{"gene":"TAF4","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":1997,"finding":"The N-terminal domain of yeast TAF4 (yTAF(II)130) binds TBP with high affinity (Kd ~1 nM), and this interaction is physiologically significant for cell growth; furthermore, the N-terminal domain actively dissociates TBP from TATA box-containing DNA.","method":"Coimmunoprecipitation, protein blotting, fluorescence anisotropy spectroscopy, genetic complementation of taf130Δ null allele","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro binding assay with Kd measurement, mutagenesis, and genetic complementation in multiple experiments","pmids":["9154807"],"is_preprint":false},{"year":1997,"finding":"Human TAF(II)135 potentiates transcriptional activation by the AF-2 of retinoic acid, thyroid hormone, and vitamin D3 receptors (RAR, TR, VDR) but not by estrogen or RXR receptors; the coactivator activity maps to a region between two conserved domains.","method":"Mammalian cell overexpression transcriptional assays with receptor-specific reporters","journal":"Genes & development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional transcriptional assays in mammalian cells with domain mapping, single lab","pmids":["9192867"],"is_preprint":false},{"year":1997,"finding":"The C-terminal 105 amino acids of hTAF(II)135 directly bind the CR3 activation domain of adenovirus E1A, and overexpression of this C-terminal fragment blocks E1A-inducible transcriptional activation in vivo.","method":"In vitro protein-protein interaction (pulldown), in vivo transcriptional reporter assay","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vitro binding and functional in vivo assay, single lab","pmids":["9311891"],"is_preprint":false},{"year":1997,"finding":"The proline-rich N-terminal activation domain of p45NF-E2 binds specifically to TAFII130, and this interaction is required for enhancer-dependent transcription of the alpha- and beta-globin loci.","method":"Protein-protein interaction studies, mutational analysis, transient transcription assays in NF-E2 null cell line, endogenous locus reactivation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay combined with functional rescue in null cell line, single lab","pmids":["9294161"],"is_preprint":false},{"year":1998,"finding":"Distinct subdomains of hTAFII130 mediate interactions with different activation domains: the Q1 region interacts with Sp1B; Q1-Q4 interact with Sp1A; Q1-Q2 interact with the N-terminal activation domain of CREB. Overexpression of the Q1-Q4 region in HeLa cells inhibits Sp1- but not VP16-mediated transcription.","method":"Yeast two-hybrid, deletion mutagenesis, in vivo transcriptional repression assay in HeLa cells","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast two-hybrid with systematic mutagenesis replicated by functional in-cell assay, two orthogonal methods","pmids":["9742090"],"is_preprint":false},{"year":2000,"finding":"Expanded polyglutamine stretches preferentially bind TAFII130 and suppress CREB-dependent transcription; co-expression of TAFII130 restores CREB-dependent transcription and rescues polyQ-induced cell death.","method":"Protein-protein interaction assays, transcriptional reporter assays, cell viability assays with polyQ constructs","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding assay combined with functional rescue experiments (transcription and cell death), multiple orthogonal readouts","pmids":["10973244"],"is_preprint":false},{"year":2001,"finding":"hTAFII130 serves as a coactivator for NFATp: it binds directly to the C-terminal domain (aa 688–921) of NFATp, and a partial TFIID complex (TBP + TAF250 + TAF130) supports NFATp-activated transcription in vitro.","method":"Reconstituted in vitro transcription assay, in vitro pulldown interaction assay, overexpression in Cos-1 cells","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of transcription with defined recombinant components plus binding assay, single lab","pmids":["11313476"],"is_preprint":false},{"year":2001,"finding":"TBP and TAFII135 are selectively depleted during retinoic acid-induced differentiation of F9 embryonal carcinoma cells via targeted proteasome-mediated proteolysis; ectopic TAFII135 expression delays RARγ2 proteolysis and impairs differentiation.","method":"Western blotting, proteasome inhibitor treatment, gain-of-function overexpression, differentiation marker assays","journal":"BMC molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteasome inhibitor experiments plus functional overexpression phenotype, single lab","pmids":["11285139"],"is_preprint":false},{"year":2002,"finding":"hTAFII130 interacts with HP1alpha and HP1gamma (but not HP1beta) in an isoform-specific manner through a pentapeptide HP1-binding motif; mutation of this motif abolishes the interaction. Gal4-HP1 proteins interfere with hTAFII130-mediated transcriptional activation.","method":"Yeast two-hybrid, GST pulldown of endogenous TFIID components from HeLa nuclear extracts, HP1-binding motif mutagenesis, transcriptional reporter assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding assays (yeast two-hybrid + GST pulldown with endogenous proteins) plus mutagenesis and functional transcription assay, multiple orthogonal methods","pmids":["11959914"],"is_preprint":false},{"year":2002,"finding":"The histone-fold domain (HFD) and a short conserved C-terminal domain (CCTD) of yTAF4 are both required for heterodimerization with yTAF12; temperature-sensitive mutations in the HFD α2 helix or CCTD are suppressed by overexpression of yTAF12. Crystal structure of the hTAF4-hTAF12 histone-like heterodimer reveals an atypical HFD organization where the α3 helix lies within the CCTD.","method":"Genetic complementation (ts alleles + overexpression suppression), coexpression in E. coli to test direct heterodimerization, X-ray crystallography","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with genetic and biochemical reconstitution, multiple orthogonal methods","pmids":["12237303"],"is_preprint":false},{"year":2002,"finding":"Mutant huntingtin interacts with transcriptional activator Sp1 and coactivator TAFII130; co-expression of Sp1 and TAFII130 reverses huntingtin-induced transcriptional inhibition of the dopamine D2 receptor gene and protects neurons from huntingtin-induced toxicity.","method":"Co-immunoprecipitation, transcriptional reporter assay in striatal cell cultures, neuroprotection assay, DNA-binding assay in postmortem HD brain","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP combined with functional rescue assays (transcription and neuroprotection), replicated in multiple model systems","pmids":["11988536"],"is_preprint":false},{"year":2005,"finding":"TAF4 inactivation in mouse embryonic fibroblasts deregulates >1000 genes, activates TGF-β signalling and autocrine growth; TAF4 is an essential cofactor for activation by RAR and CREB but not for Sp1 or the vitamin D3 receptor. Loss of TAF4 is compensated by TAF4b-containing TFIID.","method":"Conditional gene inactivation (Taf4−/− MEFs), microarray expression profiling, transcriptional assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with genome-wide transcriptional profiling plus specific activator rescue assays, multiple readouts","pmids":["16015375"],"is_preprint":false},{"year":2005,"finding":"RanBPM is a co-factor of TAF4 in neural progenitor cells; endogenous TAF4 and RanBPM co-immunoprecipitate from neural stem cell extracts. Co-transfection of TAF4 and RanBPM increases primary neurite processes, an effect lost with a TAF4 isoform lacking the RanBPM-interacting domain.","method":"Yeast two-hybrid/protein interaction screen, co-immunoprecipitation, co-transfection morphological assay","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP with endogenous proteins and domain-deletion functional assay, single lab","pmids":["15911349"],"is_preprint":false},{"year":2006,"finding":"TAF4 is the most critical subunit for maintaining the stability of the TFIID complex in Drosophila; RNAi knockdown of TAF4 destabilizes holo-TFIID more than knockdown of TBP or TAF1. TAF4 and TAF1 specifically mediate transcription from TATA-less, DPE-containing promoters, whereas TATA-containing promoters are less dependent on these subunits.","method":"RNAi knockdown of individual TFIID subunits in Drosophila S2 cells, in vitro transcription assays with TATA-less vs. TATA-containing promoter reporters","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic RNAi of all major TFIID subunits combined with functional transcription assays, multiple orthogonal readouts","pmids":["16895980"],"is_preprint":false},{"year":2007,"finding":"The TAF-homology (TAFH) domain of ETO, related in sequence to TAF4, has a structure similar to yeast Rpb4 and E. coli σ70 and acts as a docking platform: overlapping surfaces interact with a repression domain of N-CoR and with an activation domain from E-box transcription factors, enabling interchange of positive and negative coregulators.","method":"X-ray crystallography of ETO-TAFH domain, protein-protein interaction mapping","journal":"Nature structural & molecular biology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — crystal structure with binding surface mapping, but ETO is a TAF4-related but distinct protein; findings inform TAF4 TAFH domain mechanism","pmids":["17572682"],"is_preprint":false},{"year":2007,"finding":"TAF4 inactivation in basal keratinocytes reduces expression of skin barrier genes, causes hair cycle defects, and promotes malignant transformation; TAF4 has cell-autonomous and non-cell-autonomous tumour suppressor activity in mouse epidermis.","method":"Conditional Cre-lox Taf4 inactivation in keratinocytes, gene expression analysis, chemical carcinogenesis assay","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue-specific KO with defined molecular and phenotypic readouts, single lab","pmids":["17626060"],"is_preprint":false},{"year":2008,"finding":"OMA-1 and OMA-2 in C. elegans repress transcription in germline blastomeres P0 and P1 by binding to and sequestering TAF-4 in the cytoplasm, preventing its incorporation into TFIID and the pol II preinitiation complex. This binding requires phosphorylation of OMA-1/2 by the DYRK kinase MBK-2, activated at meiosis II after fertilization.","method":"Genetic epistasis, biochemical binding assays, live imaging, ectopic expression experiments in C. elegans embryos","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis combined with biochemical binding and functional transcriptional repression assays, multiple orthogonal methods","pmids":["18854162"],"is_preprint":false},{"year":2008,"finding":"The ETO coactivation domain of TAF4 is targeted by Wnt/Wingless signalling through Pygopus in Drosophila; expression of TAF4 lacking the ETO domain specifically impairs Wingless-induced transcription of naked cuticle.","method":"Generation of altered holo-TFIID in Drosophila by ETO-domain deletion, in vivo transcription assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-specific deletion in the context of holo-TFIID in vivo, functional transcription readout, single lab","pmids":["19116271"],"is_preprint":false},{"year":2009,"finding":"The TAF4/4b–TAF12 complex binds DNA with high affinity requiring ~70 bp length but with only weak sequence preference; a DNA-binding mutant of TAF4 reduces TFIID occupancy and Initiator activity at a subset of TATA-box/Initiator-containing promoters.","method":"In vitro DNA-binding assays, expression profiling of wild-type vs. DNA-binding mutant TAF4 cells, ChIP for TFIID occupancy","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro binding characterization combined with genome-wide expression profiling and ChIP validation, multiple orthogonal methods","pmids":["19635797"],"is_preprint":false},{"year":2013,"finding":"TAF4 directly interacts with the E-protein activation domain 3 (AD3) through its TAFH domain; this interaction enhances TFIID binding to core promoters and is required for activation of natural E-protein target genes. The TAFH domain has a gene-specific role in TFIID recruitment in vivo.","method":"Biochemical pulldown assays, ChIP, gene expression analysis, domain-specific mutagenesis","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct biochemical interaction mapping with TAFH domain combined with ChIP and transcriptional activation readouts, multiple orthogonal methods","pmids":["23873942"],"is_preprint":false},{"year":2013,"finding":"TAF4b (but not TAF4) interacts with the pluripotency factor Oct4 in embryonic stem cells; TAF4b cooperates with Oct4 to regulate a subset of genes (including Sohlh2 and Yes1), whereas TAF4 inhibits ESC proliferation and is required for later differentiation stages.","method":"Co-immunoprecipitation, knockdown (siRNA), expression profiling","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP showing TAF4b-Oct4 interaction combined with KD gene expression profiling; directly informs TAF4 by contrast, single lab","pmids":["23350932"],"is_preprint":false},{"year":2014,"finding":"The TAF4–TAF12 heterodimer interacts directly with HNF4A, and TAF4 is required in vivo to maintain HNF4A-directed gene expression and to promote HNF4A occupancy at cis-regulatory elements near transcription start sites of post-natal liver function genes; TAF4 promotes preinitiation complex formation at these promoters.","method":"Liver-specific Taf4 inactivation in mice, ChIP-seq, RNA-seq, direct protein interaction assay","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional KO with ChIP-seq and RNA-seq plus direct binding assay, multiple orthogonal methods","pmids":["25209997"],"is_preprint":false},{"year":2016,"finding":"Taf4a−/− embryos survive until E9.5 with primary germ layers intact, but require TAF4 for trunk/anterior patterning and ventral morphogenesis. Taf4a−/− embryonic stem cells contain TAF4b-containing TFIID but fail to complete differentiation into glutamatergic neurons and cardiomyocytes due to impaired preinitiation complex formation at critical differentiation gene promoters.","method":"Taf4a gene inactivation in mice, embryo analysis, ESC in vitro differentiation assays, ChIP for PIC formation","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO plus ESC differentiation assays plus ChIP-based mechanistic validation, multiple orthogonal methods","pmids":["27026076"],"is_preprint":false},{"year":2016,"finding":"Interaction between the Q1 glutamine-rich region of TAF4 and the Q-rich region of Sp1 occurs through intrinsically disordered regions without significant coupled folding; binding sites are localized to defined 20-30 residue stretches identified by NMR chemical shift perturbation.","method":"NMR spectroscopy (heteronuclear, 13C chemical shift analysis), surface plasmon resonance","journal":"Protein science","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — high-resolution NMR with quantitative SPR binding, single lab, characterizes known interaction at residue level","pmids":["27515574","28857320"],"is_preprint":false},{"year":2021,"finding":"TAF4 inactivation in adult pancreatic beta cells impairs critical beta-cell function genes, decreases insulin secretion, and causes trans-differentiation of beta cells into alpha-like cells as revealed by single-cell RNA-seq; computational analysis implicates the NuRF chromatin remodelling complex alongside critical beta-cell transcription factors in this process.","method":"Beta-cell specific Taf4 inactivation in mice, single-cell RNA-seq, glucose tolerance tests, plasma insulin measurement","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with scRNA-seq and functional metabolic assays, single lab","pmids":["34385420"],"is_preprint":false},{"year":2023,"finding":"TAF4 inactivation in intestinal epithelium increases PRC2 (Ezh2/Suz12) activity in enteroid stem/progenitor cells; pharmacological inhibition of Ezh2 restores budding, cell proliferation, and the stem/progenitor compartment in Taf4-mutant enteroids, demonstrating that TAF4 antagonizes PRC2-mediated epigenetic silencing to maintain intestinal stem cell gene expression.","method":"Tissue-specific Taf4 inactivation, enteroid culture, ChIP for PRC2 components, Ezh2 inhibitor treatment, scRNA-seq","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO combined with pharmacological rescue (Ezh2 inhibitor) and chromatin profiling, multiple orthogonal readouts","pmids":["36639541"],"is_preprint":false},{"year":2025,"finding":"TAF4A forms a complex with the heterotrimeric transcription factor NF-Y in muscle stem cells and is required for cell-type-specific expression of Kansl2. TAF4A inactivation reduces Kansl2, alters lamin A/C post-translational modification (acetylation), decreases nuclear stiffness, disrupts nuclear architecture, and causes genomic instability, thereby depleting the stem cell pool and abolishing muscle regeneration.","method":"Muscle stem cell-specific Taf4a inactivation, co-immunoprecipitation, genome stability assays, nuclear mechanics measurements, gene expression analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with multiple orthogonal mechanistic readouts (co-IP, chromatin, nuclear mechanics, transcriptomics), single lab","pmids":["41028714"],"is_preprint":false}],"current_model":"TAF4 (TAFII130/TAFII135) is a core structural subunit of the TFIID complex that nucleates complex stability through its histone-fold domain–mediated heterodimerization with TAF12; it acts as a coactivator by directly binding activation domains of multiple transcription factors (Sp1, CREB, RAR/TR/VDR, NFATp, E proteins, NF-Y, HNF4A, p45NF-E2, Rta) through its glutamine-rich and TAFH domains, thereby facilitating TFIID recruitment and preinitiation complex formation preferentially at TATA-less, DPE-containing promoters; its subcellular availability is regulated by cytoplasmic sequestration (via OMA-1/2 phosphorylated by MBK-2 in C. elegans) and by proteasome-mediated proteolysis during differentiation; in vivo, TAF4 is essential for hepatocyte maturation, neuronal and cardiomyocyte differentiation, intestinal stem cell maintenance (by antagonizing PRC2-mediated silencing), muscle stem cell genome stability (via NF-Y-dependent Kansl2 transcription), and acts as a tumour suppressor in epidermis, while its loss or sequestration broadly disrupts tissue-specific transcriptional programs."},"narrative":{"mechanistic_narrative":"TAF4 (TAFII130/TAFII135) is a core structural subunit of the TFIID general transcription factor complex that couples promoter recognition to activator-dependent transcription across diverse developmental programs [PMID:16895980, PMID:25209997]. Structurally, it anchors TFIID through its histone-fold domain, which together with a short conserved C-terminal domain forms an atypical histone-like heterodimer with TAF12 [PMID:12237303]; this TAF4-TAF12 module binds promoter DNA with high affinity but weak sequence preference, and a DNA-binding mutant reduces TFIID occupancy and Initiator activity at specific promoters [PMID:19635797]. In Drosophila, TAF4 is the subunit most critical for holo-TFIID stability and, with TAF1, preferentially supports transcription from TATA-less, DPE-containing promoters [PMID:16895980]. Functionally, TAF4 acts as a coactivator by directly engaging the activation domains of numerous transcription factors through distinct subdomains: its glutamine-rich Q-regions bind Sp1 and CREB via intrinsically disordered contacts [PMID:9742090, PMID:27515574, PMID:28857320], while its TAFH domain binds E-protein activation domains to enhance TFIID recruitment at target promoters [PMID:23873942]; additional direct partners include NFATp, p45NF-E2, HNF4A, and the AF-2 of RAR/TR/VDR receptors [PMID:9192867, PMID:9294161, PMID:11313476, PMID:25209997]. Through these contacts TAF4 promotes preinitiation complex formation and is essential in vivo for hepatocyte maturation via HNF4A [PMID:25209997], neuronal and cardiomyocyte differentiation [PMID:27026076], intestinal stem cell maintenance by antagonizing PRC2-mediated silencing [PMID:36639541], and muscle stem cell genome stability via NF-Y-dependent Kansl2 expression [PMID:41028714]; it also functions as a tumour suppressor in epidermis [PMID:17626060]. TAF4 availability is post-transcriptionally controlled by cytoplasmic sequestration and proteasomal proteolysis during differentiation [PMID:11285139, PMID:18854162].","teleology":[{"year":1997,"claim":"Established that TAF4 physically and functionally connects TFIID to the basal machinery and to nuclear receptor activators, defining its dual structural/coactivator role.","evidence":"Fluorescence anisotropy and Co-IP of the yeast TAF4 N-terminal domain with TBP, plus mammalian reporter assays mapping coactivation of RAR/TR/VDR","pmids":["9154807","9192867"],"confidence":"High","gaps":["How TBP dissociation from DNA by the N-terminal domain integrates into PIC assembly was not resolved","Receptor selectivity (active on RAR/TR/VDR but not ER/RXR) mechanism unexplained"]},{"year":1998,"claim":"Resolved that TAF4 uses distinct glutamine-rich subdomains to contact different activators, explaining how one subunit serves multiple transcription factors.","evidence":"Yeast two-hybrid deletion mapping of Q1-Q4 against Sp1A/B and CREB, with in-cell dominant-negative repression assays","pmids":["9742090"],"confidence":"High","gaps":["Did not establish whether different activators compete for overlapping surfaces","In vivo contribution of each subdomain at endogenous promoters not tested"]},{"year":2001,"claim":"Demonstrated TAF4 is a direct coactivator sufficient, within a minimal TFIID subcomplex, to support activator-driven transcription, moving it from binding partner to functional mediator.","evidence":"Reconstituted in vitro transcription with TBP+TAF250+TAF130 and NFATp binding/pulldown assays","pmids":["11313476","9294161"],"confidence":"High","gaps":["Whether full holo-TFIID imposes additional requirements not addressed","Promoter-context dependence of coactivation untested"]},{"year":2002,"claim":"Defined the structural basis of TFIID nucleation by TAF4 and linked it to chromatin via HP1, broadening its mechanistic repertoire.","evidence":"X-ray crystallography of the hTAF4-hTAF12 histone-fold heterodimer with genetic suppression in yeast, plus yeast two-hybrid/GST pulldown of HP1 isoforms","pmids":["12237303","11959914"],"confidence":"High","gaps":["Functional consequence of HP1 binding for endogenous gene silencing not established","How the atypical histone fold packs into intact TFIID architecture unresolved"]},{"year":2002,"claim":"Connected TAF4 to polyglutamine disease pathology by showing expanded-polyQ sequestration of TAF4 disrupts CREB/Sp1-dependent transcription and neuronal survival.","evidence":"Co-IP of mutant huntingtin with Sp1/TAFII130, reporter and neuroprotection rescue assays in striatal cultures and HD brain","pmids":["10973244","11988536"],"confidence":"High","gaps":["Causal contribution of TAF4 sequestration to disease in vivo not isolated from other polyQ effects","Whether endogenous TAF4 levels are limiting in patient neurons not quantified"]},{"year":2006,"claim":"Identified TAF4 as the master stability subunit of TFIID and a determinant of promoter-class specificity, establishing why its loss has broad transcriptional consequences.","evidence":"Systematic RNAi of TFIID subunits in Drosophila S2 cells with TATA-less vs TATA-containing reporter transcription assays","pmids":["16895980"],"confidence":"High","gaps":["Whether mammalian TFIID shares the same stability hierarchy not directly shown here","Molecular basis of DPE preference unresolved"]},{"year":2005,"claim":"Showed TAF4 loss deregulates >1000 genes with activator-selective requirements, and that TAF4b-containing TFIID can partially compensate, revealing paralog redundancy.","evidence":"Conditional Taf4-/- MEFs with microarray profiling and activator-specific transcription assays","pmids":["16015375"],"confidence":"High","gaps":["Determinants of which genes are TAF4-dependent vs TAF4b-redundant not defined","TGF-beta pathway activation mechanism downstream of TAF4 loss unclear"]},{"year":2009,"claim":"Assigned a sequence-nonspecific DNA-binding function to the TAF4-TAF12 module that contributes to TFIID promoter occupancy and Initiator activity.","evidence":"In vitro DNA-binding assays, expression profiling of DNA-binding-mutant cells, and ChIP for TFIID occupancy","pmids":["19635797"],"confidence":"High","gaps":["The ~70 bp length requirement's structural basis not explained","How DNA binding is coordinated with activator contacts not resolved"]},{"year":2013,"claim":"Mapped a gene-specific role for the TAFH domain in TFIID recruitment by direct binding to E-protein activation domains.","evidence":"Biochemical pulldowns, TAFH-domain mutagenesis, ChIP, and target-gene expression analysis","pmids":["23873942"],"confidence":"High","gaps":["Full set of TAFH-dependent target genes not catalogued","Whether the TAFH surface analogous to ETO (idx 14) handles both activators and repressors at TAF4 untested"]},{"year":2016,"claim":"Defined the atomic mode of TAF4-Sp1 recognition as a fuzzy interaction between intrinsically disordered regions without coupled folding.","evidence":"NMR chemical shift perturbation and surface plasmon resonance of the Q1 and Sp1 Q-rich regions","pmids":["27515574","28857320"],"confidence":"Medium","gaps":["Single-lab characterization of one activator pair","Functional consequence of the disordered binding mode in cells not tested"]},{"year":2014,"claim":"Established TAF4 as an in vivo driver of tissue-specific transcription by anchoring HNF4A occupancy and PIC formation at liver gene promoters.","evidence":"Liver-specific Taf4 inactivation with ChIP-seq, RNA-seq, and direct TAF4-TAF12/HNF4A binding assay","pmids":["25209997"],"confidence":"High","gaps":["Whether HNF4A recruitment failure is direct or secondary to broader TFIID disruption not separated","Generality to other tissue-restricted activators not shown here"]},{"year":2016,"claim":"Demonstrated that TAF4 is required for terminal differentiation programs (neurons, cardiomyocytes) through PIC assembly at differentiation gene promoters, despite TAF4b redundancy at earlier stages.","evidence":"Taf4a-null mouse embryos and ESC in vitro differentiation with ChIP for PIC formation","pmids":["27026076"],"confidence":"High","gaps":["Why TAF4b cannot substitute at differentiation promoters not mechanistically resolved","Patterning defect's transcriptional targets not fully defined"]},{"year":2008,"claim":"Revealed post-transcriptional control of TAF4 activity by cytoplasmic sequestration and signalling, showing TFIID assembly can be gated by kinase-dependent retention.","evidence":"C. elegans genetic epistasis and binding assays showing OMA-1/2 sequester TAF-4 after MBK-2 phosphorylation; F9 cell proteasome-inhibitor and overexpression assays for differentiation-coupled proteolysis","pmids":["18854162","11285139"],"confidence":"High","gaps":["Conservation of cytoplasmic sequestration in mammals not established","Identity of the ubiquitin ligase directing TAF4 proteolysis unknown"]},{"year":2023,"claim":"Showed TAF4 maintains stem/progenitor gene expression by antagonizing PRC2-mediated epigenetic silencing, linking a TFIID subunit to chromatin repression balance.","evidence":"Intestinal Taf4 inactivation, enteroid culture, PRC2 ChIP, scRNA-seq, and Ezh2-inhibitor pharmacological rescue","pmids":["36639541"],"confidence":"High","gaps":["Whether TAF4 directly opposes PRC2 deposition or acts indirectly via target transcription not resolved","Generality of the TAF4-PRC2 antagonism to other tissues untested"]},{"year":2025,"claim":"Connected TAF4 to genome stability and nuclear mechanics by showing NF-Y-dependent Kansl2 expression maintains lamin A/C modification and nuclear integrity in muscle stem cells.","evidence":"Muscle stem cell-specific Taf4a inactivation with Co-IP, genome stability assays, nuclear mechanics measurements, and expression profiling","pmids":["41028714"],"confidence":"High","gaps":["Direct molecular link between Kansl2 loss and lamin acetylation not fully delineated","Whether nuclear instability is the primary cause of stem cell depletion vs a parallel effect unresolved"]},{"year":null,"claim":"How TAF4 integrates its multiple activator contacts, DNA binding, chromatin antagonism, and regulated availability into a unified mechanism that selects which genes require TAF4 versus TAF4b across tissues remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying rule predicts TAF4 vs TAF4b dependence at a given promoter","Structural model of holo-TFIID engaging an activator-bound TAF4 in mammalian cells lacking","Mammalian regulation of TAF4 protein levels and localization not characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[4,6,11,19,21]},{"term_id":"GO:0140223","term_label":"general transcription initiation factor activity","supporting_discovery_ids":[0,9,13]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[18]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[9,13]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,19,23]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8,16,18]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[16]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[6,11,13,19,21]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[15,21,22,24,25,26]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[8,25]}],"complexes":["TFIID"],"partners":["TAF12","TBP","SP1","CREB","HNF4A","NFATC2","HP1","NF-Y"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O00268","full_name":"Transcription initiation factor TFIID subunit 4","aliases":["RNA polymerase II TBP-associated factor subunit C","TBP-associated factor 4","Transcription initiation factor TFIID 130 kDa subunit","TAF(II)130","TAFII-130","TAFII130","Transcription initiation factor TFIID 135 kDa subunit","TAF(II)135","TAFII-135","TAFII135"],"length_aa":1085,"mass_kda":110.1,"function":"The TFIID basal transcription factor complex plays a major role in the initiation of RNA polymerase II (Pol II)-dependent transcription (PubMed:33795473). TFIID recognizes and binds promoters with or without a TATA box via its subunit TBP, a TATA-box-binding protein, and promotes assembly of the pre-initiation complex (PIC) (PubMed:33795473). The TFIID complex consists of TBP and TBP-associated factors (TAFs), including TAF1, TAF2, TAF3, TAF4, TAF5, TAF6, TAF7, TAF8, TAF9, TAF10, TAF11, TAF12 and TAF13 (PubMed:10594036, PubMed:33795473, PubMed:8942982). TAF4 may maintain an association between the TFIID and TFIIA complexes, while bound to the promoter, together with TBP, during PIC assembly (PubMed:33795473). Potentiates transcriptional activation by the AF-2S of the retinoic acid, vitamin D3 and thyroid hormone (PubMed:9192867)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/O00268/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TAF4","classification":"Not Classified","n_dependent_lines":256,"n_total_lines":1208,"dependency_fraction":0.2119205298013245},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"TAF1","stoichiometry":10.0},{"gene":"TBP","stoichiometry":4.0},{"gene":"TAF12","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TAF4","total_profiled":1310},"omim":[{"mim_id":"620450","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 73; MRD73","url":"https://www.omim.org/entry/620450"},{"mim_id":"612763","title":"TRANSCRIPTIONAL ADAPTOR 1-LIKE; TADA1L","url":"https://www.omim.org/entry/612763"},{"mim_id":"609514","title":"TATA BOX-BINDING PROTEIN-ASSOCIATED FACTOR 8; TAF8","url":"https://www.omim.org/entry/609514"},{"mim_id":"604517","title":"PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA, COACTIVATOR 1, ALPHA; PPARGC1A","url":"https://www.omim.org/entry/604517"},{"mim_id":"602955","title":"TAF6 RNA POLYMERASE II, TATA BOX-BINDING PROTEIN-ASSOCIATED FACTOR, 80-KD; TAF6","url":"https://www.omim.org/entry/602955"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Endoplasmic reticulum","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TAF4"},"hgnc":{"alias_symbol":["TAFII130","TAFII135"],"prev_symbol":["TAF4A","TAF2C1","TAF2C"]},"alphafold":{"accession":"O00268","domains":[{"cath_id":"1.20.120.1110","chopping":"587-680","consensus_level":"high","plddt":89.7529,"start":587,"end":680},{"cath_id":"1.10.20.10","chopping":"872-926_1055-1085","consensus_level":"medium","plddt":92.4288,"start":872,"end":1085}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O00268","model_url":"https://alphafold.ebi.ac.uk/files/AF-O00268-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O00268-F1-predicted_aligned_error_v6.png","plddt_mean":52.78},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TAF4","jax_strain_url":"https://www.jax.org/strain/search?query=TAF4"},"sequence":{"accession":"O00268","fasta_url":"https://rest.uniprot.org/uniprotkb/O00268.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O00268/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O00268"}},"corpus_meta":[{"pmid":"11988536","id":"PMC_11988536","title":"Sp1 and TAFII130 transcriptional activity disrupted in early Huntington's disease.","date":"2002","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/11988536","citation_count":560,"is_preprint":false},{"pmid":"10973244","id":"PMC_10973244","title":"Expanded polyglutamine stretches interact with TAFII130, interfering with CREB-dependent transcription.","date":"2000","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10973244","citation_count":324,"is_preprint":false},{"pmid":"16895980","id":"PMC_16895980","title":"TAF4 nucleates a core subcomplex of TFIID and mediates activated transcription from a TATA-less promoter.","date":"2006","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/16895980","citation_count":129,"is_preprint":false},{"pmid":"9192867","id":"PMC_9192867","title":"Human TAF(II)135 potentiates transcriptional activation by the AF-2s of the retinoic acid, vitamin D3, and thyroid hormone receptors in mammalian cells.","date":"1997","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/9192867","citation_count":124,"is_preprint":false},{"pmid":"9742090","id":"PMC_9742090","title":"Distinct subdomains of human TAFII130 are required for interactions with glutamine-rich transcriptional activators.","date":"1998","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/9742090","citation_count":119,"is_preprint":false},{"pmid":"18854162","id":"PMC_18854162","title":"Global transcriptional repression in C. elegans germline precursors by regulated sequestration of TAF-4.","date":"2008","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/18854162","citation_count":93,"is_preprint":false},{"pmid":"9154807","id":"PMC_9154807","title":"Structure-function analysis of TAF130: identification and characterization of a high-affinity TATA-binding protein interaction domain in the N terminus of yeast TAF(II)130.","date":"1997","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/9154807","citation_count":64,"is_preprint":false},{"pmid":"11959914","id":"PMC_11959914","title":"Isoform-specific interaction of HP1 with human TAFII130.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/11959914","citation_count":61,"is_preprint":false},{"pmid":"9294161","id":"PMC_9294161","title":"The activation domain of the enhancer binding protein p45NF-E2 interacts with TAFII130 and mediates long-range activation of the alpha- and beta-globin gene loci in an erythroid cell line.","date":"1997","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/9294161","citation_count":50,"is_preprint":false},{"pmid":"16015375","id":"PMC_16015375","title":"TAF4 inactivation in embryonic fibroblasts activates TGF beta signalling and autocrine growth.","date":"2005","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/16015375","citation_count":47,"is_preprint":false},{"pmid":"15911349","id":"PMC_15911349","title":"A specific role for the TFIID subunit TAF4 and RanBPM in neural progenitor differentiation.","date":"2005","source":"Molecular and cellular neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/15911349","citation_count":46,"is_preprint":false},{"pmid":"24107417","id":"PMC_24107417","title":"TAF-4 is required for the life extension of isp-1, clk-1 and tpk-1 Mit mutants.","date":"2013","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/24107417","citation_count":42,"is_preprint":false},{"pmid":"9311891","id":"PMC_9311891","title":"The transactivation domain of adenovirus E1A interacts with the C terminus of human TAF(II)135.","date":"1997","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/9311891","citation_count":42,"is_preprint":false},{"pmid":"17572682","id":"PMC_17572682","title":"A TAF4-homology domain from the corepressor ETO is a docking platform for positive and negative regulators of transcription.","date":"2007","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17572682","citation_count":35,"is_preprint":false},{"pmid":"23873942","id":"PMC_23873942","title":"A TAF4 coactivator function for E proteins that involves enhanced TFIID binding.","date":"2013","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/23873942","citation_count":33,"is_preprint":false},{"pmid":"19635797","id":"PMC_19635797","title":"TAF4/4b x TAF12 displays a unique mode of DNA binding and is required for core promoter function of a subset of genes.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19635797","citation_count":30,"is_preprint":false},{"pmid":"25209997","id":"PMC_25209997","title":"TAF4, a subunit of transcription factor II D, directs promoter occupancy of nuclear receptor HNF4A during post-natal hepatocyte differentiation.","date":"2014","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/25209997","citation_count":28,"is_preprint":false},{"pmid":"15735663","id":"PMC_15735663","title":"A functional interaction between ATF7 and TAF12 that is modulated by TAF4.","date":"2005","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/15735663","citation_count":26,"is_preprint":false},{"pmid":"27026076","id":"PMC_27026076","title":"Essential role of the TFIID subunit TAF4 in murine embryogenesis and embryonic stem cell differentiation.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/27026076","citation_count":25,"is_preprint":false},{"pmid":"17626060","id":"PMC_17626060","title":"The TFIID subunit TAF4 regulates keratinocyte proliferation and has cell-autonomous and non-cell-autonomous tumour suppressor activity in mouse epidermis.","date":"2007","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/17626060","citation_count":25,"is_preprint":false},{"pmid":"19116271","id":"PMC_19116271","title":"Wnt signaling targets ETO coactivation domain of TAF4/TFIID in vivo.","date":"2008","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/19116271","citation_count":25,"is_preprint":false},{"pmid":"12237303","id":"PMC_12237303","title":"Functional analysis of the TFIID-specific yeast TAF4 (yTAF(II)48) reveals an unexpected organization of its histone-fold domain.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12237303","citation_count":24,"is_preprint":false},{"pmid":"11285139","id":"PMC_11285139","title":"Coordinate regulation of RARgamma2, TBP, and TAFII135 by targeted proteolysis during retinoic acid-induced differentiation of F9 embryonal carcinoma cells.","date":"2001","source":"BMC molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/11285139","citation_count":23,"is_preprint":false},{"pmid":"24098348","id":"PMC_24098348","title":"Alternative splicing targeting the hTAF4-TAFH domain of TAF4 represses proliferation and accelerates chondrogenic differentiation of human mesenchymal stem cells.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24098348","citation_count":21,"is_preprint":false},{"pmid":"27515574","id":"PMC_27515574","title":"Interaction between intrinsically disordered regions in transcription factors Sp1 and TAF4.","date":"2016","source":"Protein science : a publication of the Protein Society","url":"https://pubmed.ncbi.nlm.nih.gov/27515574","citation_count":15,"is_preprint":false},{"pmid":"11313476","id":"PMC_11313476","title":"Human Taf(II)130 is a coactivator for NFATp.","date":"2001","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/11313476","citation_count":15,"is_preprint":false},{"pmid":"34385420","id":"PMC_34385420","title":"Single cell transcriptomics reveal trans-differentiation of pancreatic beta cells following inactivation of the TFIID subunit Taf4.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/34385420","citation_count":13,"is_preprint":false},{"pmid":"28857320","id":"PMC_28857320","title":"Identification of heteromolecular binding sites in transcription factors Sp1 and TAF4 using high-resolution nuclear magnetic resonance spectroscopy.","date":"2017","source":"Protein science : a publication of the Protein Society","url":"https://pubmed.ncbi.nlm.nih.gov/28857320","citation_count":13,"is_preprint":false},{"pmid":"24498316","id":"PMC_24498316","title":"TAF4 inactivation reveals the 3 dimensional growth promoting activities of collagen 6A3.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24498316","citation_count":12,"is_preprint":false},{"pmid":"23350932","id":"PMC_23350932","title":"TAF4b and TAF4 differentially regulate mouse embryonic stem cells maintenance and proliferation.","date":"2013","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/23350932","citation_count":10,"is_preprint":false},{"pmid":"23326574","id":"PMC_23326574","title":"Role of TAF4 in transcriptional activation by Rta of Epstein-Barr Virus.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23326574","citation_count":10,"is_preprint":false},{"pmid":"27499390","id":"PMC_27499390","title":"Targeted alternative splicing of TAF4: a new strategy for cell reprogramming.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27499390","citation_count":10,"is_preprint":false},{"pmid":"15530431","id":"PMC_15530431","title":"Novel isoforms of the TFIID subunit TAF4 modulate nuclear receptor-mediated transcriptional activity.","date":"2004","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/15530431","citation_count":9,"is_preprint":false},{"pmid":"36639541","id":"PMC_36639541","title":"General transcription factor TAF4 antagonizes epigenetic silencing by Polycomb to maintain intestine stem cell functions.","date":"2023","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/36639541","citation_count":8,"is_preprint":false},{"pmid":"35904126","id":"PMC_35904126","title":"De novo putative loss-of-function variants in TAF4 are associated with a neuro-developmental disorder.","date":"2022","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/35904126","citation_count":8,"is_preprint":false},{"pmid":"32182349","id":"PMC_32182349","title":"Kin28 depletion increases association of TFIID subunits Taf1 and Taf4 with promoters in Saccharomyces cerevisiae.","date":"2020","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/32182349","citation_count":8,"is_preprint":false},{"pmid":"24696168","id":"PMC_24696168","title":"TAF4 controls differentiation of human neural progenitor cells through hTAF4-TAFH activity.","date":"2014","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/24696168","citation_count":6,"is_preprint":false},{"pmid":"11570813","id":"PMC_11570813","title":"Cell-type-specific expression of the TFIID component TAF(II)135 in the nervous system.","date":"2001","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/11570813","citation_count":6,"is_preprint":false},{"pmid":"19936079","id":"PMC_19936079","title":"Intensity dependent confidence intervals on microarray measurements of differentially expressed genes: a case study of the effect of MK5, FKRP and TAF4 on the transcriptome.","date":"2007","source":"Gene regulation and systems biology","url":"https://pubmed.ncbi.nlm.nih.gov/19936079","citation_count":4,"is_preprint":false},{"pmid":"41028714","id":"PMC_41028714","title":"Regulation of NSL by TAF4A is critical for genome stability and quiescence of muscle stem cells.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/41028714","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.06.23.660276","title":"Cotranslational assembly confers specificity for in vivo target heterodimerization of paralogous H2B-like TAF12 proteins in the human fungal pathogen  <i>Candida albicans</i>","date":"2025-06-26","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.23.660276","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.18.660344","title":"Epigenetic genes are differentially methylated in the blood of persons with mild cognitive impairment and Alzheimer’s disease","date":"2025-06-24","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.18.660344","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19967,"output_tokens":6420,"usd":0.078101,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15268,"output_tokens":5003,"usd":0.100708,"stage2_stop_reason":"end_turn"},"total_usd":0.178809,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"The N-terminal domain of yeast TAF4 (yTAF(II)130) binds TBP with high affinity (Kd ~1 nM), and this interaction is physiologically significant for cell growth; furthermore, the N-terminal domain actively dissociates TBP from TATA box-containing DNA.\",\n      \"method\": \"Coimmunoprecipitation, protein blotting, fluorescence anisotropy spectroscopy, genetic complementation of taf130Δ null allele\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro binding assay with Kd measurement, mutagenesis, and genetic complementation in multiple experiments\",\n      \"pmids\": [\"9154807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Human TAF(II)135 potentiates transcriptional activation by the AF-2 of retinoic acid, thyroid hormone, and vitamin D3 receptors (RAR, TR, VDR) but not by estrogen or RXR receptors; the coactivator activity maps to a region between two conserved domains.\",\n      \"method\": \"Mammalian cell overexpression transcriptional assays with receptor-specific reporters\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional transcriptional assays in mammalian cells with domain mapping, single lab\",\n      \"pmids\": [\"9192867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The C-terminal 105 amino acids of hTAF(II)135 directly bind the CR3 activation domain of adenovirus E1A, and overexpression of this C-terminal fragment blocks E1A-inducible transcriptional activation in vivo.\",\n      \"method\": \"In vitro protein-protein interaction (pulldown), in vivo transcriptional reporter assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vitro binding and functional in vivo assay, single lab\",\n      \"pmids\": [\"9311891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The proline-rich N-terminal activation domain of p45NF-E2 binds specifically to TAFII130, and this interaction is required for enhancer-dependent transcription of the alpha- and beta-globin loci.\",\n      \"method\": \"Protein-protein interaction studies, mutational analysis, transient transcription assays in NF-E2 null cell line, endogenous locus reactivation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay combined with functional rescue in null cell line, single lab\",\n      \"pmids\": [\"9294161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Distinct subdomains of hTAFII130 mediate interactions with different activation domains: the Q1 region interacts with Sp1B; Q1-Q4 interact with Sp1A; Q1-Q2 interact with the N-terminal activation domain of CREB. Overexpression of the Q1-Q4 region in HeLa cells inhibits Sp1- but not VP16-mediated transcription.\",\n      \"method\": \"Yeast two-hybrid, deletion mutagenesis, in vivo transcriptional repression assay in HeLa cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast two-hybrid with systematic mutagenesis replicated by functional in-cell assay, two orthogonal methods\",\n      \"pmids\": [\"9742090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Expanded polyglutamine stretches preferentially bind TAFII130 and suppress CREB-dependent transcription; co-expression of TAFII130 restores CREB-dependent transcription and rescues polyQ-induced cell death.\",\n      \"method\": \"Protein-protein interaction assays, transcriptional reporter assays, cell viability assays with polyQ constructs\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding assay combined with functional rescue experiments (transcription and cell death), multiple orthogonal readouts\",\n      \"pmids\": [\"10973244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"hTAFII130 serves as a coactivator for NFATp: it binds directly to the C-terminal domain (aa 688–921) of NFATp, and a partial TFIID complex (TBP + TAF250 + TAF130) supports NFATp-activated transcription in vitro.\",\n      \"method\": \"Reconstituted in vitro transcription assay, in vitro pulldown interaction assay, overexpression in Cos-1 cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of transcription with defined recombinant components plus binding assay, single lab\",\n      \"pmids\": [\"11313476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"TBP and TAFII135 are selectively depleted during retinoic acid-induced differentiation of F9 embryonal carcinoma cells via targeted proteasome-mediated proteolysis; ectopic TAFII135 expression delays RARγ2 proteolysis and impairs differentiation.\",\n      \"method\": \"Western blotting, proteasome inhibitor treatment, gain-of-function overexpression, differentiation marker assays\",\n      \"journal\": \"BMC molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteasome inhibitor experiments plus functional overexpression phenotype, single lab\",\n      \"pmids\": [\"11285139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"hTAFII130 interacts with HP1alpha and HP1gamma (but not HP1beta) in an isoform-specific manner through a pentapeptide HP1-binding motif; mutation of this motif abolishes the interaction. Gal4-HP1 proteins interfere with hTAFII130-mediated transcriptional activation.\",\n      \"method\": \"Yeast two-hybrid, GST pulldown of endogenous TFIID components from HeLa nuclear extracts, HP1-binding motif mutagenesis, transcriptional reporter assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding assays (yeast two-hybrid + GST pulldown with endogenous proteins) plus mutagenesis and functional transcription assay, multiple orthogonal methods\",\n      \"pmids\": [\"11959914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The histone-fold domain (HFD) and a short conserved C-terminal domain (CCTD) of yTAF4 are both required for heterodimerization with yTAF12; temperature-sensitive mutations in the HFD α2 helix or CCTD are suppressed by overexpression of yTAF12. Crystal structure of the hTAF4-hTAF12 histone-like heterodimer reveals an atypical HFD organization where the α3 helix lies within the CCTD.\",\n      \"method\": \"Genetic complementation (ts alleles + overexpression suppression), coexpression in E. coli to test direct heterodimerization, X-ray crystallography\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with genetic and biochemical reconstitution, multiple orthogonal methods\",\n      \"pmids\": [\"12237303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Mutant huntingtin interacts with transcriptional activator Sp1 and coactivator TAFII130; co-expression of Sp1 and TAFII130 reverses huntingtin-induced transcriptional inhibition of the dopamine D2 receptor gene and protects neurons from huntingtin-induced toxicity.\",\n      \"method\": \"Co-immunoprecipitation, transcriptional reporter assay in striatal cell cultures, neuroprotection assay, DNA-binding assay in postmortem HD brain\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP combined with functional rescue assays (transcription and neuroprotection), replicated in multiple model systems\",\n      \"pmids\": [\"11988536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TAF4 inactivation in mouse embryonic fibroblasts deregulates >1000 genes, activates TGF-β signalling and autocrine growth; TAF4 is an essential cofactor for activation by RAR and CREB but not for Sp1 or the vitamin D3 receptor. Loss of TAF4 is compensated by TAF4b-containing TFIID.\",\n      \"method\": \"Conditional gene inactivation (Taf4−/− MEFs), microarray expression profiling, transcriptional assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with genome-wide transcriptional profiling plus specific activator rescue assays, multiple readouts\",\n      \"pmids\": [\"16015375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"RanBPM is a co-factor of TAF4 in neural progenitor cells; endogenous TAF4 and RanBPM co-immunoprecipitate from neural stem cell extracts. Co-transfection of TAF4 and RanBPM increases primary neurite processes, an effect lost with a TAF4 isoform lacking the RanBPM-interacting domain.\",\n      \"method\": \"Yeast two-hybrid/protein interaction screen, co-immunoprecipitation, co-transfection morphological assay\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP with endogenous proteins and domain-deletion functional assay, single lab\",\n      \"pmids\": [\"15911349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TAF4 is the most critical subunit for maintaining the stability of the TFIID complex in Drosophila; RNAi knockdown of TAF4 destabilizes holo-TFIID more than knockdown of TBP or TAF1. TAF4 and TAF1 specifically mediate transcription from TATA-less, DPE-containing promoters, whereas TATA-containing promoters are less dependent on these subunits.\",\n      \"method\": \"RNAi knockdown of individual TFIID subunits in Drosophila S2 cells, in vitro transcription assays with TATA-less vs. TATA-containing promoter reporters\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic RNAi of all major TFIID subunits combined with functional transcription assays, multiple orthogonal readouts\",\n      \"pmids\": [\"16895980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The TAF-homology (TAFH) domain of ETO, related in sequence to TAF4, has a structure similar to yeast Rpb4 and E. coli σ70 and acts as a docking platform: overlapping surfaces interact with a repression domain of N-CoR and with an activation domain from E-box transcription factors, enabling interchange of positive and negative coregulators.\",\n      \"method\": \"X-ray crystallography of ETO-TAFH domain, protein-protein interaction mapping\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with binding surface mapping, but ETO is a TAF4-related but distinct protein; findings inform TAF4 TAFH domain mechanism\",\n      \"pmids\": [\"17572682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TAF4 inactivation in basal keratinocytes reduces expression of skin barrier genes, causes hair cycle defects, and promotes malignant transformation; TAF4 has cell-autonomous and non-cell-autonomous tumour suppressor activity in mouse epidermis.\",\n      \"method\": \"Conditional Cre-lox Taf4 inactivation in keratinocytes, gene expression analysis, chemical carcinogenesis assay\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific KO with defined molecular and phenotypic readouts, single lab\",\n      \"pmids\": [\"17626060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"OMA-1 and OMA-2 in C. elegans repress transcription in germline blastomeres P0 and P1 by binding to and sequestering TAF-4 in the cytoplasm, preventing its incorporation into TFIID and the pol II preinitiation complex. This binding requires phosphorylation of OMA-1/2 by the DYRK kinase MBK-2, activated at meiosis II after fertilization.\",\n      \"method\": \"Genetic epistasis, biochemical binding assays, live imaging, ectopic expression experiments in C. elegans embryos\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis combined with biochemical binding and functional transcriptional repression assays, multiple orthogonal methods\",\n      \"pmids\": [\"18854162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The ETO coactivation domain of TAF4 is targeted by Wnt/Wingless signalling through Pygopus in Drosophila; expression of TAF4 lacking the ETO domain specifically impairs Wingless-induced transcription of naked cuticle.\",\n      \"method\": \"Generation of altered holo-TFIID in Drosophila by ETO-domain deletion, in vivo transcription assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-specific deletion in the context of holo-TFIID in vivo, functional transcription readout, single lab\",\n      \"pmids\": [\"19116271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The TAF4/4b–TAF12 complex binds DNA with high affinity requiring ~70 bp length but with only weak sequence preference; a DNA-binding mutant of TAF4 reduces TFIID occupancy and Initiator activity at a subset of TATA-box/Initiator-containing promoters.\",\n      \"method\": \"In vitro DNA-binding assays, expression profiling of wild-type vs. DNA-binding mutant TAF4 cells, ChIP for TFIID occupancy\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro binding characterization combined with genome-wide expression profiling and ChIP validation, multiple orthogonal methods\",\n      \"pmids\": [\"19635797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TAF4 directly interacts with the E-protein activation domain 3 (AD3) through its TAFH domain; this interaction enhances TFIID binding to core promoters and is required for activation of natural E-protein target genes. The TAFH domain has a gene-specific role in TFIID recruitment in vivo.\",\n      \"method\": \"Biochemical pulldown assays, ChIP, gene expression analysis, domain-specific mutagenesis\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct biochemical interaction mapping with TAFH domain combined with ChIP and transcriptional activation readouts, multiple orthogonal methods\",\n      \"pmids\": [\"23873942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TAF4b (but not TAF4) interacts with the pluripotency factor Oct4 in embryonic stem cells; TAF4b cooperates with Oct4 to regulate a subset of genes (including Sohlh2 and Yes1), whereas TAF4 inhibits ESC proliferation and is required for later differentiation stages.\",\n      \"method\": \"Co-immunoprecipitation, knockdown (siRNA), expression profiling\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP showing TAF4b-Oct4 interaction combined with KD gene expression profiling; directly informs TAF4 by contrast, single lab\",\n      \"pmids\": [\"23350932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The TAF4–TAF12 heterodimer interacts directly with HNF4A, and TAF4 is required in vivo to maintain HNF4A-directed gene expression and to promote HNF4A occupancy at cis-regulatory elements near transcription start sites of post-natal liver function genes; TAF4 promotes preinitiation complex formation at these promoters.\",\n      \"method\": \"Liver-specific Taf4 inactivation in mice, ChIP-seq, RNA-seq, direct protein interaction assay\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional KO with ChIP-seq and RNA-seq plus direct binding assay, multiple orthogonal methods\",\n      \"pmids\": [\"25209997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Taf4a−/− embryos survive until E9.5 with primary germ layers intact, but require TAF4 for trunk/anterior patterning and ventral morphogenesis. Taf4a−/− embryonic stem cells contain TAF4b-containing TFIID but fail to complete differentiation into glutamatergic neurons and cardiomyocytes due to impaired preinitiation complex formation at critical differentiation gene promoters.\",\n      \"method\": \"Taf4a gene inactivation in mice, embryo analysis, ESC in vitro differentiation assays, ChIP for PIC formation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO plus ESC differentiation assays plus ChIP-based mechanistic validation, multiple orthogonal methods\",\n      \"pmids\": [\"27026076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Interaction between the Q1 glutamine-rich region of TAF4 and the Q-rich region of Sp1 occurs through intrinsically disordered regions without significant coupled folding; binding sites are localized to defined 20-30 residue stretches identified by NMR chemical shift perturbation.\",\n      \"method\": \"NMR spectroscopy (heteronuclear, 13C chemical shift analysis), surface plasmon resonance\",\n      \"journal\": \"Protein science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — high-resolution NMR with quantitative SPR binding, single lab, characterizes known interaction at residue level\",\n      \"pmids\": [\"27515574\", \"28857320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TAF4 inactivation in adult pancreatic beta cells impairs critical beta-cell function genes, decreases insulin secretion, and causes trans-differentiation of beta cells into alpha-like cells as revealed by single-cell RNA-seq; computational analysis implicates the NuRF chromatin remodelling complex alongside critical beta-cell transcription factors in this process.\",\n      \"method\": \"Beta-cell specific Taf4 inactivation in mice, single-cell RNA-seq, glucose tolerance tests, plasma insulin measurement\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with scRNA-seq and functional metabolic assays, single lab\",\n      \"pmids\": [\"34385420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TAF4 inactivation in intestinal epithelium increases PRC2 (Ezh2/Suz12) activity in enteroid stem/progenitor cells; pharmacological inhibition of Ezh2 restores budding, cell proliferation, and the stem/progenitor compartment in Taf4-mutant enteroids, demonstrating that TAF4 antagonizes PRC2-mediated epigenetic silencing to maintain intestinal stem cell gene expression.\",\n      \"method\": \"Tissue-specific Taf4 inactivation, enteroid culture, ChIP for PRC2 components, Ezh2 inhibitor treatment, scRNA-seq\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO combined with pharmacological rescue (Ezh2 inhibitor) and chromatin profiling, multiple orthogonal readouts\",\n      \"pmids\": [\"36639541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TAF4A forms a complex with the heterotrimeric transcription factor NF-Y in muscle stem cells and is required for cell-type-specific expression of Kansl2. TAF4A inactivation reduces Kansl2, alters lamin A/C post-translational modification (acetylation), decreases nuclear stiffness, disrupts nuclear architecture, and causes genomic instability, thereby depleting the stem cell pool and abolishing muscle regeneration.\",\n      \"method\": \"Muscle stem cell-specific Taf4a inactivation, co-immunoprecipitation, genome stability assays, nuclear mechanics measurements, gene expression analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with multiple orthogonal mechanistic readouts (co-IP, chromatin, nuclear mechanics, transcriptomics), single lab\",\n      \"pmids\": [\"41028714\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TAF4 (TAFII130/TAFII135) is a core structural subunit of the TFIID complex that nucleates complex stability through its histone-fold domain–mediated heterodimerization with TAF12; it acts as a coactivator by directly binding activation domains of multiple transcription factors (Sp1, CREB, RAR/TR/VDR, NFATp, E proteins, NF-Y, HNF4A, p45NF-E2, Rta) through its glutamine-rich and TAFH domains, thereby facilitating TFIID recruitment and preinitiation complex formation preferentially at TATA-less, DPE-containing promoters; its subcellular availability is regulated by cytoplasmic sequestration (via OMA-1/2 phosphorylated by MBK-2 in C. elegans) and by proteasome-mediated proteolysis during differentiation; in vivo, TAF4 is essential for hepatocyte maturation, neuronal and cardiomyocyte differentiation, intestinal stem cell maintenance (by antagonizing PRC2-mediated silencing), muscle stem cell genome stability (via NF-Y-dependent Kansl2 transcription), and acts as a tumour suppressor in epidermis, while its loss or sequestration broadly disrupts tissue-specific transcriptional programs.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TAF4 (TAFII130/TAFII135) is a core structural subunit of the TFIID general transcription factor complex that couples promoter recognition to activator-dependent transcription across diverse developmental programs [#13, #21]. Structurally, it anchors TFIID through its histone-fold domain, which together with a short conserved C-terminal domain forms an atypical histone-like heterodimer with TAF12 [#9]; this TAF4-TAF12 module binds promoter DNA with high affinity but weak sequence preference, and a DNA-binding mutant reduces TFIID occupancy and Initiator activity at specific promoters [#18]. In Drosophila, TAF4 is the subunit most critical for holo-TFIID stability and, with TAF1, preferentially supports transcription from TATA-less, DPE-containing promoters [#13]. Functionally, TAF4 acts as a coactivator by directly engaging the activation domains of numerous transcription factors through distinct subdomains: its glutamine-rich Q-regions bind Sp1 and CREB via intrinsically disordered contacts [#4, #23], while its TAFH domain binds E-protein activation domains to enhance TFIID recruitment at target promoters [#19]; additional direct partners include NFATp, p45NF-E2, HNF4A, and the AF-2 of RAR/TR/VDR receptors [#1, #3, #6, #21]. Through these contacts TAF4 promotes preinitiation complex formation and is essential in vivo for hepatocyte maturation via HNF4A [#21], neuronal and cardiomyocyte differentiation [#22], intestinal stem cell maintenance by antagonizing PRC2-mediated silencing [#25], and muscle stem cell genome stability via NF-Y-dependent Kansl2 expression [#26]; it also functions as a tumour suppressor in epidermis [#15]. TAF4 availability is post-transcriptionally controlled by cytoplasmic sequestration and proteasomal proteolysis during differentiation [#7, #16].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established that TAF4 physically and functionally connects TFIID to the basal machinery and to nuclear receptor activators, defining its dual structural/coactivator role.\",\n      \"evidence\": \"Fluorescence anisotropy and Co-IP of the yeast TAF4 N-terminal domain with TBP, plus mammalian reporter assays mapping coactivation of RAR/TR/VDR\",\n      \"pmids\": [\"9154807\", \"9192867\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TBP dissociation from DNA by the N-terminal domain integrates into PIC assembly was not resolved\", \"Receptor selectivity (active on RAR/TR/VDR but not ER/RXR) mechanism unexplained\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Resolved that TAF4 uses distinct glutamine-rich subdomains to contact different activators, explaining how one subunit serves multiple transcription factors.\",\n      \"evidence\": \"Yeast two-hybrid deletion mapping of Q1-Q4 against Sp1A/B and CREB, with in-cell dominant-negative repression assays\",\n      \"pmids\": [\"9742090\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish whether different activators compete for overlapping surfaces\", \"In vivo contribution of each subdomain at endogenous promoters not tested\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstrated TAF4 is a direct coactivator sufficient, within a minimal TFIID subcomplex, to support activator-driven transcription, moving it from binding partner to functional mediator.\",\n      \"evidence\": \"Reconstituted in vitro transcription with TBP+TAF250+TAF130 and NFATp binding/pulldown assays\",\n      \"pmids\": [\"11313476\", \"9294161\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether full holo-TFIID imposes additional requirements not addressed\", \"Promoter-context dependence of coactivation untested\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined the structural basis of TFIID nucleation by TAF4 and linked it to chromatin via HP1, broadening its mechanistic repertoire.\",\n      \"evidence\": \"X-ray crystallography of the hTAF4-hTAF12 histone-fold heterodimer with genetic suppression in yeast, plus yeast two-hybrid/GST pulldown of HP1 isoforms\",\n      \"pmids\": [\"12237303\", \"11959914\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of HP1 binding for endogenous gene silencing not established\", \"How the atypical histone fold packs into intact TFIID architecture unresolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Connected TAF4 to polyglutamine disease pathology by showing expanded-polyQ sequestration of TAF4 disrupts CREB/Sp1-dependent transcription and neuronal survival.\",\n      \"evidence\": \"Co-IP of mutant huntingtin with Sp1/TAFII130, reporter and neuroprotection rescue assays in striatal cultures and HD brain\",\n      \"pmids\": [\"10973244\", \"11988536\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal contribution of TAF4 sequestration to disease in vivo not isolated from other polyQ effects\", \"Whether endogenous TAF4 levels are limiting in patient neurons not quantified\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified TAF4 as the master stability subunit of TFIID and a determinant of promoter-class specificity, establishing why its loss has broad transcriptional consequences.\",\n      \"evidence\": \"Systematic RNAi of TFIID subunits in Drosophila S2 cells with TATA-less vs TATA-containing reporter transcription assays\",\n      \"pmids\": [\"16895980\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether mammalian TFIID shares the same stability hierarchy not directly shown here\", \"Molecular basis of DPE preference unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed TAF4 loss deregulates >1000 genes with activator-selective requirements, and that TAF4b-containing TFIID can partially compensate, revealing paralog redundancy.\",\n      \"evidence\": \"Conditional Taf4-/- MEFs with microarray profiling and activator-specific transcription assays\",\n      \"pmids\": [\"16015375\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of which genes are TAF4-dependent vs TAF4b-redundant not defined\", \"TGF-beta pathway activation mechanism downstream of TAF4 loss unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Assigned a sequence-nonspecific DNA-binding function to the TAF4-TAF12 module that contributes to TFIID promoter occupancy and Initiator activity.\",\n      \"evidence\": \"In vitro DNA-binding assays, expression profiling of DNA-binding-mutant cells, and ChIP for TFIID occupancy\",\n      \"pmids\": [\"19635797\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The ~70 bp length requirement's structural basis not explained\", \"How DNA binding is coordinated with activator contacts not resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Mapped a gene-specific role for the TAFH domain in TFIID recruitment by direct binding to E-protein activation domains.\",\n      \"evidence\": \"Biochemical pulldowns, TAFH-domain mutagenesis, ChIP, and target-gene expression analysis\",\n      \"pmids\": [\"23873942\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full set of TAFH-dependent target genes not catalogued\", \"Whether the TAFH surface analogous to ETO (idx 14) handles both activators and repressors at TAF4 untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined the atomic mode of TAF4-Sp1 recognition as a fuzzy interaction between intrinsically disordered regions without coupled folding.\",\n      \"evidence\": \"NMR chemical shift perturbation and surface plasmon resonance of the Q1 and Sp1 Q-rich regions\",\n      \"pmids\": [\"27515574\", \"28857320\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab characterization of one activator pair\", \"Functional consequence of the disordered binding mode in cells not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established TAF4 as an in vivo driver of tissue-specific transcription by anchoring HNF4A occupancy and PIC formation at liver gene promoters.\",\n      \"evidence\": \"Liver-specific Taf4 inactivation with ChIP-seq, RNA-seq, and direct TAF4-TAF12/HNF4A binding assay\",\n      \"pmids\": [\"25209997\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HNF4A recruitment failure is direct or secondary to broader TFIID disruption not separated\", \"Generality to other tissue-restricted activators not shown here\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated that TAF4 is required for terminal differentiation programs (neurons, cardiomyocytes) through PIC assembly at differentiation gene promoters, despite TAF4b redundancy at earlier stages.\",\n      \"evidence\": \"Taf4a-null mouse embryos and ESC in vitro differentiation with ChIP for PIC formation\",\n      \"pmids\": [\"27026076\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why TAF4b cannot substitute at differentiation promoters not mechanistically resolved\", \"Patterning defect's transcriptional targets not fully defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Revealed post-transcriptional control of TAF4 activity by cytoplasmic sequestration and signalling, showing TFIID assembly can be gated by kinase-dependent retention.\",\n      \"evidence\": \"C. elegans genetic epistasis and binding assays showing OMA-1/2 sequester TAF-4 after MBK-2 phosphorylation; F9 cell proteasome-inhibitor and overexpression assays for differentiation-coupled proteolysis\",\n      \"pmids\": [\"18854162\", \"11285139\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conservation of cytoplasmic sequestration in mammals not established\", \"Identity of the ubiquitin ligase directing TAF4 proteolysis unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed TAF4 maintains stem/progenitor gene expression by antagonizing PRC2-mediated epigenetic silencing, linking a TFIID subunit to chromatin repression balance.\",\n      \"evidence\": \"Intestinal Taf4 inactivation, enteroid culture, PRC2 ChIP, scRNA-seq, and Ezh2-inhibitor pharmacological rescue\",\n      \"pmids\": [\"36639541\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TAF4 directly opposes PRC2 deposition or acts indirectly via target transcription not resolved\", \"Generality of the TAF4-PRC2 antagonism to other tissues untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected TAF4 to genome stability and nuclear mechanics by showing NF-Y-dependent Kansl2 expression maintains lamin A/C modification and nuclear integrity in muscle stem cells.\",\n      \"evidence\": \"Muscle stem cell-specific Taf4a inactivation with Co-IP, genome stability assays, nuclear mechanics measurements, and expression profiling\",\n      \"pmids\": [\"41028714\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular link between Kansl2 loss and lamin acetylation not fully delineated\", \"Whether nuclear instability is the primary cause of stem cell depletion vs a parallel effect unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TAF4 integrates its multiple activator contacts, DNA binding, chromatin antagonism, and regulated availability into a unified mechanism that selects which genes require TAF4 versus TAF4b across tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying rule predicts TAF4 vs TAF4b dependence at a given promoter\", \"Structural model of holo-TFIID engaging an activator-bound TAF4 in mammalian cells lacking\", \"Mammalian regulation of TAF4 protein levels and localization not characterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [4, 6, 11, 19, 21]},\n      {\"term_id\": \"GO:0140223\", \"supporting_discovery_ids\": [0, 9, 13]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [18]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [9, 13]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 19, 23]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8, 16, 18]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [6, 11, 13, 19, 21]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [15, 21, 22, 24, 25, 26]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [8, 25]}\n    ],\n    \"complexes\": [\"TFIID\"],\n    \"partners\": [\"TAF12\", \"TBP\", \"SP1\", \"CREB\", \"HNF4A\", \"NFATC2\", \"HP1\", \"NF-Y\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}