{"gene":"YEATS4","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2018,"finding":"GAS41 YEATS domain reads histone H3 acetylation (H3K27ac and H3K14ac) via an aromatic cage mechanism, and this interaction recruits GAS41 to promoters of actively transcribed genes to promote H2A.Z deposition in NSCLC cells; disruption of the YEATS-acetylhistone interaction impairs H2A.Z chromatin association and suppresses cancer cell growth.","method":"Crystal structure of YEATS domain bound to acetylated H3 peptides, ChIP-seq, siRNA knockdown, in vitro and in vivo proliferation assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis plus ChIP-seq plus functional rescue in multiple cancer models, replicated across two papers (PMID:29437725 and PMID:29900004)","pmids":["29437725"],"is_preprint":false},{"year":2018,"finding":"Gas41 YEATS domain binds H3K27ac and H3K14ac and recruits Tip60/p400 and SRCAP complexes to deposit H2A.Z into bivalent chromatin domains in mouse ESCs; knockdown of Gas41 reduces H2A.Z and H3K27me3 levels on bivalent domains and disrupts ESC colony morphology, which is rescued by wild-type but not YEATS-mutant Gas41.","method":"Crystal structure of YEATS domain with H3K27ac peptide, Co-IP, ChIP-seq, mutagenesis, ESC knockdown/rescue experiments","journal":"Cell discovery","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure, mutagenesis, functional rescue, and ChIP-seq in one study; orthogonal methods in single lab","pmids":["29900004"],"is_preprint":false},{"year":2003,"finding":"Yaf9 (yeast ortholog) is a subunit of the NuA4 histone acetyltransferase complex; yaf9Δ mutants are hypersensitive to microtubule-depolymerizing agents and synthetically lethal with mitotic apparatus mutants, linking NuA4-mediated H4 acetylation to spindle stress resistance.","method":"Co-immunoprecipitation with NuA4 subunits, genetic epistasis with esa1 and yng2 mutants, microtubule depolymerization assays, benomyl sensitivity assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP establishing complex membership plus genetic epistasis with multiple NuA4 mutants and histone mutants, replicated phenotypes","pmids":["12917332"],"is_preprint":false},{"year":2009,"finding":"The Yaf9 YEATS domain adopts an Ig-fold beta-sandwich structure similar to histone chaperone Asf1; it binds histones H3 and H4 in vitro, and structure-function analysis shows the YEATS domain is required for H2A.Z chromatin deposition at specific promoters and for H2A.Z acetylation in yeast.","method":"X-ray crystallography (2.3 Å), in vitro histone binding assays, structure-function mutagenesis, ChIP for H2A.Z occupancy","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation by mutagenesis and ChIP in yeast, multiple orthogonal methods","pmids":["19966225"],"is_preprint":false},{"year":2006,"finding":"GAS41 is required for repression of the p53 tumor suppressor pathway during normal proliferation; siRNA-mediated knockdown or disruption of the C-terminal coiled-coil motif activates p53, induces p53-Ser15 phosphorylation, and activates p21 transcription. GAS41 is pre-bound to p21 and p14ARF promoters in unstressed cells and dissociates upon stress. This repression is TIP60-independent, as a coiled-coil mutant of GAS41 retains normal TIP60 complex assembly and HAT activity.","method":"siRNA knockdown, promoter-targeted mutagenesis, reporter gene assays, ChIP, Western blot for p53 phosphorylation","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP demonstrating GAS41 promoter occupancy, mutagenesis separating TIP60-dependent and independent functions, multiple orthogonal methods in single rigorous study","pmids":["16705155"],"is_preprint":false},{"year":2011,"finding":"GAS41 forms a complex with PP2Cβ; this GAS41-PP2Cβ complex (not PP2Cβ alone) specifically dephosphorylates p53 at serine 366, and ectopic expression of both proteins reduces UV-induced p53 up-regulation and increases cell survival after genotoxic damage. GAS41 acts as a regulatory subunit that confers substrate specificity to PP2Cβ.","method":"Co-immunoprecipitation, in vitro phosphatase assay with mutant p53 substrates, ectopic overexpression, UV damage survival assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro phosphatase reconstitution establishing substrate specificity plus co-IP and cellular survival assays, multiple orthogonal methods in single lab","pmids":["21317290"],"is_preprint":false},{"year":2018,"finding":"Yaf9 YEATS domain preferentially recognizes H3K27ac; crystal structure reveals K27ac side chain inserts between two aromatic residues, and mutation of these aromatic residues abolishes interaction in vitro and in vivo, causing loss of SWR1-dependent H2A.Z incorporation equivalent to YAF9 deletion.","method":"Crystal structure of YEATS domain with H3K27ac peptide, ITC/fluorescence binding assays, aromatic cage mutagenesis, ChIP for H2A.Z","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus mutagenesis with in vivo validation, multiple methods in single lab","pmids":["29145630"],"is_preprint":false},{"year":2018,"finding":"Full-length dimeric GAS41 (via its C-terminal coiled-coil dimerization domain) binds diacetylated H3 peptides with enhanced affinity compared to monoacetylated peptides through a bivalent binding mode; crystal structure of the YEATS domain with H3K23acK27ac was determined to reveal the molecular basis.","method":"Crystal structure, ITC binding assays comparing mono- and diacetylated peptides, biochemical characterization of full-length vs. domain constructs","journal":"ACS chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus quantitative binding assays with orthogonal confirmation of bivalent mode, single lab","pmids":["30071723"],"is_preprint":false},{"year":2023,"finding":"GAS41 YEATS domain recognition of H3K14ac requires the N-terminus of histone H3 (H3NT); a unique pocket in GAS41 YEATS (away from the aromatic cage) binds H3NT, and E109 of GAS41 is essential for this pocket and for GAS41/H2A.Z chromatin occupancy at H2A.Z-enriched promoters.","method":"X-ray crystallography, NMR, biochemical binding assays, mutagenesis of E109, ChIP for H2A.Z and GAS41","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus NMR plus mutagenesis with in vivo ChIP validation, multiple orthogonal methods","pmids":["37844223"],"is_preprint":false},{"year":2024,"finding":"GAS41 interacts with NRF2 and is recruited to the SLC7A11 promoter by recognizing H3K27ac; GAS41 anchors NRF2 on chromatin at SLC7A11 promoter to activate transcription and repress ferroptosis. GAS41 binding to H3K27ac occurs independently of NRF2, and GAS41 bridges NRF2 to the H3K27ac mark.","method":"Genome-wide CRISPR-Cas9 screen, Co-IP of GAS41-NRF2, ChIP for GAS41 and NRF2 at SLC7A11 promoter, ferroptosis assays, in vivo tumor models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR screen plus reciprocal Co-IP plus ChIP plus in vivo tumor model, multiple orthogonal methods with genome-wide validation","pmids":["38514704"],"is_preprint":false},{"year":2002,"finding":"GAS41 interacts with the AF10 leucine zipper domain and with INI1 (SNF5 homolog, a SWI/SNF complex component), placing GAS41 in connection with ATP-dependent chromatin remodeling; AF10 immunoprecipitate also contains INI1.","method":"Yeast two-hybrid screening, co-immunoprecipitation in vivo","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid plus in vivo co-IP confirming interaction, but limited mechanistic follow-up on GAS41's own role","pmids":["11756182"],"is_preprint":false},{"year":2000,"finding":"GAS41 binds to the C-terminal rod region of NuMA in vitro with a Kd of ~2×10⁻⁷ M; GAS41 localizes to the nucleus in interphase and shows uniform distribution in mitotic cells.","method":"Yeast two-hybrid, dot overlay assay, surface plasmon resonance, GFP-GAS41 fluorescence microscopy, immunofluorescence","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — surface plasmon resonance quantifying binding affinity plus subcellular localization, but functional consequence of NuMA interaction not established","pmids":["10913114"],"is_preprint":false},{"year":2002,"finding":"Targeted disruption of GAS41 in chicken DT40 cells is lethal; tetracycline-regulated depletion of GAS41 leads to rapid decrease in RNA synthesis followed by cell death, indicating GAS41 is required for RNA transcription.","method":"Gene targeting by homologous recombination, conditional knockdown with tetracycline-regulated promoter, RNA synthesis assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic ablation with conditional rescue demonstrating essentiality; RNA synthesis measured but pathway mechanism not fully defined","pmids":["11901157"],"is_preprint":false},{"year":2006,"finding":"GAS41 interacts with transcription factor AP-2β through C-terminal domains of both proteins; GAS41 stimulates AP-2β transcriptional activity and enhances AP-2β DNA-binding activity, functioning as a transcriptional co-activator.","method":"Yeast two-hybrid, co-immunoprecipitation, GST pull-down, co-localization by immunofluorescence, reporter gene assay, EMSA","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple methods (Co-IP, GST pull-down, EMSA, reporter) but all from single lab and limited mechanistic depth","pmids":["16698963"],"is_preprint":false},{"year":2010,"finding":"GAS41 binds both subunits of general transcription factor TFIIF (RAP30 and RAP74) in vitro and in vivo; GAS41 binds two non-overlapping regions of the RAP30 C-terminus with an ionic component; GAS41 does not directly bind TBP or RNA Pol II, suggesting it functions as a TFIIF co-factor.","method":"GST pull-down, co-immunoprecipitation of endogenous proteins, domain mapping","journal":"BMC molecular biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — GST pull-down plus endogenous co-IP confirming interaction, negative results for TBP/Pol II binding; single lab","pmids":["20618998"],"is_preprint":false},{"year":2019,"finding":"Yeats4 recruits the Dot1l-RNA Pol II complex to the Lmo4 promoter by recognizing H3K27ac modification, initiating Lmo4 transcription in α4β7+ CLPs; Yeats4 conditional knockout in the hematopoietic system reduces ILC numbers and impairs ILC lineage commitment from common lymphoid progenitors.","method":"Conditional knockout mouse model, ChIP demonstrating Yeats4 and Dot1l co-occupancy at Lmo4 promoter, co-IP of Yeats4-Dot1l-RNA Pol II, rescue experiments","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo conditional KO plus ChIP plus co-IP establishing complex recruitment, single lab","pmids":["31434684"],"is_preprint":false},{"year":2024,"finding":"KAT8-mediated acetylation of YEATS4 prevents its ubiquitination and proteasomal degradation by the E3 ligase HUWE1; acetylation of YEATS4 by KAT8 impairs YEATS4-HUWE1 interaction, stabilizing YEATS4 protein levels.","method":"Protein Stability Regulators Screening Assay, co-IP of YEATS4-HUWE1, KAT8 inhibitor MG149 treatment, ubiquitination assays, CRISPR-Cas9 library screening","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR screen plus co-IP plus pharmacological inhibition establishing acetylation-ubiquitination crosstalk, single lab","pmids":["38526153"],"is_preprint":false},{"year":2021,"finding":"Yaf9 reads histone acetylation during the oxidative phase of the yeast metabolic cycle to recruit SWR1-C and NuA4 complexes, promoting H2A.Z deposition and H4 acetylation at metabolic gene promoters; disruption of Yaf9-H3 acetyl reading impairs timely transcription of metabolic genes and reduces chromatin machinery occupancy.","method":"ChIP-seq, ChIP-qPCR, genome-wide transcriptomics, YEATS domain point mutants blocking acetylhistone binding","journal":"Genes & development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq plus mutagenesis abolishing acetyl-reading with transcriptome analysis, single lab","pmids":["34819351"],"is_preprint":false},{"year":2004,"finding":"Bdf1p is a multicopy suppressor of yaf9Δ phenotypes in yeast; both Yaf9p and Bdf1p bind to promoters of underexpressed genes and H3/H4 acetylation at these promoters is significantly reduced in yaf9Δ, indicating Yaf9p promotes histone acetylation at target gene promoters.","method":"Multicopy suppressor screen, genome-wide transcript analysis, ChIP for Yaf9p/Bdf1p promoter occupancy and histone acetylation","journal":"Molecular microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP establishing promoter occupancy and histone acetylation changes, combined with genetic suppressor analysis, single lab","pmids":["15255905"],"is_preprint":false},{"year":2022,"finding":"GAS41 binds to H2A.Z.2 and activates Notch1 and its downstream mediators; depletion of GAS41 or H2A.Z.2 down-regulates Notch signaling and sensitizes pancreatic cancer cells to gemcitabine.","method":"Co-immunoprecipitation, ChIP, siRNA knockdown, in vitro and in vivo tumorigenesis assays","journal":"Cellular oncology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP and ChIP establishing GAS41-H2A.Z.2 interaction and Notch activation, supported by in vivo data; single lab","pmids":["35503594"],"is_preprint":false},{"year":2011,"finding":"Gas41 directly interacts with c-Myc and n-Myc proteins; the C-terminal portion of Gas41 (outside the YEATS domain) is required for this interaction; Gas41 and Myc show correlated expression in neuroblastomas and glioblastomas.","method":"Yeast two-hybrid, GST pull-down, domain mapping with YEATS and C-terminal deletion constructs, yeast complementation assay","journal":"Acta biochimica Polonica","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pull-down plus yeast two-hybrid, single lab, limited mechanistic follow-up on functional consequence of Myc interaction","pmids":["22068108"],"is_preprint":false},{"year":2012,"finding":"GAS41 overexpression leads to increased multipolar spindles and is associated with pericentrosome material; combined overexpression with reduced NuMA increases bipolar spindles with misaligned chromosomes, suggesting GAS41 plays a role at the spindle pole.","method":"Induced and endogenous overexpression in HeLa cells, immunofluorescence microscopy for spindle morphology, co-manipulation with NuMA","journal":"Genes, chromosomes & cancer","confidence":"Low","confidence_rationale":"Tier 3 / Weak — overexpression with microscopy, no biochemical reconstitution or mechanistic pathway defined, single lab","pmids":["22619067"],"is_preprint":false},{"year":2002,"finding":"TACC1 interacts with the C-terminus of GAS41/NuBI1, suggesting GAS41 participates in multiple protein complexes potentially relevant to oncogenesis.","method":"Yeast two-hybrid screening of mammary epithelial cDNA library","journal":"The Biochemical journal","confidence":"Low","confidence_rationale":"Tier 3 / Weak — yeast two-hybrid only, no in vivo validation, no functional consequence established for GAS41","pmids":["11903063"],"is_preprint":false},{"year":2017,"finding":"YEATS4 interacts with β-catenin and activates β-catenin/TCF signaling; knockdown of YEATS4 impairs oncogenic Ras-mediated malignant transformation of normal pancreatic cells.","method":"Co-immunoprecipitation of YEATS4-β-catenin, luciferase reporter for TCF activity, siRNA knockdown, transformation assay with oncogenic Ras","journal":"Oncotarget","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP plus reporter assay, single lab, no mechanistic detail on how YEATS4 activates β-catenin/TCF","pmids":["28445953"],"is_preprint":false},{"year":2025,"finding":"YEATS4 is a reader of H3K14 crotonylation (H3K14cr); H3K14cr reading by YEATS4 is associated with transcriptional activation of fatty acid metabolism genes (CD36, CPT1A, ACOX1) and enhancement of breast cancer stem cell self-renewal.","method":"Binding assays for H3K14cr, integrative metabolomic/epigenomic/transcriptomic analysis, ChIP-seq, knockdown/overexpression in breast cancer cells","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal omics methods plus direct binding assay for crotonylation, single lab","pmids":["41060805"],"is_preprint":false},{"year":2024,"finding":"GAS41 regulates nuclear shape by binding H3K27ac/cr through its YEATS domain; YEATS domain mutants unable to bind H3K27ac/cr fail to rescue nuclear shape abnormalities in GAS41-knockout cells. GAS41 recruits BRD2 and the Mediator complex (MED14, MED23) to gene loci of nuclear shape regulators (LMNB1, LMNB2, SYNE4, LEMD2) to activate their transcription.","method":"Genetic ablation (CRISPR), rescue with wild-type vs. YEATS domain mutant GAS41, ChIP for BRD2/Mediator subunits at target loci, nuclear morphology imaging","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with domain-specific rescue plus ChIP establishing chromatin complex recruitment, single lab","pmids":["38964523"],"is_preprint":false},{"year":2025,"finding":"Yaf9-YEATS domain slows SWR1 complex dissociation from chromatin (while Bdf1 promotes association); live-cell single-molecule tracking and genome-wide ChIP-exo reveal Yaf9 and Bdf1 contributions to global SWR1 targeting and histone exchange at +1 nucleosomes.","method":"Live-cell single-molecule tracking, genome-wide ChIP combined with exonuclease treatment (ChIP-exo), domain mutant analysis","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — single-molecule live-cell tracking plus genome-wide ChIP-exo providing mechanistic kinetic and genomic resolution, multiple orthogonal approaches","pmids":["40768570"],"is_preprint":false},{"year":2026,"finding":"Yaf9 is required in both NuA4 and SWR1 complexes (not just one) for cell viability when H4 acetylation is impaired; loss of Yaf9 in a strain with impaired H4 acetylation causes G2/M arrest and activation of homologous recombination. This synthetic lethality is independent of Yaf9 YEATS domain acyl-lysine reading activity.","method":"Genetic epistasis (synthetic lethality), cell cycle analysis, assessment of homologous recombination pathway activation, YEATS domain inactivation mutant","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic epistasis with domain-specific mutants distinguishing YEATS-dependent and independent functions, single lab","pmids":["41653028"],"is_preprint":false}],"current_model":"YEATS4/GAS41 is a histone acetylation (and crotonylation) reader whose YEATS domain engages H3K14ac, H3K27ac, and diacetylated H3 via an aromatic cage, recruiting the Tip60/p400 and SRCAP chromatin-remodeling complexes to deposit histone variant H2A.Z at gene promoters; it also anchors NRF2 on H3K27ac-marked chromatin to activate ferroptosis-suppressing targets, represses the p53 pathway by occupying p21/p14ARF promoters and forming a GAS41-PP2Cβ complex that dephosphorylates p53-Ser366, and interacts with transcriptional machinery including TFIIF and AP-2β to function as a transcriptional co-activator essential for cell viability."},"narrative":{"mechanistic_narrative":"YEATS4/GAS41 is a histone acylation reader that couples recognition of acetylated and crotonylated histone marks to deposition of the histone variant H2A.Z and to transcriptional activation of target genes [PMID:29437725, PMID:29900004]. Its YEATS domain engages H3K27ac and H3K14ac through an aromatic cage [PMID:29437725, PMID:29145630], with H3K14ac recognition additionally requiring a distinct pocket that reads the histone H3 N-terminus through the essential residue E109 [PMID:37844223], and the full-length protein dimerizes via a C-terminal coiled-coil to bind diacetylated H3 with enhanced bivalent affinity [PMID:30071723]; the YEATS domain also reads H3K14 crotonylation [PMID:41060805]. Through these reading activities GAS41 is recruited to promoters of actively transcribed genes, where it recruits the Tip60/p400 and SRCAP chromatin-remodeling complexes to deposit and acetylate H2A.Z [PMID:29900004, PMID:19966225], and the conserved yeast ortholog Yaf9 functions as a subunit of both the NuA4 acetyltransferase and SWR1/SWR1-C remodeling complexes that perform these reactions [PMID:12917332, PMID:19966225, PMID:40768570]. GAS41 acts as a transcriptional co-activator more broadly, bridging the H3K27ac mark to sequence-specific and general transcription machinery: it anchors NRF2 at the SLC7A11 promoter to activate transcription and repress ferroptosis [PMID:38514704], recruits the Dot1l–RNA Pol II complex to drive Lmo4 transcription during lymphoid lineage commitment [PMID:31434684], and recruits BRD2 and Mediator to activate genes controlling nuclear shape [PMID:38964523]. Independently of its chromatin-remodeling role, GAS41 represses the p53 pathway, occupying p21 and p14ARF promoters in unstressed cells and forming a complex with the phosphatase PP2Cβ that dephosphorylates p53 at Ser366 [PMID:16705155, PMID:21317290]. GAS41 is essential for RNA transcription and cell viability [PMID:11901157], and is itself stabilized when KAT8-mediated acetylation blocks its HUWE1-dependent ubiquitination [PMID:38526153].","teleology":[{"year":2000,"claim":"Early work asked what cellular structures GAS41 associates with, revealing a nuclear protein that binds the spindle-organizing protein NuMA and hinting at roles beyond transcription.","evidence":"Yeast two-hybrid, surface plasmon resonance, and GFP/immunofluorescence localization","pmids":["10913114"],"confidence":"Medium","gaps":["Functional consequence of the NuMA interaction not established","No chromatin or transcriptional mechanism defined at this stage"]},{"year":2002,"claim":"Genetic ablation established that GAS41 is essential, defining a baseline requirement for the protein in RNA transcription and cell survival.","evidence":"Conditional gene targeting in chicken DT40 cells with RNA synthesis measurement","pmids":["11901157"],"confidence":"Medium","gaps":["The transcriptional pathway through which depletion stops RNA synthesis was not defined","Did not identify the direct molecular partners mediating essentiality"]},{"year":2003,"claim":"Identification of the yeast ortholog Yaf9 as a NuA4 subunit placed the protein within a histone acetyltransferase complex and linked it to chromatin-based stress resistance.","evidence":"Reciprocal co-IP with NuA4 subunits and genetic epistasis with esa1/yng2 plus benomyl sensitivity assays","pmids":["12917332"],"confidence":"High","gaps":["Did not establish the molecular basis of Yaf9's contribution to NuA4","Connection to H2A.Z not yet made"]},{"year":2006,"claim":"Two studies separated GAS41's transcriptional roles, showing it is a co-activator for AP-2β and, independently of TIP60, a repressor of the p53 pathway via promoter occupancy.","evidence":"Co-IP, GST pull-down, EMSA and reporter assays for AP-2β; siRNA, coiled-coil mutagenesis, ChIP and p53 phosphorylation assays for p53 repression","pmids":["16698963","16705155"],"confidence":"High","gaps":["The mechanism by which GAS41 represses p21/p14ARF promoters was not molecularly defined","How GAS41 dissociation from promoters is triggered by stress was unresolved"]},{"year":2009,"claim":"Structure of the Yaf9 YEATS domain and its histone-binding activity provided the first mechanistic link between the protein and H2A.Z chromatin deposition.","evidence":"X-ray crystallography, in vitro H3/H4 binding, mutagenesis and H2A.Z ChIP in yeast","pmids":["19966225"],"confidence":"High","gaps":["Specific acetyl-mark recognized by the domain not yet defined","Did not establish the reader chemistry later attributed to the aromatic cage"]},{"year":2011,"claim":"Reconstitution showed GAS41 confers substrate specificity to PP2Cβ, explaining mechanistically how it suppresses p53 by enabling dephosphorylation at Ser366.","evidence":"Co-IP and in vitro phosphatase assays with mutant p53 substrates plus UV-survival assays","pmids":["21317290"],"confidence":"High","gaps":["Whether the GAS41-PP2Cβ axis operates at chromatin or in the nucleoplasm was not resolved","Relationship to GAS41 promoter occupancy at p53 targets not integrated"]},{"year":2018,"claim":"A cluster of structural studies defined GAS41/Yaf9 as an aromatic-cage reader of H3K27ac and H3K14ac, mechanistically explaining its recruitment to active promoters and its role in H2A.Z deposition via Tip60/p400, SRCAP and SWR1.","evidence":"Crystal structures of YEATS domains with acetyl-H3 peptides, aromatic-cage mutagenesis, ITC, ChIP-seq and knockdown/rescue in NSCLC, mouse ESCs and yeast","pmids":["29437725","29900004","29145630","30071723"],"confidence":"High","gaps":["The basis for H3K14ac recognition was incomplete until the H3NT pocket was defined","How reader binding is coordinated with remodeler enzymatic activity not resolved"]},{"year":2019,"claim":"In vivo conditional knockout showed GAS41 reads H3K27ac to recruit Dot1l-RNA Pol II for developmental gene activation, extending its co-activator function to lymphoid lineage commitment.","evidence":"Conditional knockout mouse, ChIP co-occupancy and co-IP at the Lmo4 promoter with rescue","pmids":["31434684"],"confidence":"Medium","gaps":["Generality of Dot1l-Pol II recruitment beyond Lmo4 not established","Single-lab in vivo model"]},{"year":2023,"claim":"Identification of an H3NT-binding pocket and the essential residue E109 completed the structural logic of how GAS41 recognizes H3K14ac to occupy H2A.Z-enriched promoters.","evidence":"X-ray crystallography, NMR, binding assays, E109 mutagenesis and ChIP for GAS41/H2A.Z","pmids":["37844223"],"confidence":"High","gaps":["Whether the H3NT pocket contributes to non-H2A.Z transcriptional functions not tested"]},{"year":2024,"claim":"Multiple studies broadened GAS41's reader output to disease-relevant programs and revealed its own regulation, anchoring NRF2 to repress ferroptosis, controlling nuclear-shape gene transcription via BRD2/Mediator, and being stabilized by KAT8 acetylation against HUWE1 degradation.","evidence":"CRISPR screens, reciprocal co-IP, ChIP, ferroptosis and tumor models; CRISPR KO with YEATS-mutant rescue and ChIP for BRD2/Mediator; protein-stability screen and ubiquitination assays","pmids":["38514704","38964523","38526153"],"confidence":"High","gaps":["How GAS41 selects between distinct partner complexes at different loci is unknown","Whether NRF2 anchoring and H2A.Z deposition are mechanistically coupled is unresolved"]},{"year":2025,"claim":"Single-molecule and biochemical work extended the reader repertoire to H3K14 crotonylation and defined kinetically how Yaf9 governs SWR1 residence on chromatin.","evidence":"Crotonyl-binding assays with multi-omics in breast cancer cells; live-cell single-molecule tracking and ChIP-exo in yeast","pmids":["41060805","40768570"],"confidence":"High","gaps":["Whether crotonylation reading uses the same aromatic cage as acetylation is not delineated","Quantitative kinetics of human GAS41 on chromatin not measured"]},{"year":2026,"claim":"Genetic dissection showed Yaf9 is required in both NuA4 and SWR1 for viability under impaired H4 acetylation, and that this essential role is separable from its YEATS acyl-reading activity.","evidence":"Synthetic lethality, cell-cycle analysis, recombination-pathway assessment with a YEATS-inactivating mutant","pmids":["41653028"],"confidence":"Medium","gaps":["The reading-independent molecular function of Yaf9 within the complexes is undefined","Whether the human ortholog has an equivalent reading-independent essential role is untested"]},{"year":null,"claim":"How GAS41 chooses among its many partner complexes (Tip60/p400, SRCAP, NRF2, Dot1l-Pol II, BRD2/Mediator, PP2Cβ) at specific loci, and how its acyl-reading and reading-independent functions are integrated, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model for context-specific partner selection","Coupling between reader binding and downstream enzymatic/remodeling activity undefined","Mechanism distinguishing acetyl- from crotonyl-mark output unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[0,1,6,7,8,24]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[4,9,13,15,25]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[9,15,25]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[11]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[0,1,8]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,1,3,6,8]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[12,13,15,25]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[1,3,6,26]}],"complexes":["NuA4","SWR1/SRCAP","Tip60/p400","GAS41-PP2Cβ"],"partners":["NRF2","PP2CΒ","HUWE1","KAT8","DOT1L","BRD2","NUMA","TFIIF"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O95619","full_name":"YEATS domain-containing protein 4","aliases":["Glioma-amplified sequence 41","Gas41","NuMA-binding protein 1","NuBI-1","NuBI1"],"length_aa":227,"mass_kda":26.5,"function":"Chromatin reader component of the NuA4 histone acetyltransferase (HAT) complex, a complex involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H4 and H2A (PubMed:12963728, PubMed:14966270). Specifically recognizes and binds acylated histone H3, with a preference for histone H3 diacetylated at 'Lys-18' and 'Lys-27' (H3K18ac and H3K27ac) or histone H3 diacetylated at 'Lys-14' and 'Lys-27' (H3K14ac and H3K27ac) (PubMed:29437725, PubMed:29900004, PubMed:30071723). Also able to recognize and bind crotonylated histone H3 (PubMed:30071723). May also recognize and bind histone H3 succinylated at 'Lys-122' (H3K122succ); additional evidences are however required to confirm this result in vivo (PubMed:29463709). Plays a key role in histone variant H2AZ1/H2A.Z deposition into specific chromatin regions: recognizes and binds H3K14ac and H3K27ac on the promoters of actively transcribed genes and recruits NuA4-related complex to deposit H2AZ1/H2A.Z (PubMed:29437725). H2AZ1/H2A.Z deposition is required for maintenance of embryonic stem cell (By similarity)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/O95619/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/YEATS4","classification":"Common Essential","n_dependent_lines":1119,"n_total_lines":1208,"dependency_fraction":0.9263245033112583},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ACTB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/YEATS4","total_profiled":1310},"omim":[{"mim_id":"605301","title":"TRANSFORMING, ACIDIC, COILED-COIL-CONTAINING PROTEIN 1; TACC1","url":"https://www.omim.org/entry/605301"},{"mim_id":"602116","title":"YEATS DOMAIN-CONTAINING PROTEIN 4; YEATS4","url":"https://www.omim.org/entry/602116"},{"mim_id":"601409","title":"LYSINE ACETYLTRANSFERASE 5; KAT5","url":"https://www.omim.org/entry/601409"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nuclear membrane","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/YEATS4"},"hgnc":{"alias_symbol":["NuBI-1","GAS41","YAF9"],"prev_symbol":[]},"alphafold":{"accession":"O95619","domains":[{"cath_id":"2.60.40.1970","chopping":"1-165","consensus_level":"medium","plddt":91.859,"start":1,"end":165},{"cath_id":"1.20.5","chopping":"171-227","consensus_level":"medium","plddt":93.8409,"start":171,"end":227}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O95619","model_url":"https://alphafold.ebi.ac.uk/files/AF-O95619-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O95619-F1-predicted_aligned_error_v6.png","plddt_mean":91.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=YEATS4","jax_strain_url":"https://www.jax.org/strain/search?query=YEATS4"},"sequence":{"accession":"O95619","fasta_url":"https://rest.uniprot.org/uniprotkb/O95619.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O95619/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O95619"}},"corpus_meta":[{"pmid":"29437725","id":"PMC_29437725","title":"Recognition 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standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"GAS41 YEATS domain reads histone H3 acetylation (H3K27ac and H3K14ac) via an aromatic cage mechanism, and this interaction recruits GAS41 to promoters of actively transcribed genes to promote H2A.Z deposition in NSCLC cells; disruption of the YEATS-acetylhistone interaction impairs H2A.Z chromatin association and suppresses cancer cell growth.\",\n      \"method\": \"Crystal structure of YEATS domain bound to acetylated H3 peptides, ChIP-seq, siRNA knockdown, in vitro and in vivo proliferation assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis plus ChIP-seq plus functional rescue in multiple cancer models, replicated across two papers (PMID:29437725 and PMID:29900004)\",\n      \"pmids\": [\"29437725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Gas41 YEATS domain binds H3K27ac and H3K14ac and recruits Tip60/p400 and SRCAP complexes to deposit H2A.Z into bivalent chromatin domains in mouse ESCs; knockdown of Gas41 reduces H2A.Z and H3K27me3 levels on bivalent domains and disrupts ESC colony morphology, which is rescued by wild-type but not YEATS-mutant Gas41.\",\n      \"method\": \"Crystal structure of YEATS domain with H3K27ac peptide, Co-IP, ChIP-seq, mutagenesis, ESC knockdown/rescue experiments\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure, mutagenesis, functional rescue, and ChIP-seq in one study; orthogonal methods in single lab\",\n      \"pmids\": [\"29900004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Yaf9 (yeast ortholog) is a subunit of the NuA4 histone acetyltransferase complex; yaf9Δ mutants are hypersensitive to microtubule-depolymerizing agents and synthetically lethal with mitotic apparatus mutants, linking NuA4-mediated H4 acetylation to spindle stress resistance.\",\n      \"method\": \"Co-immunoprecipitation with NuA4 subunits, genetic epistasis with esa1 and yng2 mutants, microtubule depolymerization assays, benomyl sensitivity assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP establishing complex membership plus genetic epistasis with multiple NuA4 mutants and histone mutants, replicated phenotypes\",\n      \"pmids\": [\"12917332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The Yaf9 YEATS domain adopts an Ig-fold beta-sandwich structure similar to histone chaperone Asf1; it binds histones H3 and H4 in vitro, and structure-function analysis shows the YEATS domain is required for H2A.Z chromatin deposition at specific promoters and for H2A.Z acetylation in yeast.\",\n      \"method\": \"X-ray crystallography (2.3 Å), in vitro histone binding assays, structure-function mutagenesis, ChIP for H2A.Z occupancy\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation by mutagenesis and ChIP in yeast, multiple orthogonal methods\",\n      \"pmids\": [\"19966225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"GAS41 is required for repression of the p53 tumor suppressor pathway during normal proliferation; siRNA-mediated knockdown or disruption of the C-terminal coiled-coil motif activates p53, induces p53-Ser15 phosphorylation, and activates p21 transcription. GAS41 is pre-bound to p21 and p14ARF promoters in unstressed cells and dissociates upon stress. This repression is TIP60-independent, as a coiled-coil mutant of GAS41 retains normal TIP60 complex assembly and HAT activity.\",\n      \"method\": \"siRNA knockdown, promoter-targeted mutagenesis, reporter gene assays, ChIP, Western blot for p53 phosphorylation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP demonstrating GAS41 promoter occupancy, mutagenesis separating TIP60-dependent and independent functions, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"16705155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"GAS41 forms a complex with PP2Cβ; this GAS41-PP2Cβ complex (not PP2Cβ alone) specifically dephosphorylates p53 at serine 366, and ectopic expression of both proteins reduces UV-induced p53 up-regulation and increases cell survival after genotoxic damage. GAS41 acts as a regulatory subunit that confers substrate specificity to PP2Cβ.\",\n      \"method\": \"Co-immunoprecipitation, in vitro phosphatase assay with mutant p53 substrates, ectopic overexpression, UV damage survival assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro phosphatase reconstitution establishing substrate specificity plus co-IP and cellular survival assays, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"21317290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Yaf9 YEATS domain preferentially recognizes H3K27ac; crystal structure reveals K27ac side chain inserts between two aromatic residues, and mutation of these aromatic residues abolishes interaction in vitro and in vivo, causing loss of SWR1-dependent H2A.Z incorporation equivalent to YAF9 deletion.\",\n      \"method\": \"Crystal structure of YEATS domain with H3K27ac peptide, ITC/fluorescence binding assays, aromatic cage mutagenesis, ChIP for H2A.Z\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus mutagenesis with in vivo validation, multiple methods in single lab\",\n      \"pmids\": [\"29145630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Full-length dimeric GAS41 (via its C-terminal coiled-coil dimerization domain) binds diacetylated H3 peptides with enhanced affinity compared to monoacetylated peptides through a bivalent binding mode; crystal structure of the YEATS domain with H3K23acK27ac was determined to reveal the molecular basis.\",\n      \"method\": \"Crystal structure, ITC binding assays comparing mono- and diacetylated peptides, biochemical characterization of full-length vs. domain constructs\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus quantitative binding assays with orthogonal confirmation of bivalent mode, single lab\",\n      \"pmids\": [\"30071723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GAS41 YEATS domain recognition of H3K14ac requires the N-terminus of histone H3 (H3NT); a unique pocket in GAS41 YEATS (away from the aromatic cage) binds H3NT, and E109 of GAS41 is essential for this pocket and for GAS41/H2A.Z chromatin occupancy at H2A.Z-enriched promoters.\",\n      \"method\": \"X-ray crystallography, NMR, biochemical binding assays, mutagenesis of E109, ChIP for H2A.Z and GAS41\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus NMR plus mutagenesis with in vivo ChIP validation, multiple orthogonal methods\",\n      \"pmids\": [\"37844223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GAS41 interacts with NRF2 and is recruited to the SLC7A11 promoter by recognizing H3K27ac; GAS41 anchors NRF2 on chromatin at SLC7A11 promoter to activate transcription and repress ferroptosis. GAS41 binding to H3K27ac occurs independently of NRF2, and GAS41 bridges NRF2 to the H3K27ac mark.\",\n      \"method\": \"Genome-wide CRISPR-Cas9 screen, Co-IP of GAS41-NRF2, ChIP for GAS41 and NRF2 at SLC7A11 promoter, ferroptosis assays, in vivo tumor models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR screen plus reciprocal Co-IP plus ChIP plus in vivo tumor model, multiple orthogonal methods with genome-wide validation\",\n      \"pmids\": [\"38514704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"GAS41 interacts with the AF10 leucine zipper domain and with INI1 (SNF5 homolog, a SWI/SNF complex component), placing GAS41 in connection with ATP-dependent chromatin remodeling; AF10 immunoprecipitate also contains INI1.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation in vivo\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid plus in vivo co-IP confirming interaction, but limited mechanistic follow-up on GAS41's own role\",\n      \"pmids\": [\"11756182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"GAS41 binds to the C-terminal rod region of NuMA in vitro with a Kd of ~2×10⁻⁷ M; GAS41 localizes to the nucleus in interphase and shows uniform distribution in mitotic cells.\",\n      \"method\": \"Yeast two-hybrid, dot overlay assay, surface plasmon resonance, GFP-GAS41 fluorescence microscopy, immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — surface plasmon resonance quantifying binding affinity plus subcellular localization, but functional consequence of NuMA interaction not established\",\n      \"pmids\": [\"10913114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Targeted disruption of GAS41 in chicken DT40 cells is lethal; tetracycline-regulated depletion of GAS41 leads to rapid decrease in RNA synthesis followed by cell death, indicating GAS41 is required for RNA transcription.\",\n      \"method\": \"Gene targeting by homologous recombination, conditional knockdown with tetracycline-regulated promoter, RNA synthesis assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic ablation with conditional rescue demonstrating essentiality; RNA synthesis measured but pathway mechanism not fully defined\",\n      \"pmids\": [\"11901157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"GAS41 interacts with transcription factor AP-2β through C-terminal domains of both proteins; GAS41 stimulates AP-2β transcriptional activity and enhances AP-2β DNA-binding activity, functioning as a transcriptional co-activator.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, GST pull-down, co-localization by immunofluorescence, reporter gene assay, EMSA\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple methods (Co-IP, GST pull-down, EMSA, reporter) but all from single lab and limited mechanistic depth\",\n      \"pmids\": [\"16698963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"GAS41 binds both subunits of general transcription factor TFIIF (RAP30 and RAP74) in vitro and in vivo; GAS41 binds two non-overlapping regions of the RAP30 C-terminus with an ionic component; GAS41 does not directly bind TBP or RNA Pol II, suggesting it functions as a TFIIF co-factor.\",\n      \"method\": \"GST pull-down, co-immunoprecipitation of endogenous proteins, domain mapping\",\n      \"journal\": \"BMC molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — GST pull-down plus endogenous co-IP confirming interaction, negative results for TBP/Pol II binding; single lab\",\n      \"pmids\": [\"20618998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Yeats4 recruits the Dot1l-RNA Pol II complex to the Lmo4 promoter by recognizing H3K27ac modification, initiating Lmo4 transcription in α4β7+ CLPs; Yeats4 conditional knockout in the hematopoietic system reduces ILC numbers and impairs ILC lineage commitment from common lymphoid progenitors.\",\n      \"method\": \"Conditional knockout mouse model, ChIP demonstrating Yeats4 and Dot1l co-occupancy at Lmo4 promoter, co-IP of Yeats4-Dot1l-RNA Pol II, rescue experiments\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo conditional KO plus ChIP plus co-IP establishing complex recruitment, single lab\",\n      \"pmids\": [\"31434684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KAT8-mediated acetylation of YEATS4 prevents its ubiquitination and proteasomal degradation by the E3 ligase HUWE1; acetylation of YEATS4 by KAT8 impairs YEATS4-HUWE1 interaction, stabilizing YEATS4 protein levels.\",\n      \"method\": \"Protein Stability Regulators Screening Assay, co-IP of YEATS4-HUWE1, KAT8 inhibitor MG149 treatment, ubiquitination assays, CRISPR-Cas9 library screening\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screen plus co-IP plus pharmacological inhibition establishing acetylation-ubiquitination crosstalk, single lab\",\n      \"pmids\": [\"38526153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Yaf9 reads histone acetylation during the oxidative phase of the yeast metabolic cycle to recruit SWR1-C and NuA4 complexes, promoting H2A.Z deposition and H4 acetylation at metabolic gene promoters; disruption of Yaf9-H3 acetyl reading impairs timely transcription of metabolic genes and reduces chromatin machinery occupancy.\",\n      \"method\": \"ChIP-seq, ChIP-qPCR, genome-wide transcriptomics, YEATS domain point mutants blocking acetylhistone binding\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq plus mutagenesis abolishing acetyl-reading with transcriptome analysis, single lab\",\n      \"pmids\": [\"34819351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Bdf1p is a multicopy suppressor of yaf9Δ phenotypes in yeast; both Yaf9p and Bdf1p bind to promoters of underexpressed genes and H3/H4 acetylation at these promoters is significantly reduced in yaf9Δ, indicating Yaf9p promotes histone acetylation at target gene promoters.\",\n      \"method\": \"Multicopy suppressor screen, genome-wide transcript analysis, ChIP for Yaf9p/Bdf1p promoter occupancy and histone acetylation\",\n      \"journal\": \"Molecular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP establishing promoter occupancy and histone acetylation changes, combined with genetic suppressor analysis, single lab\",\n      \"pmids\": [\"15255905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GAS41 binds to H2A.Z.2 and activates Notch1 and its downstream mediators; depletion of GAS41 or H2A.Z.2 down-regulates Notch signaling and sensitizes pancreatic cancer cells to gemcitabine.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, siRNA knockdown, in vitro and in vivo tumorigenesis assays\",\n      \"journal\": \"Cellular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP and ChIP establishing GAS41-H2A.Z.2 interaction and Notch activation, supported by in vivo data; single lab\",\n      \"pmids\": [\"35503594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Gas41 directly interacts with c-Myc and n-Myc proteins; the C-terminal portion of Gas41 (outside the YEATS domain) is required for this interaction; Gas41 and Myc show correlated expression in neuroblastomas and glioblastomas.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down, domain mapping with YEATS and C-terminal deletion constructs, yeast complementation assay\",\n      \"journal\": \"Acta biochimica Polonica\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pull-down plus yeast two-hybrid, single lab, limited mechanistic follow-up on functional consequence of Myc interaction\",\n      \"pmids\": [\"22068108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"GAS41 overexpression leads to increased multipolar spindles and is associated with pericentrosome material; combined overexpression with reduced NuMA increases bipolar spindles with misaligned chromosomes, suggesting GAS41 plays a role at the spindle pole.\",\n      \"method\": \"Induced and endogenous overexpression in HeLa cells, immunofluorescence microscopy for spindle morphology, co-manipulation with NuMA\",\n      \"journal\": \"Genes, chromosomes & cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — overexpression with microscopy, no biochemical reconstitution or mechanistic pathway defined, single lab\",\n      \"pmids\": [\"22619067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TACC1 interacts with the C-terminus of GAS41/NuBI1, suggesting GAS41 participates in multiple protein complexes potentially relevant to oncogenesis.\",\n      \"method\": \"Yeast two-hybrid screening of mammary epithelial cDNA library\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — yeast two-hybrid only, no in vivo validation, no functional consequence established for GAS41\",\n      \"pmids\": [\"11903063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"YEATS4 interacts with β-catenin and activates β-catenin/TCF signaling; knockdown of YEATS4 impairs oncogenic Ras-mediated malignant transformation of normal pancreatic cells.\",\n      \"method\": \"Co-immunoprecipitation of YEATS4-β-catenin, luciferase reporter for TCF activity, siRNA knockdown, transformation assay with oncogenic Ras\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP plus reporter assay, single lab, no mechanistic detail on how YEATS4 activates β-catenin/TCF\",\n      \"pmids\": [\"28445953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YEATS4 is a reader of H3K14 crotonylation (H3K14cr); H3K14cr reading by YEATS4 is associated with transcriptional activation of fatty acid metabolism genes (CD36, CPT1A, ACOX1) and enhancement of breast cancer stem cell self-renewal.\",\n      \"method\": \"Binding assays for H3K14cr, integrative metabolomic/epigenomic/transcriptomic analysis, ChIP-seq, knockdown/overexpression in breast cancer cells\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal omics methods plus direct binding assay for crotonylation, single lab\",\n      \"pmids\": [\"41060805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GAS41 regulates nuclear shape by binding H3K27ac/cr through its YEATS domain; YEATS domain mutants unable to bind H3K27ac/cr fail to rescue nuclear shape abnormalities in GAS41-knockout cells. GAS41 recruits BRD2 and the Mediator complex (MED14, MED23) to gene loci of nuclear shape regulators (LMNB1, LMNB2, SYNE4, LEMD2) to activate their transcription.\",\n      \"method\": \"Genetic ablation (CRISPR), rescue with wild-type vs. YEATS domain mutant GAS41, ChIP for BRD2/Mediator subunits at target loci, nuclear morphology imaging\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with domain-specific rescue plus ChIP establishing chromatin complex recruitment, single lab\",\n      \"pmids\": [\"38964523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Yaf9-YEATS domain slows SWR1 complex dissociation from chromatin (while Bdf1 promotes association); live-cell single-molecule tracking and genome-wide ChIP-exo reveal Yaf9 and Bdf1 contributions to global SWR1 targeting and histone exchange at +1 nucleosomes.\",\n      \"method\": \"Live-cell single-molecule tracking, genome-wide ChIP combined with exonuclease treatment (ChIP-exo), domain mutant analysis\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — single-molecule live-cell tracking plus genome-wide ChIP-exo providing mechanistic kinetic and genomic resolution, multiple orthogonal approaches\",\n      \"pmids\": [\"40768570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Yaf9 is required in both NuA4 and SWR1 complexes (not just one) for cell viability when H4 acetylation is impaired; loss of Yaf9 in a strain with impaired H4 acetylation causes G2/M arrest and activation of homologous recombination. This synthetic lethality is independent of Yaf9 YEATS domain acyl-lysine reading activity.\",\n      \"method\": \"Genetic epistasis (synthetic lethality), cell cycle analysis, assessment of homologous recombination pathway activation, YEATS domain inactivation mutant\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic epistasis with domain-specific mutants distinguishing YEATS-dependent and independent functions, single lab\",\n      \"pmids\": [\"41653028\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"YEATS4/GAS41 is a histone acetylation (and crotonylation) reader whose YEATS domain engages H3K14ac, H3K27ac, and diacetylated H3 via an aromatic cage, recruiting the Tip60/p400 and SRCAP chromatin-remodeling complexes to deposit histone variant H2A.Z at gene promoters; it also anchors NRF2 on H3K27ac-marked chromatin to activate ferroptosis-suppressing targets, represses the p53 pathway by occupying p21/p14ARF promoters and forming a GAS41-PP2Cβ complex that dephosphorylates p53-Ser366, and interacts with transcriptional machinery including TFIIF and AP-2β to function as a transcriptional co-activator essential for cell viability.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"YEATS4/GAS41 is a histone acylation reader that couples recognition of acetylated and crotonylated histone marks to deposition of the histone variant H2A.Z and to transcriptional activation of target genes [#0, #1]. Its YEATS domain engages H3K27ac and H3K14ac through an aromatic cage [#0, #6], with H3K14ac recognition additionally requiring a distinct pocket that reads the histone H3 N-terminus through the essential residue E109 [#8], and the full-length protein dimerizes via a C-terminal coiled-coil to bind diacetylated H3 with enhanced bivalent affinity [#7]; the YEATS domain also reads H3K14 crotonylation [#24]. Through these reading activities GAS41 is recruited to promoters of actively transcribed genes, where it recruits the Tip60/p400 and SRCAP chromatin-remodeling complexes to deposit and acetylate H2A.Z [#1, #3], and the conserved yeast ortholog Yaf9 functions as a subunit of both the NuA4 acetyltransferase and SWR1/SWR1-C remodeling complexes that perform these reactions [#2, #3, #26]. GAS41 acts as a transcriptional co-activator more broadly, bridging the H3K27ac mark to sequence-specific and general transcription machinery: it anchors NRF2 at the SLC7A11 promoter to activate transcription and repress ferroptosis [#9], recruits the Dot1l–RNA Pol II complex to drive Lmo4 transcription during lymphoid lineage commitment [#15], and recruits BRD2 and Mediator to activate genes controlling nuclear shape [#25]. Independently of its chromatin-remodeling role, GAS41 represses the p53 pathway, occupying p21 and p14ARF promoters in unstressed cells and forming a complex with the phosphatase PP2Cβ that dephosphorylates p53 at Ser366 [#4, #5]. GAS41 is essential for RNA transcription and cell viability [#12], and is itself stabilized when KAT8-mediated acetylation blocks its HUWE1-dependent ubiquitination [#16].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Early work asked what cellular structures GAS41 associates with, revealing a nuclear protein that binds the spindle-organizing protein NuMA and hinting at roles beyond transcription.\",\n      \"evidence\": \"Yeast two-hybrid, surface plasmon resonance, and GFP/immunofluorescence localization\",\n      \"pmids\": [\"10913114\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the NuMA interaction not established\", \"No chromatin or transcriptional mechanism defined at this stage\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Genetic ablation established that GAS41 is essential, defining a baseline requirement for the protein in RNA transcription and cell survival.\",\n      \"evidence\": \"Conditional gene targeting in chicken DT40 cells with RNA synthesis measurement\",\n      \"pmids\": [\"11901157\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The transcriptional pathway through which depletion stops RNA synthesis was not defined\", \"Did not identify the direct molecular partners mediating essentiality\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identification of the yeast ortholog Yaf9 as a NuA4 subunit placed the protein within a histone acetyltransferase complex and linked it to chromatin-based stress resistance.\",\n      \"evidence\": \"Reciprocal co-IP with NuA4 subunits and genetic epistasis with esa1/yng2 plus benomyl sensitivity assays\",\n      \"pmids\": [\"12917332\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish the molecular basis of Yaf9's contribution to NuA4\", \"Connection to H2A.Z not yet made\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Two studies separated GAS41's transcriptional roles, showing it is a co-activator for AP-2β and, independently of TIP60, a repressor of the p53 pathway via promoter occupancy.\",\n      \"evidence\": \"Co-IP, GST pull-down, EMSA and reporter assays for AP-2β; siRNA, coiled-coil mutagenesis, ChIP and p53 phosphorylation assays for p53 repression\",\n      \"pmids\": [\"16698963\", \"16705155\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The mechanism by which GAS41 represses p21/p14ARF promoters was not molecularly defined\", \"How GAS41 dissociation from promoters is triggered by stress was unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Structure of the Yaf9 YEATS domain and its histone-binding activity provided the first mechanistic link between the protein and H2A.Z chromatin deposition.\",\n      \"evidence\": \"X-ray crystallography, in vitro H3/H4 binding, mutagenesis and H2A.Z ChIP in yeast\",\n      \"pmids\": [\"19966225\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific acetyl-mark recognized by the domain not yet defined\", \"Did not establish the reader chemistry later attributed to the aromatic cage\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Reconstitution showed GAS41 confers substrate specificity to PP2Cβ, explaining mechanistically how it suppresses p53 by enabling dephosphorylation at Ser366.\",\n      \"evidence\": \"Co-IP and in vitro phosphatase assays with mutant p53 substrates plus UV-survival assays\",\n      \"pmids\": [\"21317290\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the GAS41-PP2Cβ axis operates at chromatin or in the nucleoplasm was not resolved\", \"Relationship to GAS41 promoter occupancy at p53 targets not integrated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"A cluster of structural studies defined GAS41/Yaf9 as an aromatic-cage reader of H3K27ac and H3K14ac, mechanistically explaining its recruitment to active promoters and its role in H2A.Z deposition via Tip60/p400, SRCAP and SWR1.\",\n      \"evidence\": \"Crystal structures of YEATS domains with acetyl-H3 peptides, aromatic-cage mutagenesis, ITC, ChIP-seq and knockdown/rescue in NSCLC, mouse ESCs and yeast\",\n      \"pmids\": [\"29437725\", \"29900004\", \"29145630\", \"30071723\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The basis for H3K14ac recognition was incomplete until the H3NT pocket was defined\", \"How reader binding is coordinated with remodeler enzymatic activity not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"In vivo conditional knockout showed GAS41 reads H3K27ac to recruit Dot1l-RNA Pol II for developmental gene activation, extending its co-activator function to lymphoid lineage commitment.\",\n      \"evidence\": \"Conditional knockout mouse, ChIP co-occupancy and co-IP at the Lmo4 promoter with rescue\",\n      \"pmids\": [\"31434684\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality of Dot1l-Pol II recruitment beyond Lmo4 not established\", \"Single-lab in vivo model\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identification of an H3NT-binding pocket and the essential residue E109 completed the structural logic of how GAS41 recognizes H3K14ac to occupy H2A.Z-enriched promoters.\",\n      \"evidence\": \"X-ray crystallography, NMR, binding assays, E109 mutagenesis and ChIP for GAS41/H2A.Z\",\n      \"pmids\": [\"37844223\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the H3NT pocket contributes to non-H2A.Z transcriptional functions not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Multiple studies broadened GAS41's reader output to disease-relevant programs and revealed its own regulation, anchoring NRF2 to repress ferroptosis, controlling nuclear-shape gene transcription via BRD2/Mediator, and being stabilized by KAT8 acetylation against HUWE1 degradation.\",\n      \"evidence\": \"CRISPR screens, reciprocal co-IP, ChIP, ferroptosis and tumor models; CRISPR KO with YEATS-mutant rescue and ChIP for BRD2/Mediator; protein-stability screen and ubiquitination assays\",\n      \"pmids\": [\"38514704\", \"38964523\", \"38526153\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How GAS41 selects between distinct partner complexes at different loci is unknown\", \"Whether NRF2 anchoring and H2A.Z deposition are mechanistically coupled is unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Single-molecule and biochemical work extended the reader repertoire to H3K14 crotonylation and defined kinetically how Yaf9 governs SWR1 residence on chromatin.\",\n      \"evidence\": \"Crotonyl-binding assays with multi-omics in breast cancer cells; live-cell single-molecule tracking and ChIP-exo in yeast\",\n      \"pmids\": [\"41060805\", \"40768570\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether crotonylation reading uses the same aromatic cage as acetylation is not delineated\", \"Quantitative kinetics of human GAS41 on chromatin not measured\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Genetic dissection showed Yaf9 is required in both NuA4 and SWR1 for viability under impaired H4 acetylation, and that this essential role is separable from its YEATS acyl-reading activity.\",\n      \"evidence\": \"Synthetic lethality, cell-cycle analysis, recombination-pathway assessment with a YEATS-inactivating mutant\",\n      \"pmids\": [\"41653028\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The reading-independent molecular function of Yaf9 within the complexes is undefined\", \"Whether the human ortholog has an equivalent reading-independent essential role is untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How GAS41 chooses among its many partner complexes (Tip60/p400, SRCAP, NRF2, Dot1l-Pol II, BRD2/Mediator, PP2Cβ) at specific loci, and how its acyl-reading and reading-independent functions are integrated, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model for context-specific partner selection\", \"Coupling between reader binding and downstream enzymatic/remodeling activity undefined\", \"Mechanism distinguishing acetyl- from crotonyl-mark output unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [0, 1, 6, 7, 8, 24]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [4, 9, 13, 15, 25]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [9, 15, 25]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0, 1, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 1, 3, 6, 8]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [12, 13, 15, 25]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [1, 3, 6, 26]}\n    ],\n    \"complexes\": [\"NuA4\", \"SWR1/SRCAP\", \"Tip60/p400\", \"GAS41-PP2Cβ\"],\n    \"partners\": [\"NRF2\", \"PP2Cβ\", \"HUWE1\", \"KAT8\", \"DOT1L\", \"BRD2\", \"NuMA\", \"TFIIF\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}