{"gene":"YEATS2","run_date":"2026-04-28T23:00:23","timeline":{"discoveries":[{"year":2017,"finding":"YEATS2 binds acetylated histone H3 (H3K27ac) via its YEATS domain, and the YEATS2-containing ATAC complex co-localizes with H3K27ac on promoters of actively transcribed genes; depletion of YEATS2 or disruption of the YEATS domain–acetyllysine interaction reduces ATAC complex-dependent promoter H3K9ac levels and deactivates essential gene expression in NSCLC cells.","method":"ChIP-seq, YEATS domain mutation/disruption assays, cell depletion with defined transcriptional phenotype","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 — reciprocal ChIP, domain-mutation disruption, and defined downstream phenotype; replicated across multiple methods in a single study with >100 citations","pmids":["29057918"],"is_preprint":false},{"year":2021,"finding":"YEATS2 physically interacts with TAK1 and NF-κB; depletion of YEATS2 reduces TAK1 abundance and NF-κB transcriptional activity, establishing YEATS2 as a co-transcriptional factor that promotes NF-κB signaling through modulating TAK1 stability in pancreatic ductal adenocarcinoma cells.","method":"Co-immunoprecipitation, luciferase reporter assay, western blotting, YEATS2 depletion with defined NF-κB pathway phenotype","journal":"Cell Biology and Toxicology","confidence":"Medium","confidence_rationale":"Tier 2/3 — Co-IP plus reporter assay in a single lab; replicated conceptually in a subsequent cinobufacini study","pmids":["34686948"],"is_preprint":false},{"year":2022,"finding":"Cinobufacini treatment reduces intracellular YEATS2 and total TAK1 protein levels; ectopic YEATS2 re-elevates TAK1 and phosphorylated IKKα/β, IκBα, and p65, confirming YEATS2 maintains TAK1 abundance upstream of NF-κB in PDAC.","method":"Ectopic gene expression rescue assay, western blotting, xenograft model","journal":"Phytomedicine","confidence":"Medium","confidence_rationale":"Tier 2 — rescue experiment with ectopic expression provides pathway placement; single lab","pmids":["36610152"],"is_preprint":false},{"year":2020,"finding":"HIF1α directly regulates YEATS2 expression by binding to a hypoxia response element (HRE) in the YEATS2 promoter; overexpression of YEATS2 rescues the inhibitory effects of HIF1α silencing on pancreatic cancer cell proliferation and migration under hypoxia.","method":"ChIP (HIF1α binding to HRE), overexpression rescue assay, qRT-PCR, in vitro and in vivo proliferation/migration assays","journal":"Journal of Cellular Physiology","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP plus genetic rescue; single lab, moderate orthogonal methods","pmids":["32749678"],"is_preprint":false},{"year":2025,"finding":"YEATS2 is O-GlcNAcylated by O-GlcNAc transferase primarily at Thr604; this modification promotes YEATS2 chromatin association and strengthens its affinity for ATAC complex components (ZZZ3, GCN5, PCAF) on chromatin, thereby sustaining ATAC-dependent H3K9ac levels and ribosomal gene expression, and promoting lung cancer tumorigenesis in xenograft models.","method":"Electron transfer dissociation mass spectrometry (O-GlcNAcylation site mapping), YEATS2-T604A mutagenesis, Co-IP, ChIP, xenograft experiments","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 — site-specific mutagenesis combined with MS-based PTM mapping, ChIP, Co-IP, and in vivo xenograft; multiple orthogonal methods in one study","pmids":["40541806"],"is_preprint":false},{"year":2025,"finding":"MYC enhancer RNA (eRNA) interacts directly with YEATS2 protein; TNF-α-induced tyrosine dephosphorylation of the YEATS domain enhances MYC eRNA binding to YEATS2, augmenting ATAC complex association at the MYC promoter/enhancer and increasing MYC gene expression in pancreatic cancer cells.","method":"RNA-protein interaction assay, ChIP, signaling perturbation (TNF-α treatment), Co-immunoprecipitation","journal":"EMBO Reports","confidence":"Medium","confidence_rationale":"Tier 2 — RNA-protein binding assay plus ChIP and signaling manipulation; single lab","pmids":["40216980"],"is_preprint":false},{"year":2025,"finding":"YEATS2 maintains histone crotonylation (H3K27cr) at the SPARC promoter by recruiting crotonyltransferase p300, thereby promoting EMT-related gene expression in head and neck cancer; abrogation of YEATS2 causes global decrease in H3K27cr, and this activity is also dependent on the crotonyl-CoA-producing enzyme GCDH.","method":"ChIP, Co-IP, knockdown/overexpression with EMT phenotype readout, global histone modification analysis","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and Co-IP with defined chromatin and phenotypic readout; single lab","pmids":["40810390"],"is_preprint":false},{"year":2025,"finding":"YEATS2 activates IL6ST transcription in esophageal squamous cell carcinoma by reading H3K27ac at the IL6ST promoter and recruiting TAF15 and KAT5, thereby enhancing local H3K27ac enrichment and activating NF-κB signaling.","method":"Co-IP-based mass spectrometry, ChIP, overexpression/knockdown with NF-κB pathway readout","journal":"Frontiers in Cell and Developmental Biology","confidence":"Medium","confidence_rationale":"Tier 2 — MS-based interactome plus ChIP; single lab","pmids":["40040791"],"is_preprint":false},{"year":2026,"finding":"YEATS2 increases chromatin accessibility at the RAD50 promoter by recognizing H3K27ac and recruits transcription factor NR2C2, upregulating RAD50 expression to promote DNA damage repair and anoikis resistance in prostate cancer metastasis.","method":"ATAC-seq (chromatin accessibility), ChIP (H3K27ac), Co-IP (YEATS2-NR2C2 interaction), knockdown/overexpression with in vivo metastasis phenotype","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — ATAC-seq, ChIP, and Co-IP with defined downstream gene and phenotype; single lab","pmids":["41708952"],"is_preprint":false},{"year":2026,"finding":"YEATS2 interacts with KAT2A (GCN5) to increase H3K9ac and H3K14ac at the TGFBR2 promoter, activating TGFBR2 transcription and downstream TAZ/AKT signaling and aerobic glycolysis in HCC; matrix stiffness induces YEATS2 expression via HIF-1α binding to the YEATS2 promoter.","method":"ChIP (H3K9ac, H3K14ac at TGFBR2 promoter), Co-IP (YEATS2-KAT2A), RNA-seq, mass spectrometry, xenograft experiments","journal":"Cell Death and Differentiation","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP, Co-IP, and RNA-seq with mechanistic pathway placement; single lab","pmids":["41776086"],"is_preprint":false},{"year":2026,"finding":"YEATS2 physically interacts with TGF-β-activated kinase 1 (TAK1) as confirmed by reciprocal Co-IP, structural modeling, and molecular dynamics simulation; YEATS2 enhances TAK1 activation and downstream stress-response signaling to drive adaptive sorafenib resistance in HCC.","method":"Reciprocal Co-immunoprecipitation, structural/molecular dynamics modeling, pharmacological TAK1 inhibition, genetic YEATS2 silencing","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP plus structural simulation and pharmacological rescue; single lab","pmids":["41962409"],"is_preprint":false},{"year":2024,"finding":"YEATS2 knockdown in HCC cells leads to DNA damage (elevated γ-H2A.X), activates the p53/p21Cip1 senescence pathway, and enhances p21Cip1 expression via the c-Myc/miR-93-5p axis, resulting in cellular senescence and reduced tumor growth with increased NK cell infiltration in vivo.","method":"YEATS2 knockdown, γ-H2A.X immunostaining, transcriptomic analysis, xenograft tumor model, NK cell quantification","journal":"Cell Cycle","confidence":"Medium","confidence_rationale":"Tier 2 — KD with multiple defined phenotypic readouts and pathway placement; single lab","pmids":["38619971"],"is_preprint":false},{"year":2024,"finding":"LINC00887 promotes GCN5 expression (via blocking SIRT3 at GCN5 promoter), increasing global H3K27cr; this leads to enrichment of GCN5, H3K27cr, and YEATS2 at the ETS1 promoter, where YEATS2 reads H3K27cr to activate ETS1 transcription and promote colorectal cancer metastasis.","method":"ChIP (GCN5, H3K27cr, YEATS2 at ETS1 promoter), Co-IP (LINC00887-SIRT3), overexpression/knockdown, in vivo metastasis model","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and Co-IP with defined gene activation and in vivo phenotype; single lab","pmids":["39349460"],"is_preprint":false},{"year":2023,"finding":"Knockdown of YEATS2 (dYEATS2) in Drosophila neurons reduces tyrosine hydroxylase (TH) gene expression and dopamine biosynthesis, causing seizure-like behaviors, locomotion defects, and stress intolerance; L-DOPA administration rescues seizure-like behaviors, placing YEATS2 upstream of dopaminergic gene regulation.","method":"Pan-neuronal RNAi knockdown in Drosophila, behavioral assays, TH mRNA/protein analysis, pharmacological rescue with L-DOPA","journal":"Progress in Neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KD with pharmacological rescue establishing pathway position; ortholog functional study in Drosophila","pmids":["38128822"],"is_preprint":false},{"year":2025,"finding":"Neuronal depletion of YEATS2 in Drosophila reshapes the brain transcriptome (downregulating metabolic genes, upregulating GPCRs), causes elevated intracellular calcium and selective dopaminergic neuron loss; inhibition of the store-operated calcium entry channel Orai restores calcium homeostasis and rescues DA neuron survival, defining a YEATS2-dependent epigenetic–calcium axis.","method":"Drosophila neuronal RNAi, transcriptomics, intracellular calcium measurement, genetic/pharmacological Orai inhibition with DA neuron survival readout","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 2 — genetic rescue plus transcriptomics and calcium imaging; Drosophila ortholog, preprint","pmids":["bio_10.1101_2025.09.06.674642"],"is_preprint":true}],"current_model":"YEATS2 functions as a chromatin reader within the ATAC complex, recognizing histone H3 acetylation (H3K27ac) and crotonylation (H3K27cr) via its YEATS domain to recruit acetyltransferases (GCN5/KAT2A, KAT5, p300) and sustain promoter H3K9ac/H3K14ac levels that drive transcription of oncogenic programs (MYC, IL6ST, RAD50, TGFBR2, ETS1, ribosomal genes); this activity is further regulated by O-GlcNAcylation at Thr604 (which stabilizes ATAC complex assembly on chromatin), by post-translational tyrosine dephosphorylation of the YEATS domain (which enhances eRNA binding), and by upstream HIF-1α-mediated transcriptional induction; additionally, YEATS2 physically interacts with TAK1 to sustain NF-κB signaling, and in neurons it governs dopaminergic gene expression and calcium homeostasis."},"narrative":{"teleology":[{"year":2017,"claim":"Establishing YEATS2 as a histone acetylation reader within the ATAC complex resolved how this HAT complex is recruited to active promoters: the YEATS domain directly recognizes H3K27ac, and loss of this interaction collapses ATAC-dependent H3K9ac and downstream gene expression in lung cancer cells.","evidence":"ChIP-seq, YEATS domain mutagenesis, and YEATS2 depletion with transcriptional phenotyping in NSCLC cells","pmids":["29057918"],"confidence":"High","gaps":["Whether YEATS2 reads acyl marks beyond acetylation was unknown","Post-translational regulation of YEATS2 chromatin engagement was uncharacterized","The breadth of target gene programs beyond NSCLC was not explored"]},{"year":2020,"claim":"Identifying HIF-1α as a direct transcriptional activator of YEATS2 via an HRE in its promoter established how hypoxia upregulates chromatin remodeling through YEATS2, linking microenvironmental stress to epigenetic gene activation in pancreatic cancer.","evidence":"ChIP for HIF-1α at YEATS2 promoter HRE, overexpression rescue of HIF-1α knockdown phenotype in pancreatic cancer cells","pmids":["32749678"],"confidence":"Medium","gaps":["Whether other stress-responsive transcription factors also regulate YEATS2 expression was not tested","The downstream chromatin targets of HIF-1α–induced YEATS2 were not mapped genome-wide"]},{"year":2021,"claim":"Discovery of a physical YEATS2–TAK1 interaction that stabilizes TAK1 protein and sustains NF-κB transcriptional activity revealed a non-chromatin-reader function for YEATS2 in inflammatory signaling in PDAC.","evidence":"Co-immunoprecipitation, NF-κB luciferase reporter, YEATS2 depletion in PDAC cells","pmids":["34686948"],"confidence":"Medium","gaps":["The mechanism by which YEATS2 stabilizes TAK1 (e.g., blocking ubiquitination) was not defined","Whether the TAK1 interaction is independent of ATAC complex membership was unclear"]},{"year":2022,"claim":"Ectopic YEATS2 rescue of TAK1 and phospho-IKKα/β levels after cinobufacini treatment confirmed that YEATS2 acts upstream of the TAK1–NF-κB axis, solidifying pathway placement.","evidence":"Ectopic YEATS2 rescue, western blot for phospho-IKKα/β and IκBα, xenograft model","pmids":["36610152"],"confidence":"Medium","gaps":["Whether YEATS2 directly prevents TAK1 degradation or acts through an intermediary was not resolved","In vivo confirmation limited to xenograft with pharmacological perturbation"]},{"year":2023,"claim":"Neuronal knockdown of Drosophila YEATS2 reduced tyrosine hydroxylase expression and dopamine biosynthesis, with L-DOPA rescue of seizure phenotypes, extending YEATS2's epigenetic role to dopaminergic neuron gene regulation.","evidence":"Pan-neuronal RNAi in Drosophila, TH mRNA/protein quantification, behavioral assays, L-DOPA pharmacological rescue","pmids":["38128822"],"confidence":"Medium","gaps":["Whether the dopaminergic gene regulation is direct (YEATS2 binding at TH promoter) was not shown by ChIP","Relevance to mammalian dopaminergic neurons was not tested"]},{"year":2024,"claim":"YEATS2 depletion in HCC triggered DNA damage, activated p53/p21-dependent senescence via a c-Myc/miR-93-5p axis, and enhanced NK cell infiltration, revealing that YEATS2 suppresses senescence and modulates tumor immune surveillance.","evidence":"YEATS2 knockdown, γ-H2A.X staining, transcriptomic analysis, xenograft with NK cell quantification","pmids":["38619971"],"confidence":"Medium","gaps":["Whether DNA damage results from loss of specific YEATS2-dependent DNA repair genes (e.g., RAD50) was not dissected","The mechanism linking YEATS2 loss to enhanced NK cell infiltration was not defined"]},{"year":2024,"claim":"Demonstration that YEATS2 reads H3K27cr at the ETS1 promoter downstream of GCN5-deposited crotonylation established YEATS2 as a dual acylation reader (acetylation and crotonylation), broadening the range of histone marks it interprets.","evidence":"ChIP for GCN5, H3K27cr, and YEATS2 at ETS1 promoter; LINC00887 overexpression/knockdown; in vivo colorectal cancer metastasis model","pmids":["39349460"],"confidence":"Medium","gaps":["Structural basis for YEATS domain recognition of crotonyl versus acetyl lysine on H3K27 was not resolved","Genome-wide overlap of YEATS2-bound crotonylated versus acetylated sites was not profiled"]},{"year":2025,"claim":"Identification of O-GlcNAcylation at Thr604 as a modification that strengthens YEATS2–ATAC complex assembly on chromatin provided the first metabolic regulatory input controlling YEATS2 chromatin reader function.","evidence":"ETD mass spectrometry for O-GlcNAc site mapping, T604A mutagenesis, Co-IP, ChIP, lung cancer xenograft","pmids":["40541806"],"confidence":"High","gaps":["Whether O-GlcNAcylation affects YEATS domain histone-binding affinity or only complex stability was not distinguished","The phosphatase or signaling pathway opposing O-GlcNAcylation at Thr604 was not identified"]},{"year":2025,"claim":"TNF-α-induced tyrosine dephosphorylation of the YEATS domain enhances MYC enhancer RNA binding, augmenting ATAC complex association at the MYC locus, revealing a signal-responsive eRNA–YEATS2 regulatory circuit.","evidence":"RNA-protein interaction assay, ChIP, TNF-α signaling perturbation in pancreatic cancer cells","pmids":["40216980"],"confidence":"Medium","gaps":["The specific tyrosine residue(s) dephosphorylated and the responsible phosphatase were not fully defined","Whether eRNA binding is a general mechanism at other YEATS2-bound enhancers was not tested"]},{"year":2025,"claim":"YEATS2 reads H3K27ac at the IL6ST promoter and recruits TAF15 and KAT5 to amplify local acetylation and activate NF-κB in esophageal cancer, expanding the acetyltransferase cofactor repertoire beyond GCN5 to include KAT5.","evidence":"Co-IP-based mass spectrometry, ChIP, YEATS2 overexpression/knockdown with NF-κB readout in ESCC","pmids":["40040791"],"confidence":"Medium","gaps":["Whether YEATS2–KAT5 interaction occurs within or outside the ATAC complex was not resolved","The role of TAF15 in this complex was not mechanistically dissected"]},{"year":2025,"claim":"YEATS2 recruits crotonyltransferase p300 to maintain H3K27cr at the SPARC promoter in head and neck cancer, demonstrating that YEATS2 can serve as a platform for both HAT (GCN5, KAT5) and non-ATAC acyltransferase (p300) recruitment.","evidence":"ChIP, Co-IP, YEATS2 knockdown/overexpression, global histone crotonylation analysis in HNSCC","pmids":["40810390"],"confidence":"Medium","gaps":["Whether YEATS2 directly binds p300 or requires a bridging factor was not determined","The distinction between YEATS2 reading pre-existing H3K27cr versus recruiting p300 to deposit new marks was not cleanly separated"]},{"year":2026,"claim":"YEATS2 increases chromatin accessibility at the RAD50 promoter and recruits NR2C2 to drive DNA repair gene expression and anoikis resistance in metastatic prostate cancer, linking the reader function to DNA damage repair and metastatic fitness.","evidence":"ATAC-seq, ChIP for H3K27ac, Co-IP for YEATS2–NR2C2, in vivo metastasis model","pmids":["41708952"],"confidence":"Medium","gaps":["Whether YEATS2 directly opens chromatin or indirectly does so through recruited remodelers was not distinguished","Generality to other DNA repair loci beyond RAD50 was not tested"]},{"year":2026,"claim":"Reciprocal Co-IP and molecular dynamics confirmed direct YEATS2–TAK1 interaction and showed YEATS2 enhances TAK1 kinase activation driving sorafenib resistance in HCC, extending the TAK1 axis from PDAC to HCC and drug resistance contexts.","evidence":"Reciprocal Co-IP, molecular dynamics simulation, pharmacological TAK1 inhibition, YEATS2 silencing in HCC","pmids":["41962409"],"confidence":"Medium","gaps":["The binding interface between YEATS2 and TAK1 lacks crystallographic validation","Whether YEATS2–TAK1 interaction is constitutive or signal-regulated was not addressed"]},{"year":null,"claim":"Key unresolved questions include: (1) the structural basis for YEATS domain selectivity among different acylation marks; (2) whether YEATS2 reader and TAK1-stabilizing functions are mechanistically coupled or independent; (3) relevance of YEATS2 dopaminergic regulation to mammalian neurodegeneration.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No crystal structure of full-length YEATS2 or YEATS domain bound to crotonylated peptide is available","Separation-of-function mutants distinguishing chromatin reader from TAK1-binding roles have not been generated","Mammalian neuronal studies of YEATS2 function are absent"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[0,4,6,7,8,12]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,7,9,12]}],"localization":[{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[0,4,6,8]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,4,7,9]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,4,6,12]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,7,9,13]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2,7,10]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,3,9,11]}],"complexes":["ATAC complex"],"partners":["GCN5","TAK1","ZZZ3","KAT5","NR2C2","TAF15","PCAF","EP300"],"other_free_text":[]},"mechanistic_narrative":"YEATS2 is a chromatin reader subunit of the ATAC histone acetyltransferase complex that recognizes acetylated and crotonylated histone H3 (H3K27ac, H3K27cr) via its YEATS domain to sustain promoter-proximal histone acetylation and activate transcription of growth, metabolic, and DNA repair genes across multiple cancer contexts [PMID:29057918, PMID:39349460, PMID:40810390]. YEATS2 recruits acetyltransferases including GCN5/KAT2A, KAT5, and p300 to target promoters, maintaining H3K9ac, H3K14ac, and H3K27cr marks that drive expression of oncogenic programs such as MYC, TGFBR2, RAD50, ETS1, and ribosomal genes [PMID:41776086, PMID:41708952, PMID:40040791, PMID:29057918]. Its chromatin engagement is positively regulated by O-GlcNAcylation at Thr604, which strengthens ATAC complex assembly, and by TNF-α-induced tyrosine dephosphorylation of the YEATS domain, which enhances enhancer RNA binding [PMID:40541806, PMID:40216980]. Beyond chromatin reading, YEATS2 physically interacts with TAK1 to sustain NF-κB signaling in pancreatic and hepatocellular carcinoma, and in Drosophila neurons it governs dopaminergic gene expression and calcium homeostasis [PMID:34686948, PMID:41962409, PMID:38128822]."},"prefetch_data":{"uniprot":{"accession":"Q9ULM3","full_name":"YEATS domain-containing protein 2","aliases":[],"length_aa":1422,"mass_kda":150.8,"function":"Chromatin reader component of the ATAC complex, a complex with histone acetyltransferase activity on histones H3 and H4 (PubMed:18838386, PubMed:19103755, PubMed:27103431). YEATS2 specifically recognizes and binds histone H3 crotonylated at 'Lys-27' (H3K27cr) (PubMed:27103431). Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors (PubMed:27103431)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9ULM3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/YEATS2","classification":"Common Essential","n_dependent_lines":808,"n_total_lines":1208,"dependency_fraction":0.6688741721854304},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ACTB","stoichiometry":0.2},{"gene":"H2AFZ","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/YEATS2","total_profiled":1310},"omim":[{"mim_id":"617501","title":"LYSINE ACETYLTRANSFERASE 14; KAT14","url":"https://www.omim.org/entry/617501"},{"mim_id":"615127","title":"EPILEPSY, FAMILIAL ADULT MYOCLONIC, 4; FAME4","url":"https://www.omim.org/entry/615127"},{"mim_id":"613373","title":"YEATS DOMAIN-CONTAINING PROTEIN 2; YEATS2","url":"https://www.omim.org/entry/613373"},{"mim_id":"602303","title":"LYSINE ACETYLTRANSFERASE 2B; KAT2B","url":"https://www.omim.org/entry/602303"},{"mim_id":"602301","title":"LYSINE ACETYLTRANSFERASE 2A; KAT2A","url":"https://www.omim.org/entry/602301"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/YEATS2"},"hgnc":{"alias_symbol":["FLJ10201","FLJ12841","FLJ13308","KIAA1197"],"prev_symbol":[]},"alphafold":{"accession":"Q9ULM3","domains":[{"cath_id":"2.60.40.1970","chopping":"203-331","consensus_level":"high","plddt":91.4826,"start":203,"end":331},{"cath_id":"-","chopping":"1141-1245","consensus_level":"medium","plddt":82.7706,"start":1141,"end":1245},{"cath_id":"1.10.20,1.10.20","chopping":"1320-1418","consensus_level":"medium","plddt":83.662,"start":1320,"end":1418}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULM3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULM3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULM3-F1-predicted_aligned_error_v6.png","plddt_mean":49.84},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=YEATS2","jax_strain_url":"https://www.jax.org/strain/search?query=YEATS2"},"sequence":{"accession":"Q9ULM3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9ULM3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9ULM3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULM3"}},"corpus_meta":[{"pmid":"29057918","id":"PMC_29057918","title":"YEATS2 links histone acetylation to tumorigenesis of non-small cell lung cancer.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29057918","citation_count":119,"is_preprint":false},{"pmid":"31539032","id":"PMC_31539032","title":"TTTCA repeat insertions in an intron of YEATS2 in benign adult familial myoclonic epilepsy type 4.","date":"2019","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/31539032","citation_count":88,"is_preprint":false},{"pmid":"32749678","id":"PMC_32749678","title":"YEATS2 is a target of HIF1α and promotes pancreatic cancer cell proliferation and migration.","date":"2020","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/32749678","citation_count":36,"is_preprint":false},{"pmid":"36980736","id":"PMC_36980736","title":"Overexpression of YEATS2 Remodels the Extracellular Matrix to Promote Hepatocellular Carcinoma Progression via the PI3K/AKT Pathway.","date":"2023","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/36980736","citation_count":20,"is_preprint":false},{"pmid":"34686948","id":"PMC_34686948","title":"YEATS2 regulates the activation of TAK1/NF-κB pathway and is critical for pancreatic ductal adenocarcinoma cell survival.","date":"2021","source":"Cell biology and toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/34686948","citation_count":17,"is_preprint":false},{"pmid":"34587874","id":"PMC_34587874","title":"YEATS domain-containing 2 (YEATS2), targeted by microRNA miR-378a-5p, regulates growth and metastasis in head and neck squamous cell carcinoma.","date":"2021","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/34587874","citation_count":13,"is_preprint":false},{"pmid":"36610152","id":"PMC_36610152","title":"Cinobufacini retards progression of pancreatic ductal adenocarcinoma through targeting YEATS2/TAK1/NF-κB axis.","date":"2022","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/36610152","citation_count":12,"is_preprint":false},{"pmid":"38619971","id":"PMC_38619971","title":"Repression of YEATS2 induces cellular senescence in hepatocellular carcinoma and inhibits tumor growth.","date":"2024","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/38619971","citation_count":9,"is_preprint":false},{"pmid":"39718737","id":"PMC_39718737","title":"The survival prediction analysis and preliminary study of the biological function of YEATS2 in hepatocellular carcinoma.","date":"2024","source":"Cellular oncology (Dordrecht, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/39718737","citation_count":7,"is_preprint":false},{"pmid":"39349460","id":"PMC_39349460","title":"LINC00887 promotes GCN5-dependent H3K27cr level and CRC metastasis via recruitment of YEATS2 and enhancing ETS1 expression.","date":"2024","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/39349460","citation_count":7,"is_preprint":false},{"pmid":"40148389","id":"PMC_40148389","title":"LINC00894, YEATS2-AS1, and SUGP2 genes as novel biomarkers for N0 status of lung adenocarcinoma.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/40148389","citation_count":6,"is_preprint":false},{"pmid":"40216980","id":"PMC_40216980","title":"Dynamic interaction of MYC enhancer RNA with YEATS2 protein regulates MYC gene transcription in pancreatic cancer.","date":"2025","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/40216980","citation_count":4,"is_preprint":false},{"pmid":"40287757","id":"PMC_40287757","title":"YEATS2: a novel cancer epigenetic reader and potential therapeutic target.","date":"2025","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/40287757","citation_count":3,"is_preprint":false},{"pmid":"40040791","id":"PMC_40040791","title":"YEATS2 promotes malignant phenotypes of esophageal squamous cell carcinoma via H3K27ac activated-IL6ST.","date":"2025","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/40040791","citation_count":2,"is_preprint":false},{"pmid":"38128822","id":"PMC_38128822","title":"FAME4-associating YEATS2 knockdown impairs dopaminergic synaptic integrity and leads to seizure-like behaviours in Drosophila melanogaster.","date":"2023","source":"Progress in neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/38128822","citation_count":2,"is_preprint":false},{"pmid":"40810390","id":"PMC_40810390","title":"Interplay of YEATS2 and GCDH regulates histone crotonylation and drives EMT in head and neck cancer.","date":"2025","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/40810390","citation_count":2,"is_preprint":false},{"pmid":"40541806","id":"PMC_40541806","title":"YEATS2 O-GlcNAcylation promotes chromatin association of the ATAC complex and lung cancer tumorigenesis.","date":"2025","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/40541806","citation_count":1,"is_preprint":false},{"pmid":"41708952","id":"PMC_41708952","title":"YEATS2 promotes DNA repair and induces anoikis resistance by enhancing chromatin accessibility to drive prostate cancer metastasis.","date":"2026","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/41708952","citation_count":0,"is_preprint":false},{"pmid":"40731114","id":"PMC_40731114","title":"The value of acetylation reader YEATS2 in hepatocellular carcinoma management.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/40731114","citation_count":0,"is_preprint":false},{"pmid":"41776086","id":"PMC_41776086","title":"Matrix stiffness-induced YEATS2 drives HCC progression via epigenetic activation of the TGFBR2-TAZ-AKT pathway.","date":"2026","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/41776086","citation_count":0,"is_preprint":false},{"pmid":"41311083","id":"PMC_41311083","title":"[High YEATS2 expression promotes epithelial-mesenchymal transition in gastric cancer cells by activating the Wnt/β-catenin signaling pathway].","date":"2025","source":"Nan fang yi ke da xue xue bao = Journal of Southern Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/41311083","citation_count":0,"is_preprint":false},{"pmid":"41962409","id":"PMC_41962409","title":"YEATS2/TAK1 axis mediates TGF-β1 driven adaptive resistance to sorafenib in hepatocellular carcinoma.","date":"2026","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/41962409","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.06.674642","title":"Dopaminergic neurons are vulnerable to dysregulation of YEATS2-dependent calcium homeostasis","date":"2025-09-11","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.06.674642","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.25.672079","title":"Comprehensive pan-cancer characterization of cancer-testis genes at single-cell resolution","date":"2025-08-29","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.25.672079","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12569,"output_tokens":3795,"usd":0.047316},"stage2":{"model":"claude-opus-4-6","input_tokens":7280,"output_tokens":3836,"usd":0.19845},"total_usd":0.245766,"stage1_batch_id":"msgbatch_01BparvgRZ9S2LMidvaoo86K","stage2_batch_id":"msgbatch_01NkBfv9SVZWthhS7j6mU6G3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2017,\n      \"finding\": \"YEATS2 binds acetylated histone H3 (H3K27ac) via its YEATS domain, and the YEATS2-containing ATAC complex co-localizes with H3K27ac on promoters of actively transcribed genes; depletion of YEATS2 or disruption of the YEATS domain–acetyllysine interaction reduces ATAC complex-dependent promoter H3K9ac levels and deactivates essential gene expression in NSCLC cells.\",\n      \"method\": \"ChIP-seq, YEATS domain mutation/disruption assays, cell depletion with defined transcriptional phenotype\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal ChIP, domain-mutation disruption, and defined downstream phenotype; replicated across multiple methods in a single study with >100 citations\",\n      \"pmids\": [\"29057918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YEATS2 physically interacts with TAK1 and NF-κB; depletion of YEATS2 reduces TAK1 abundance and NF-κB transcriptional activity, establishing YEATS2 as a co-transcriptional factor that promotes NF-κB signaling through modulating TAK1 stability in pancreatic ductal adenocarcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation, luciferase reporter assay, western blotting, YEATS2 depletion with defined NF-κB pathway phenotype\",\n      \"journal\": \"Cell Biology and Toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — Co-IP plus reporter assay in a single lab; replicated conceptually in a subsequent cinobufacini study\",\n      \"pmids\": [\"34686948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cinobufacini treatment reduces intracellular YEATS2 and total TAK1 protein levels; ectopic YEATS2 re-elevates TAK1 and phosphorylated IKKα/β, IκBα, and p65, confirming YEATS2 maintains TAK1 abundance upstream of NF-κB in PDAC.\",\n      \"method\": \"Ectopic gene expression rescue assay, western blotting, xenograft model\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — rescue experiment with ectopic expression provides pathway placement; single lab\",\n      \"pmids\": [\"36610152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HIF1α directly regulates YEATS2 expression by binding to a hypoxia response element (HRE) in the YEATS2 promoter; overexpression of YEATS2 rescues the inhibitory effects of HIF1α silencing on pancreatic cancer cell proliferation and migration under hypoxia.\",\n      \"method\": \"ChIP (HIF1α binding to HRE), overexpression rescue assay, qRT-PCR, in vitro and in vivo proliferation/migration assays\",\n      \"journal\": \"Journal of Cellular Physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus genetic rescue; single lab, moderate orthogonal methods\",\n      \"pmids\": [\"32749678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YEATS2 is O-GlcNAcylated by O-GlcNAc transferase primarily at Thr604; this modification promotes YEATS2 chromatin association and strengthens its affinity for ATAC complex components (ZZZ3, GCN5, PCAF) on chromatin, thereby sustaining ATAC-dependent H3K9ac levels and ribosomal gene expression, and promoting lung cancer tumorigenesis in xenograft models.\",\n      \"method\": \"Electron transfer dissociation mass spectrometry (O-GlcNAcylation site mapping), YEATS2-T604A mutagenesis, Co-IP, ChIP, xenograft experiments\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — site-specific mutagenesis combined with MS-based PTM mapping, ChIP, Co-IP, and in vivo xenograft; multiple orthogonal methods in one study\",\n      \"pmids\": [\"40541806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MYC enhancer RNA (eRNA) interacts directly with YEATS2 protein; TNF-α-induced tyrosine dephosphorylation of the YEATS domain enhances MYC eRNA binding to YEATS2, augmenting ATAC complex association at the MYC promoter/enhancer and increasing MYC gene expression in pancreatic cancer cells.\",\n      \"method\": \"RNA-protein interaction assay, ChIP, signaling perturbation (TNF-α treatment), Co-immunoprecipitation\",\n      \"journal\": \"EMBO Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RNA-protein binding assay plus ChIP and signaling manipulation; single lab\",\n      \"pmids\": [\"40216980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YEATS2 maintains histone crotonylation (H3K27cr) at the SPARC promoter by recruiting crotonyltransferase p300, thereby promoting EMT-related gene expression in head and neck cancer; abrogation of YEATS2 causes global decrease in H3K27cr, and this activity is also dependent on the crotonyl-CoA-producing enzyme GCDH.\",\n      \"method\": \"ChIP, Co-IP, knockdown/overexpression with EMT phenotype readout, global histone modification analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and Co-IP with defined chromatin and phenotypic readout; single lab\",\n      \"pmids\": [\"40810390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YEATS2 activates IL6ST transcription in esophageal squamous cell carcinoma by reading H3K27ac at the IL6ST promoter and recruiting TAF15 and KAT5, thereby enhancing local H3K27ac enrichment and activating NF-κB signaling.\",\n      \"method\": \"Co-IP-based mass spectrometry, ChIP, overexpression/knockdown with NF-κB pathway readout\",\n      \"journal\": \"Frontiers in Cell and Developmental Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — MS-based interactome plus ChIP; single lab\",\n      \"pmids\": [\"40040791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"YEATS2 increases chromatin accessibility at the RAD50 promoter by recognizing H3K27ac and recruits transcription factor NR2C2, upregulating RAD50 expression to promote DNA damage repair and anoikis resistance in prostate cancer metastasis.\",\n      \"method\": \"ATAC-seq (chromatin accessibility), ChIP (H3K27ac), Co-IP (YEATS2-NR2C2 interaction), knockdown/overexpression with in vivo metastasis phenotype\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ATAC-seq, ChIP, and Co-IP with defined downstream gene and phenotype; single lab\",\n      \"pmids\": [\"41708952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"YEATS2 interacts with KAT2A (GCN5) to increase H3K9ac and H3K14ac at the TGFBR2 promoter, activating TGFBR2 transcription and downstream TAZ/AKT signaling and aerobic glycolysis in HCC; matrix stiffness induces YEATS2 expression via HIF-1α binding to the YEATS2 promoter.\",\n      \"method\": \"ChIP (H3K9ac, H3K14ac at TGFBR2 promoter), Co-IP (YEATS2-KAT2A), RNA-seq, mass spectrometry, xenograft experiments\",\n      \"journal\": \"Cell Death and Differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP, Co-IP, and RNA-seq with mechanistic pathway placement; single lab\",\n      \"pmids\": [\"41776086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"YEATS2 physically interacts with TGF-β-activated kinase 1 (TAK1) as confirmed by reciprocal Co-IP, structural modeling, and molecular dynamics simulation; YEATS2 enhances TAK1 activation and downstream stress-response signaling to drive adaptive sorafenib resistance in HCC.\",\n      \"method\": \"Reciprocal Co-immunoprecipitation, structural/molecular dynamics modeling, pharmacological TAK1 inhibition, genetic YEATS2 silencing\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus structural simulation and pharmacological rescue; single lab\",\n      \"pmids\": [\"41962409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YEATS2 knockdown in HCC cells leads to DNA damage (elevated γ-H2A.X), activates the p53/p21Cip1 senescence pathway, and enhances p21Cip1 expression via the c-Myc/miR-93-5p axis, resulting in cellular senescence and reduced tumor growth with increased NK cell infiltration in vivo.\",\n      \"method\": \"YEATS2 knockdown, γ-H2A.X immunostaining, transcriptomic analysis, xenograft tumor model, NK cell quantification\",\n      \"journal\": \"Cell Cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD with multiple defined phenotypic readouts and pathway placement; single lab\",\n      \"pmids\": [\"38619971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LINC00887 promotes GCN5 expression (via blocking SIRT3 at GCN5 promoter), increasing global H3K27cr; this leads to enrichment of GCN5, H3K27cr, and YEATS2 at the ETS1 promoter, where YEATS2 reads H3K27cr to activate ETS1 transcription and promote colorectal cancer metastasis.\",\n      \"method\": \"ChIP (GCN5, H3K27cr, YEATS2 at ETS1 promoter), Co-IP (LINC00887-SIRT3), overexpression/knockdown, in vivo metastasis model\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and Co-IP with defined gene activation and in vivo phenotype; single lab\",\n      \"pmids\": [\"39349460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Knockdown of YEATS2 (dYEATS2) in Drosophila neurons reduces tyrosine hydroxylase (TH) gene expression and dopamine biosynthesis, causing seizure-like behaviors, locomotion defects, and stress intolerance; L-DOPA administration rescues seizure-like behaviors, placing YEATS2 upstream of dopaminergic gene regulation.\",\n      \"method\": \"Pan-neuronal RNAi knockdown in Drosophila, behavioral assays, TH mRNA/protein analysis, pharmacological rescue with L-DOPA\",\n      \"journal\": \"Progress in Neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KD with pharmacological rescue establishing pathway position; ortholog functional study in Drosophila\",\n      \"pmids\": [\"38128822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Neuronal depletion of YEATS2 in Drosophila reshapes the brain transcriptome (downregulating metabolic genes, upregulating GPCRs), causes elevated intracellular calcium and selective dopaminergic neuron loss; inhibition of the store-operated calcium entry channel Orai restores calcium homeostasis and rescues DA neuron survival, defining a YEATS2-dependent epigenetic–calcium axis.\",\n      \"method\": \"Drosophila neuronal RNAi, transcriptomics, intracellular calcium measurement, genetic/pharmacological Orai inhibition with DA neuron survival readout\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic rescue plus transcriptomics and calcium imaging; Drosophila ortholog, preprint\",\n      \"pmids\": [\"bio_10.1101_2025.09.06.674642\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"YEATS2 functions as a chromatin reader within the ATAC complex, recognizing histone H3 acetylation (H3K27ac) and crotonylation (H3K27cr) via its YEATS domain to recruit acetyltransferases (GCN5/KAT2A, KAT5, p300) and sustain promoter H3K9ac/H3K14ac levels that drive transcription of oncogenic programs (MYC, IL6ST, RAD50, TGFBR2, ETS1, ribosomal genes); this activity is further regulated by O-GlcNAcylation at Thr604 (which stabilizes ATAC complex assembly on chromatin), by post-translational tyrosine dephosphorylation of the YEATS domain (which enhances eRNA binding), and by upstream HIF-1α-mediated transcriptional induction; additionally, YEATS2 physically interacts with TAK1 to sustain NF-κB signaling, and in neurons it governs dopaminergic gene expression and calcium homeostasis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"YEATS2 is a chromatin reader subunit of the ATAC histone acetyltransferase complex that recognizes acetylated and crotonylated histone H3 (H3K27ac, H3K27cr) via its YEATS domain to sustain promoter-proximal histone acetylation and activate transcription of growth, metabolic, and DNA repair genes across multiple cancer contexts [PMID:29057918, PMID:39349460, PMID:40810390]. YEATS2 recruits acetyltransferases including GCN5/KAT2A, KAT5, and p300 to target promoters, maintaining H3K9ac, H3K14ac, and H3K27cr marks that drive expression of oncogenic programs such as MYC, TGFBR2, RAD50, ETS1, and ribosomal genes [PMID:41776086, PMID:41708952, PMID:40040791, PMID:29057918]. Its chromatin engagement is positively regulated by O-GlcNAcylation at Thr604, which strengthens ATAC complex assembly, and by TNF-α-induced tyrosine dephosphorylation of the YEATS domain, which enhances enhancer RNA binding [PMID:40541806, PMID:40216980]. Beyond chromatin reading, YEATS2 physically interacts with TAK1 to sustain NF-κB signaling in pancreatic and hepatocellular carcinoma, and in Drosophila neurons it governs dopaminergic gene expression and calcium homeostasis [PMID:34686948, PMID:41962409, PMID:38128822].\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"Establishing YEATS2 as a histone acetylation reader within the ATAC complex resolved how this HAT complex is recruited to active promoters: the YEATS domain directly recognizes H3K27ac, and loss of this interaction collapses ATAC-dependent H3K9ac and downstream gene expression in lung cancer cells.\",\n      \"evidence\": \"ChIP-seq, YEATS domain mutagenesis, and YEATS2 depletion with transcriptional phenotyping in NSCLC cells\",\n      \"pmids\": [\"29057918\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether YEATS2 reads acyl marks beyond acetylation was unknown\",\n        \"Post-translational regulation of YEATS2 chromatin engagement was uncharacterized\",\n        \"The breadth of target gene programs beyond NSCLC was not explored\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identifying HIF-1α as a direct transcriptional activator of YEATS2 via an HRE in its promoter established how hypoxia upregulates chromatin remodeling through YEATS2, linking microenvironmental stress to epigenetic gene activation in pancreatic cancer.\",\n      \"evidence\": \"ChIP for HIF-1α at YEATS2 promoter HRE, overexpression rescue of HIF-1α knockdown phenotype in pancreatic cancer cells\",\n      \"pmids\": [\"32749678\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether other stress-responsive transcription factors also regulate YEATS2 expression was not tested\",\n        \"The downstream chromatin targets of HIF-1α–induced YEATS2 were not mapped genome-wide\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Discovery of a physical YEATS2–TAK1 interaction that stabilizes TAK1 protein and sustains NF-κB transcriptional activity revealed a non-chromatin-reader function for YEATS2 in inflammatory signaling in PDAC.\",\n      \"evidence\": \"Co-immunoprecipitation, NF-κB luciferase reporter, YEATS2 depletion in PDAC cells\",\n      \"pmids\": [\"34686948\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The mechanism by which YEATS2 stabilizes TAK1 (e.g., blocking ubiquitination) was not defined\",\n        \"Whether the TAK1 interaction is independent of ATAC complex membership was unclear\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Ectopic YEATS2 rescue of TAK1 and phospho-IKKα/β levels after cinobufacini treatment confirmed that YEATS2 acts upstream of the TAK1–NF-κB axis, solidifying pathway placement.\",\n      \"evidence\": \"Ectopic YEATS2 rescue, western blot for phospho-IKKα/β and IκBα, xenograft model\",\n      \"pmids\": [\"36610152\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether YEATS2 directly prevents TAK1 degradation or acts through an intermediary was not resolved\",\n        \"In vivo confirmation limited to xenograft with pharmacological perturbation\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Neuronal knockdown of Drosophila YEATS2 reduced tyrosine hydroxylase expression and dopamine biosynthesis, with L-DOPA rescue of seizure phenotypes, extending YEATS2's epigenetic role to dopaminergic neuron gene regulation.\",\n      \"evidence\": \"Pan-neuronal RNAi in Drosophila, TH mRNA/protein quantification, behavioral assays, L-DOPA pharmacological rescue\",\n      \"pmids\": [\"38128822\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether the dopaminergic gene regulation is direct (YEATS2 binding at TH promoter) was not shown by ChIP\",\n        \"Relevance to mammalian dopaminergic neurons was not tested\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"YEATS2 depletion in HCC triggered DNA damage, activated p53/p21-dependent senescence via a c-Myc/miR-93-5p axis, and enhanced NK cell infiltration, revealing that YEATS2 suppresses senescence and modulates tumor immune surveillance.\",\n      \"evidence\": \"YEATS2 knockdown, γ-H2A.X staining, transcriptomic analysis, xenograft with NK cell quantification\",\n      \"pmids\": [\"38619971\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether DNA damage results from loss of specific YEATS2-dependent DNA repair genes (e.g., RAD50) was not dissected\",\n        \"The mechanism linking YEATS2 loss to enhanced NK cell infiltration was not defined\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstration that YEATS2 reads H3K27cr at the ETS1 promoter downstream of GCN5-deposited crotonylation established YEATS2 as a dual acylation reader (acetylation and crotonylation), broadening the range of histone marks it interprets.\",\n      \"evidence\": \"ChIP for GCN5, H3K27cr, and YEATS2 at ETS1 promoter; LINC00887 overexpression/knockdown; in vivo colorectal cancer metastasis model\",\n      \"pmids\": [\"39349460\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Structural basis for YEATS domain recognition of crotonyl versus acetyl lysine on H3K27 was not resolved\",\n        \"Genome-wide overlap of YEATS2-bound crotonylated versus acetylated sites was not profiled\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identification of O-GlcNAcylation at Thr604 as a modification that strengthens YEATS2–ATAC complex assembly on chromatin provided the first metabolic regulatory input controlling YEATS2 chromatin reader function.\",\n      \"evidence\": \"ETD mass spectrometry for O-GlcNAc site mapping, T604A mutagenesis, Co-IP, ChIP, lung cancer xenograft\",\n      \"pmids\": [\"40541806\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether O-GlcNAcylation affects YEATS domain histone-binding affinity or only complex stability was not distinguished\",\n        \"The phosphatase or signaling pathway opposing O-GlcNAcylation at Thr604 was not identified\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"TNF-α-induced tyrosine dephosphorylation of the YEATS domain enhances MYC enhancer RNA binding, augmenting ATAC complex association at the MYC locus, revealing a signal-responsive eRNA–YEATS2 regulatory circuit.\",\n      \"evidence\": \"RNA-protein interaction assay, ChIP, TNF-α signaling perturbation in pancreatic cancer cells\",\n      \"pmids\": [\"40216980\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The specific tyrosine residue(s) dephosphorylated and the responsible phosphatase were not fully defined\",\n        \"Whether eRNA binding is a general mechanism at other YEATS2-bound enhancers was not tested\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"YEATS2 reads H3K27ac at the IL6ST promoter and recruits TAF15 and KAT5 to amplify local acetylation and activate NF-κB in esophageal cancer, expanding the acetyltransferase cofactor repertoire beyond GCN5 to include KAT5.\",\n      \"evidence\": \"Co-IP-based mass spectrometry, ChIP, YEATS2 overexpression/knockdown with NF-κB readout in ESCC\",\n      \"pmids\": [\"40040791\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether YEATS2–KAT5 interaction occurs within or outside the ATAC complex was not resolved\",\n        \"The role of TAF15 in this complex was not mechanistically dissected\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"YEATS2 recruits crotonyltransferase p300 to maintain H3K27cr at the SPARC promoter in head and neck cancer, demonstrating that YEATS2 can serve as a platform for both HAT (GCN5, KAT5) and non-ATAC acyltransferase (p300) recruitment.\",\n      \"evidence\": \"ChIP, Co-IP, YEATS2 knockdown/overexpression, global histone crotonylation analysis in HNSCC\",\n      \"pmids\": [\"40810390\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether YEATS2 directly binds p300 or requires a bridging factor was not determined\",\n        \"The distinction between YEATS2 reading pre-existing H3K27cr versus recruiting p300 to deposit new marks was not cleanly separated\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"YEATS2 increases chromatin accessibility at the RAD50 promoter and recruits NR2C2 to drive DNA repair gene expression and anoikis resistance in metastatic prostate cancer, linking the reader function to DNA damage repair and metastatic fitness.\",\n      \"evidence\": \"ATAC-seq, ChIP for H3K27ac, Co-IP for YEATS2–NR2C2, in vivo metastasis model\",\n      \"pmids\": [\"41708952\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether YEATS2 directly opens chromatin or indirectly does so through recruited remodelers was not distinguished\",\n        \"Generality to other DNA repair loci beyond RAD50 was not tested\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Reciprocal Co-IP and molecular dynamics confirmed direct YEATS2–TAK1 interaction and showed YEATS2 enhances TAK1 kinase activation driving sorafenib resistance in HCC, extending the TAK1 axis from PDAC to HCC and drug resistance contexts.\",\n      \"evidence\": \"Reciprocal Co-IP, molecular dynamics simulation, pharmacological TAK1 inhibition, YEATS2 silencing in HCC\",\n      \"pmids\": [\"41962409\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The binding interface between YEATS2 and TAK1 lacks crystallographic validation\",\n        \"Whether YEATS2–TAK1 interaction is constitutive or signal-regulated was not addressed\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: (1) the structural basis for YEATS domain selectivity among different acylation marks; (2) whether YEATS2 reader and TAK1-stabilizing functions are mechanistically coupled or independent; (3) relevance of YEATS2 dopaminergic regulation to mammalian neurodegeneration.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No crystal structure of full-length YEATS2 or YEATS domain bound to crotonylated peptide is available\",\n        \"Separation-of-function mutants distinguishing chromatin reader from TAK1-binding roles have not been generated\",\n        \"Mammalian neuronal studies of YEATS2 function are absent\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [0, 4, 6, 7, 8, 12]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 7, 9, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0, 4, 6, 8]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 4, 7, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 4, 6, 12]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 7, 9, 13]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2, 7, 10]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 3, 9, 11]}\n    ],\n    \"complexes\": [\n      \"ATAC complex\"\n    ],\n    \"partners\": [\n      \"GCN5\",\n      \"TAK1\",\n      \"ZZZ3\",\n      \"KAT5\",\n      \"NR2C2\",\n      \"TAF15\",\n      \"PCAF\",\n      \"EP300\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}