": [\"41864309\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular pathway connecting SUPT6H loss to interneuron loss not defined\", \"Causative human Mendelian link not formally established beyond SNV modeling\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SUPT6H mechanistically distinguishes its acute elongation/termination function from its longer-term chromatin-maintenance role at the level of partner engagement and CTD recognition remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of SUPT6H bound to RNAPII or the phosphorylated CTD in the corpus\", \"Direct enzymatic role in H2Bub1/H3K27me3 control not isolated from recruitment\", \"Reconciliation of cytoplasmic signaling association with nuclear function unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RNF40\", \"CDK12\", \"AICDA\", \"SHPS-1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}