{"gene":"YEATS2","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2017,"finding":"YEATS2 binds acetylated histone H3 (specifically 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, Co-IP, YEATS domain interaction disruption, knockdown with transcriptional readout","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ChIP-seq co-localization, domain-disruption mutagenesis, and KD phenotype in multiple orthogonal assays; independently corroborated by subsequent studies","pmids":["29057918"],"is_preprint":false},{"year":2021,"finding":"YEATS2 directly interacts with TAK1 and NF-κB, maintaining TAK1 activation and NF-κB transcriptional activity in pancreatic ductal adenocarcinoma cells; YEATS2 depletion reduces TAK1 abundance and NF-κB activity, while ectopic YEATS2 re-elevates TAK1 protein levels.","method":"Co-IP, luciferase reporter assay, western blotting, ectopic overexpression rescue","journal":"Cell Biology and Toxicology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct interaction shown by Co-IP, functional rescue by ectopic expression, replicated in a follow-up study (PMID:36610152); single lab","pmids":["34686948"],"is_preprint":false},{"year":2022,"finding":"Cinobufacini decreases YEATS2 protein abundance in PDAC cells, which lowers TAK1 levels and suppresses phosphorylation of IKKα/β, IκBα, and p65; ectopic YEATS2 expression rescues TAK1 levels and NF-κB signaling after cinobufacini treatment, confirming the YEATS2/TAK1/NF-κB axis.","method":"Western blotting, luciferase reporter, ectopic overexpression rescue, in vivo xenograft","journal":"Phytomedicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — mechanistic rescue experiment confirms YEATS2-TAK1 axis; replicates findings from PMID:34686948 in a different context","pmids":["36610152"],"is_preprint":false},{"year":2020,"finding":"HIF1α transcriptionally activates YEATS2 by binding to the hypoxia response element (HRE) in the YEATS2 promoter; ectopic YEATS2 overexpression rescues the inhibitory effect of HIF1α knockdown on pancreatic cancer cell proliferation and migration under hypoxia, placing YEATS2 downstream of HIF1α.","method":"ChIP, qRT-PCR, ectopic overexpression rescue, in vivo xenograft","journal":"Journal of Cellular Physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms HIF1α binding to YEATS2 HRE, genetic epistasis via rescue experiment; single lab","pmids":["32749678"],"is_preprint":false},{"year":2025,"finding":"YEATS2 is O-GlcNAcylated at Thr604 by OGT; this modification promotes YEATS2 chromatin association and stabilizes interactions between YEATS2 and other ATAC complex components (ZZZ3, GCN5, PCAF) on chromatin; a T604A mutant attenuates ATAC-dependent H3K9ac and represses ribosomal gene expression.","method":"Electron transfer dissociation mass spectrometry, Co-IP, ChIP, site-directed mutagenesis (T604A), xenograft","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — PTM site mapped by ETD-MS, active-site mutagenesis (T604A) with functional readouts (ChIP for H3K9ac, gene expression), Co-IP for complex stabilization; single lab but multiple orthogonal methods","pmids":["40541806"],"is_preprint":false},{"year":2025,"finding":"In ESCC, YEATS2 recruits TAF15 and KAT5 to the IL6ST promoter to enhance H3K27ac enrichment, thereby activating IL6ST expression and NF-κB signaling; YEATS2 and H3K27ac are co-enriched at the IL6ST promoter.","method":"Co-IP-based mass spectrometry, ChIP, knockdown/overexpression with proliferation/migration assays","journal":"Frontiers in Cell and Developmental Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP-MS identifies binding partners TAF15 and KAT5, ChIP confirms co-enrichment at IL6ST promoter; single lab","pmids":["40040791"],"is_preprint":false},{"year":2025,"finding":"YEATS2 maintains high promoter H3K27cr levels at the EMT gene SPARC by assisting recruitment of the crotonyltransferase p300; YEATS2 abrogation leads to global decrease in H3K27cr mark, reduced SPARC expression, and impaired EMT in head and neck cancer cells. This crotonylation maintenance also depends on GCDH-derived crotonyl-CoA.","method":"ChIP, knockdown with global H3K27cr measurement, co-IP, functional EMT assays","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrates YEATS2-dependent p300 recruitment and H3K27cr enrichment; multiple orthogonal methods (ChIP, KD, global mark measurement); single lab","pmids":["40810390"],"is_preprint":false},{"year":2025,"finding":"A MYC enhancer RNA (eRNA) physically interacts with YEATS2; TNF-α-induced tyrosine dephosphorylation of the YEATS domain increases MYC eRNA binding to YEATS2, augmenting ATAC complex association at the MYC promoter/enhancer and increasing MYC transcription in pancreatic cancer cells.","method":"RNA-protein interaction assay, ChIP, phosphorylation assay, knockdown/overexpression","journal":"EMBO Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA-protein interaction demonstrated, post-translational modification (dephosphorylation) linked to binding affinity, ChIP confirms ATAC complex recruitment; single lab","pmids":["40216980"],"is_preprint":false},{"year":2024,"finding":"LINC00887 indirectly increases GCN5 expression via SIRT3, leading to elevated global H3K27cr and enrichment of GCN5, H3K27cr, and YEATS2 at the ETS1 promoter; YEATS2 functions as a reader of H3K27cr at this locus to activate ETS1 transcription and promote CRC metastasis.","method":"ChIP, Co-IP, knockdown/overexpression, in vivo metastasis model","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms YEATS2 enrichment at H3K27cr-marked ETS1 promoter; pathway placement via genetic perturbation; single lab","pmids":["39349460"],"is_preprint":false},{"year":2024,"finding":"Knockdown of YEATS2 in hepatocellular carcinoma cells induces DNA damage (elevated γ-H2A.X), activates the p53/p21Cip1 senescence pathway, and increases p21Cip1 expression via c-Myc/miR-93-5p, leading to cellular senescence and reduced tumor growth in vivo.","method":"Transcriptomic analysis, western blotting, knockdown, in vivo xenograft","journal":"Cell Cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with defined molecular mechanism (dual-pathway senescence), in vivo confirmation; single lab","pmids":["38619971"],"is_preprint":false},{"year":2023,"finding":"Knockdown of Drosophila YEATS2 (dYEATS2) in neurons reduces tyrosine hydroxylase (TH) gene expression and dopamine biosynthesis, causing seizure-like behaviour, locomotor deficits, and abnormal social behaviour; these phenotypes are rescued by L-DOPA administration, placing dYEATS2 upstream of TH/dopamine in a neuronal context.","method":"Pan-neuronal RNAi knockdown in Drosophila, behavioral assays, qRT-PCR, L-DOPA pharmacological rescue","journal":"Progress in Neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KD with defined transcriptional target (TH) and pharmacological rescue; model organism study; single lab","pmids":["38128822"],"is_preprint":false},{"year":2026,"finding":"YEATS2 loss in Drosophila neurons causes elevated intracellular calcium (calcium overload) via upregulation of GPCR signaling components and dysregulated store-operated calcium entry (SOCE) through the Orai channel; genetic and pharmacological inhibition of Orai-mediated SOCE or ryanodine receptors rescues seizure-like activity and preserves dopaminergic neuron integrity.","method":"Transcriptomics, calcium imaging, genetic epistasis (Orai inhibition), pharmacological rescue, behavioral assays in Drosophila","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptomics identifies pathway, calcium imaging confirms overload, genetic/pharmacological epistasis places SOCE/Orai downstream; single lab, model organism","pmids":["42109848"],"is_preprint":false},{"year":2026,"finding":"YEATS2 physically interacts with TAK1 in HCC cells (confirmed by reciprocal Co-IP and structural/MD modeling), enhances TAK1 activation and downstream stress-response signaling; pharmacological or genetic inhibition of TAK1 abrogates YEATS2-mediated adaptive sorafenib resistance driven by TGF-β1.","method":"Reciprocal Co-IP, structural modeling + molecular dynamics simulation, TAK1 inhibition epistasis, drug sensitivity assay","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP demonstrates physical interaction, genetic epistasis via TAK1 KD; structural modeling is computational; single lab","pmids":["41962409"],"is_preprint":false},{"year":2026,"finding":"YEATS2 recognizes H3K27ac at the RAD50 promoter, recruits the transcription factor NR2C2, increases chromatin accessibility at that locus, and upregulates RAD50 expression to promote DNA damage repair, anoikis resistance, and prostate cancer metastasis.","method":"ATAC-seq (chromatin accessibility), ChIP, Co-IP, knockdown/overexpression, in vivo metastasis model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and ATAC-seq confirm YEATS2 occupancy and chromatin opening at RAD50 promoter, Co-IP for NR2C2 interaction, in vivo confirmation; single lab","pmids":["41708952"],"is_preprint":false},{"year":2026,"finding":"YEATS2 interacts with KAT2A (GCN5) via Co-IP, leading to increased H3K9ac and H3K14ac at the TGFBR2 promoter; elevated matrix stiffness induces YEATS2 expression through HIF-1α binding to the YEATS2 promoter, activating TGFBR2-TAZ-AKT signaling and aerobic glycolysis in HCC.","method":"Co-IP, ChIP, RNA-seq, mass spectrometry, in vitro/in vivo functional assays","journal":"Cell Death and Differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifies KAT2A as binding partner, ChIP confirms histone acetylation at TGFBR2 promoter, upstream HIF-1α ChIP; multiple orthogonal methods; single lab","pmids":["41776086"],"is_preprint":false}],"current_model":"YEATS2 is a histone acylation reader (H3K27ac, H3K27cr) whose YEATS domain recruits and stabilizes the ATAC histone acetyltransferase complex on gene promoters to drive transcription of oncogenic programs; O-GlcNAcylation at Thr604 by OGT further stabilizes the ATAC complex on chromatin, YEATS2 also functions as a scaffold that directly binds and activates TAK1 to sustain NF-κB signaling, recruits co-activators (KAT5/TAF15, p300, KAT2A) to specific promoters to deposit activating acetylation/crotonylation marks, and in neurons regulates dopaminergic integrity through epigenetic control of calcium homeostasis."},"narrative":{"mechanistic_narrative":"YEATS2 is a chromatin-associated reader of histone acylation marks that couples recognition of acetylated and crotonylated histone H3 to recruitment of histone-modifying complexes, driving activating transcriptional programs that are frequently co-opted in cancer [PMID:29057918, PMID:40810390]. Through its YEATS domain it binds H3K27ac and stabilizes the ATAC histone acetyltransferase complex at promoters of actively transcribed genes, where loss of YEATS2 or disruption of the YEATS domain–acetyllysine interaction reduces ATAC-dependent H3K9ac and silences essential gene expression [PMID:29057918]. Beyond reading acetylation, YEATS2 recognizes H3K27cr and assists recruitment of acyltransferases such as p300 and GCN5/KAT2A to maintain crotonylation and acetylation at specific target loci including SPARC, ETS1, RAD50, and TGFBR2, where it also engages transcription factors such as NR2C2 to open chromatin and activate gene expression [PMID:40810390, PMID:39349460, PMID:41708952, PMID:41776086]. Its chromatin engagement is tuned by post-translational modification: OGT-mediated O-GlcNAcylation at Thr604 promotes YEATS2 chromatin association and stabilizes its interactions with other ATAC subunits (ZZZ3, GCN5, PCAF), while TNF-α-induced tyrosine dephosphorylation of the YEATS domain enhances binding of a MYC enhancer RNA to augment ATAC recruitment at the MYC locus [PMID:40541806, PMID:40216980]. Independently of its histone-reader role, YEATS2 acts as a scaffold that directly binds TAK1 to sustain TAK1 activation and downstream NF-κB signaling [PMID:34686948, PMID:41962409]. Its expression is driven by HIF1α under hypoxia and by matrix stiffness, integrating microenvironmental cues into transcriptional output [PMID:32749678, PMID:41776086]. In Drosophila neurons, YEATS2 maintains dopaminergic integrity by supporting tyrosine hydroxylase expression and restraining store-operated calcium entry [PMID:38128822, PMID:42109848].","teleology":[{"year":2017,"claim":"Established YEATS2 as a functional histone acylation reader: the question was whether its YEATS domain decodes a specific mark and to what transcriptional end.","evidence":"ChIP-seq, reciprocal Co-IP, YEATS domain interaction disruption, and knockdown with transcriptional readout in NSCLC cells","pmids":["29057918"],"confidence":"High","gaps":["Does not define the full set of ATAC target genes across tissues","Structural basis of acetyllysine recognition not resolved here"]},{"year":2020,"claim":"Placed YEATS2 downstream of hypoxia signaling, addressing how its expression is controlled in the tumor microenvironment.","evidence":"ChIP for HIF1α binding to the YEATS2 HRE plus ectopic overexpression rescue and xenograft in pancreatic cancer","pmids":["32749678"],"confidence":"Medium","gaps":["Whether HIF1α regulation is direct in other cancer types untested at the time","Does not connect hypoxic induction to a specific chromatin readout"]},{"year":2021,"claim":"Revealed a histone-reading-independent scaffolding role by showing YEATS2 directly binds and stabilizes TAK1 to maintain NF-κB activity.","evidence":"Co-IP, luciferase reporter, western blotting, and ectopic overexpression rescue in PDAC cells","pmids":["34686948"],"confidence":"Medium","gaps":["Mechanism by which YEATS2 stabilizes TAK1 protein not defined","Single lab"]},{"year":2022,"claim":"Confirmed the YEATS2/TAK1/NF-κB axis as a druggable dependency by showing pharmacological depletion of YEATS2 collapses the pathway and is reversed by re-expression.","evidence":"Western blotting, luciferase reporter, ectopic overexpression rescue, and xenograft following cinobufacini treatment","pmids":["36610152"],"confidence":"Medium","gaps":["Drug specificity for YEATS2 not established","Does not separate scaffolding from reader functions in NF-κB regulation"]},{"year":2023,"claim":"Extended YEATS2 function to neurons, asking whether its transcriptional role affects an in vivo physiological program beyond cancer.","evidence":"Pan-neuronal RNAi in Drosophila with behavioral assays, qRT-PCR for TH, and L-DOPA pharmacological rescue","pmids":["38128822"],"confidence":"Medium","gaps":["Whether TH regulation is direct via histone acylation reading not shown","Mammalian neuronal relevance untested"]},{"year":2024,"claim":"Linked YEATS2 loss to genome stability and senescence, clarifying a tumor-suppressive consequence of its depletion.","evidence":"Transcriptomics, western blotting (γ-H2A.X, p53/p21), knockdown, and xenograft in HCC","pmids":["38619971"],"confidence":"Medium","gaps":["Direct chromatin targets driving the DNA damage phenotype not mapped","Single lab"]},{"year":2024,"claim":"Demonstrated YEATS2 reads crotonylation (H3K27cr) at a defined promoter, broadening its mark repertoire beyond acetylation.","evidence":"ChIP, Co-IP, knockdown/overexpression and in vivo metastasis model placing YEATS2 downstream of a LINC00887/SIRT3/GCN5 axis at the ETS1 locus","pmids":["39349460"],"confidence":"Medium","gaps":["YEATS domain selectivity for crotonyl- vs acetyl-lysine not biochemically dissected here","Single locus focus"]},{"year":2025,"claim":"Defined O-GlcNAcylation at Thr604 as a regulatory switch controlling YEATS2 chromatin association and ATAC complex integrity.","evidence":"ETD mass spectrometry mapping the site, Co-IP for complex stabilization, ChIP for H3K9ac, and T604A mutagenesis with xenograft","pmids":["40541806"],"confidence":"High","gaps":["Stimuli that regulate OGT-dependent modification of YEATS2 not defined","Single lab"]},{"year":2025,"claim":"Showed YEATS2 recruits specific co-activators (TAF15/KAT5, p300) to deposit activating acylation at named target promoters, defining how it directs the mark to genes.","evidence":"Co-IP-MS, ChIP, and functional assays at IL6ST (ESCC) and SPARC (head and neck cancer), with crotonyl-CoA supply linked to GCDH","pmids":["40040791","40810390"],"confidence":"Medium","gaps":["Determinants of locus-specific co-activator recruitment unknown","Single lab per locus"]},{"year":2025,"claim":"Connected a post-translational signal to RNA-guided targeting, showing TNF-α-induced YEATS-domain dephosphorylation enhances MYC eRNA binding and ATAC recruitment at MYC.","evidence":"RNA-protein interaction assay, phosphorylation assay, ChIP, and knockdown/overexpression in pancreatic cancer","pmids":["40216980"],"confidence":"Medium","gaps":["Kinase/phosphatase controlling the YEATS domain tyrosine not identified","Generality of eRNA-directed targeting beyond MYC untested"]},{"year":2026,"claim":"Reinforced the YEATS2–TAK1 scaffold in a new context (sorafenib resistance) and added structural support for direct binding.","evidence":"Reciprocal Co-IP, structural modeling/MD simulation, TAK1 inhibition epistasis, and drug-sensitivity assays in HCC","pmids":["41962409"],"confidence":"Medium","gaps":["Structural model is computational and not experimentally validated","Binding interface residues unverified"]},{"year":2026,"claim":"Identified transcription-factor partnering (NR2C2) and chromatin opening as the mechanism by which YEATS2 activates DNA-repair gene RAD50 to drive metastasis.","evidence":"ATAC-seq, ChIP, Co-IP, knockdown/overexpression, and in vivo metastasis model in prostate cancer","pmids":["41708952"],"confidence":"Medium","gaps":["Whether NR2C2 recruitment is direct or ATAC-dependent not fully separated","Single lab"]},{"year":2026,"claim":"Linked mechanotransduction to YEATS2-driven metabolic reprogramming via KAT2A-dependent acetylation of the TGFBR2 promoter.","evidence":"Co-IP for KAT2A, ChIP at TGFBR2, RNA-seq, mass spectrometry, and in vitro/in vivo assays with HIF-1α as upstream inducer under matrix stiffness in HCC","pmids":["41776086"],"confidence":"Medium","gaps":["Mechanism converting matrix stiffness to HIF-1α activation not detailed","Single lab"]},{"year":2026,"claim":"Defined a downstream calcium-homeostasis effector mechanism for YEATS2 in neurons, explaining the dopaminergic phenotype.","evidence":"Transcriptomics, calcium imaging, Orai/SOCE and ryanodine-receptor genetic and pharmacological epistasis, and behavioral rescue in Drosophila","pmids":["42109848"],"confidence":"Medium","gaps":["Whether YEATS2 directly controls SOCE/GPCR genes via histone acylation reading not shown","Mammalian conservation untested"]},{"year":null,"claim":"It remains unresolved how YEATS2 selects between acetyl- versus crotonyl-lysine marks and distinct co-activators at individual promoters, and how its histone-reader and TAK1-scaffold activities are integrated within a single cell.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of YEATS domain mark selectivity validated","Reader vs scaffold functions never tested side-by-side in one system","No high-resolution structure of the YEATS2-ATAC assembly"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[0,6,8,13]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,5,13,14]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,5,12,13]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[7]}],"localization":[{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[0,4,13]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,4]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,5,13,14]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,4,6,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2,12]}],"complexes":["ATAC complex"],"partners":["TAK1","OGT","ZZZ3","GCN5","PCAF","KAT5","TAF15","NR2C2"],"other_free_text":[]}},"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":122,"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":90,"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":21,"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":18,"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":"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":"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":"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":6,"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":"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":5,"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":5,"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":4,"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":3,"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":"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":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":"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":"42109848","id":"PMC_42109848","title":"Dopaminergic neurons are vulnerable to dysregulation of YEATS2-dependent calcium homeostasis.","date":"2026","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/42109848","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13075,"output_tokens":3874,"usd":0.048668,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11678,"output_tokens":4458,"usd":0.08492,"stage2_stop_reason":"end_turn"},"total_usd":0.133588,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2017,\n      \"finding\": \"YEATS2 binds acetylated histone H3 (specifically 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, Co-IP, YEATS domain interaction disruption, knockdown with transcriptional readout\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ChIP-seq co-localization, domain-disruption mutagenesis, and KD phenotype in multiple orthogonal assays; independently corroborated by subsequent studies\",\n      \"pmids\": [\"29057918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YEATS2 directly interacts with TAK1 and NF-κB, maintaining TAK1 activation and NF-κB transcriptional activity in pancreatic ductal adenocarcinoma cells; YEATS2 depletion reduces TAK1 abundance and NF-κB activity, while ectopic YEATS2 re-elevates TAK1 protein levels.\",\n      \"method\": \"Co-IP, luciferase reporter assay, western blotting, ectopic overexpression rescue\",\n      \"journal\": \"Cell Biology and Toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct interaction shown by Co-IP, functional rescue by ectopic expression, replicated in a follow-up study (PMID:36610152); single lab\",\n      \"pmids\": [\"34686948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cinobufacini decreases YEATS2 protein abundance in PDAC cells, which lowers TAK1 levels and suppresses phosphorylation of IKKα/β, IκBα, and p65; ectopic YEATS2 expression rescues TAK1 levels and NF-κB signaling after cinobufacini treatment, confirming the YEATS2/TAK1/NF-κB axis.\",\n      \"method\": \"Western blotting, luciferase reporter, ectopic overexpression rescue, in vivo xenograft\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — mechanistic rescue experiment confirms YEATS2-TAK1 axis; replicates findings from PMID:34686948 in a different context\",\n      \"pmids\": [\"36610152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HIF1α transcriptionally activates YEATS2 by binding to the hypoxia response element (HRE) in the YEATS2 promoter; ectopic YEATS2 overexpression rescues the inhibitory effect of HIF1α knockdown on pancreatic cancer cell proliferation and migration under hypoxia, placing YEATS2 downstream of HIF1α.\",\n      \"method\": \"ChIP, qRT-PCR, ectopic overexpression rescue, in vivo xenograft\",\n      \"journal\": \"Journal of Cellular Physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms HIF1α binding to YEATS2 HRE, genetic epistasis via rescue experiment; single lab\",\n      \"pmids\": [\"32749678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YEATS2 is O-GlcNAcylated at Thr604 by OGT; this modification promotes YEATS2 chromatin association and stabilizes interactions between YEATS2 and other ATAC complex components (ZZZ3, GCN5, PCAF) on chromatin; a T604A mutant attenuates ATAC-dependent H3K9ac and represses ribosomal gene expression.\",\n      \"method\": \"Electron transfer dissociation mass spectrometry, Co-IP, ChIP, site-directed mutagenesis (T604A), xenograft\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — PTM site mapped by ETD-MS, active-site mutagenesis (T604A) with functional readouts (ChIP for H3K9ac, gene expression), Co-IP for complex stabilization; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"40541806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In ESCC, YEATS2 recruits TAF15 and KAT5 to the IL6ST promoter to enhance H3K27ac enrichment, thereby activating IL6ST expression and NF-κB signaling; YEATS2 and H3K27ac are co-enriched at the IL6ST promoter.\",\n      \"method\": \"Co-IP-based mass spectrometry, ChIP, knockdown/overexpression with proliferation/migration assays\",\n      \"journal\": \"Frontiers in Cell and Developmental Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP-MS identifies binding partners TAF15 and KAT5, ChIP confirms co-enrichment at IL6ST promoter; single lab\",\n      \"pmids\": [\"40040791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YEATS2 maintains high promoter H3K27cr levels at the EMT gene SPARC by assisting recruitment of the crotonyltransferase p300; YEATS2 abrogation leads to global decrease in H3K27cr mark, reduced SPARC expression, and impaired EMT in head and neck cancer cells. This crotonylation maintenance also depends on GCDH-derived crotonyl-CoA.\",\n      \"method\": \"ChIP, knockdown with global H3K27cr measurement, co-IP, functional EMT assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrates YEATS2-dependent p300 recruitment and H3K27cr enrichment; multiple orthogonal methods (ChIP, KD, global mark measurement); single lab\",\n      \"pmids\": [\"40810390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A MYC enhancer RNA (eRNA) physically interacts with YEATS2; TNF-α-induced tyrosine dephosphorylation of the YEATS domain increases MYC eRNA binding to YEATS2, augmenting ATAC complex association at the MYC promoter/enhancer and increasing MYC transcription in pancreatic cancer cells.\",\n      \"method\": \"RNA-protein interaction assay, ChIP, phosphorylation assay, knockdown/overexpression\",\n      \"journal\": \"EMBO Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA-protein interaction demonstrated, post-translational modification (dephosphorylation) linked to binding affinity, ChIP confirms ATAC complex recruitment; single lab\",\n      \"pmids\": [\"40216980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LINC00887 indirectly increases GCN5 expression via SIRT3, leading to elevated global H3K27cr and enrichment of GCN5, H3K27cr, and YEATS2 at the ETS1 promoter; YEATS2 functions as a reader of H3K27cr at this locus to activate ETS1 transcription and promote CRC metastasis.\",\n      \"method\": \"ChIP, Co-IP, knockdown/overexpression, in vivo metastasis model\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms YEATS2 enrichment at H3K27cr-marked ETS1 promoter; pathway placement via genetic perturbation; single lab\",\n      \"pmids\": [\"39349460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Knockdown of YEATS2 in hepatocellular carcinoma cells induces DNA damage (elevated γ-H2A.X), activates the p53/p21Cip1 senescence pathway, and increases p21Cip1 expression via c-Myc/miR-93-5p, leading to cellular senescence and reduced tumor growth in vivo.\",\n      \"method\": \"Transcriptomic analysis, western blotting, knockdown, in vivo xenograft\",\n      \"journal\": \"Cell Cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with defined molecular mechanism (dual-pathway senescence), in vivo confirmation; single lab\",\n      \"pmids\": [\"38619971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Knockdown of Drosophila YEATS2 (dYEATS2) in neurons reduces tyrosine hydroxylase (TH) gene expression and dopamine biosynthesis, causing seizure-like behaviour, locomotor deficits, and abnormal social behaviour; these phenotypes are rescued by L-DOPA administration, placing dYEATS2 upstream of TH/dopamine in a neuronal context.\",\n      \"method\": \"Pan-neuronal RNAi knockdown in Drosophila, behavioral assays, qRT-PCR, L-DOPA pharmacological rescue\",\n      \"journal\": \"Progress in Neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KD with defined transcriptional target (TH) and pharmacological rescue; model organism study; single lab\",\n      \"pmids\": [\"38128822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"YEATS2 loss in Drosophila neurons causes elevated intracellular calcium (calcium overload) via upregulation of GPCR signaling components and dysregulated store-operated calcium entry (SOCE) through the Orai channel; genetic and pharmacological inhibition of Orai-mediated SOCE or ryanodine receptors rescues seizure-like activity and preserves dopaminergic neuron integrity.\",\n      \"method\": \"Transcriptomics, calcium imaging, genetic epistasis (Orai inhibition), pharmacological rescue, behavioral assays in Drosophila\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptomics identifies pathway, calcium imaging confirms overload, genetic/pharmacological epistasis places SOCE/Orai downstream; single lab, model organism\",\n      \"pmids\": [\"42109848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"YEATS2 physically interacts with TAK1 in HCC cells (confirmed by reciprocal Co-IP and structural/MD modeling), enhances TAK1 activation and downstream stress-response signaling; pharmacological or genetic inhibition of TAK1 abrogates YEATS2-mediated adaptive sorafenib resistance driven by TGF-β1.\",\n      \"method\": \"Reciprocal Co-IP, structural modeling + molecular dynamics simulation, TAK1 inhibition epistasis, drug sensitivity assay\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP demonstrates physical interaction, genetic epistasis via TAK1 KD; structural modeling is computational; single lab\",\n      \"pmids\": [\"41962409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"YEATS2 recognizes H3K27ac at the RAD50 promoter, recruits the transcription factor NR2C2, increases chromatin accessibility at that locus, and upregulates RAD50 expression to promote DNA damage repair, anoikis resistance, and prostate cancer metastasis.\",\n      \"method\": \"ATAC-seq (chromatin accessibility), ChIP, Co-IP, knockdown/overexpression, in vivo metastasis model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and ATAC-seq confirm YEATS2 occupancy and chromatin opening at RAD50 promoter, Co-IP for NR2C2 interaction, in vivo confirmation; single lab\",\n      \"pmids\": [\"41708952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"YEATS2 interacts with KAT2A (GCN5) via Co-IP, leading to increased H3K9ac and H3K14ac at the TGFBR2 promoter; elevated matrix stiffness induces YEATS2 expression through HIF-1α binding to the YEATS2 promoter, activating TGFBR2-TAZ-AKT signaling and aerobic glycolysis in HCC.\",\n      \"method\": \"Co-IP, ChIP, RNA-seq, mass spectrometry, in vitro/in vivo functional assays\",\n      \"journal\": \"Cell Death and Differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifies KAT2A as binding partner, ChIP confirms histone acetylation at TGFBR2 promoter, upstream HIF-1α ChIP; multiple orthogonal methods; single lab\",\n      \"pmids\": [\"41776086\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"YEATS2 is a histone acylation reader (H3K27ac, H3K27cr) whose YEATS domain recruits and stabilizes the ATAC histone acetyltransferase complex on gene promoters to drive transcription of oncogenic programs; O-GlcNAcylation at Thr604 by OGT further stabilizes the ATAC complex on chromatin, YEATS2 also functions as a scaffold that directly binds and activates TAK1 to sustain NF-κB signaling, recruits co-activators (KAT5/TAF15, p300, KAT2A) to specific promoters to deposit activating acetylation/crotonylation marks, and in neurons regulates dopaminergic integrity through epigenetic control of calcium homeostasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"YEATS2 is a chromatin-associated reader of histone acylation marks that couples recognition of acetylated and crotonylated histone H3 to recruitment of histone-modifying complexes, driving activating transcriptional programs that are frequently co-opted in cancer [#0, #6]. Through its YEATS domain it binds H3K27ac and stabilizes the ATAC histone acetyltransferase complex at promoters of actively transcribed genes, where loss of YEATS2 or disruption of the YEATS domain–acetyllysine interaction reduces ATAC-dependent H3K9ac and silences essential gene expression [#0]. Beyond reading acetylation, YEATS2 recognizes H3K27cr and assists recruitment of acyltransferases such as p300 and GCN5/KAT2A to maintain crotonylation and acetylation at specific target loci including SPARC, ETS1, RAD50, and TGFBR2, where it also engages transcription factors such as NR2C2 to open chromatin and activate gene expression [#6, #8, #13, #14]. Its chromatin engagement is tuned by post-translational modification: OGT-mediated O-GlcNAcylation at Thr604 promotes YEATS2 chromatin association and stabilizes its interactions with other ATAC subunits (ZZZ3, GCN5, PCAF), while TNF-α-induced tyrosine dephosphorylation of the YEATS domain enhances binding of a MYC enhancer RNA to augment ATAC recruitment at the MYC locus [#4, #7]. Independently of its histone-reader role, YEATS2 acts as a scaffold that directly binds TAK1 to sustain TAK1 activation and downstream NF-κB signaling [#1, #12]. Its expression is driven by HIF1α under hypoxia and by matrix stiffness, integrating microenvironmental cues into transcriptional output [#3, #14]. In Drosophila neurons, YEATS2 maintains dopaminergic integrity by supporting tyrosine hydroxylase expression and restraining store-operated calcium entry [#10, #11].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"Established YEATS2 as a functional histone acylation reader: the question was whether its YEATS domain decodes a specific mark and to what transcriptional end.\",\n      \"evidence\": \"ChIP-seq, reciprocal Co-IP, YEATS domain interaction disruption, and knockdown with transcriptional readout in NSCLC cells\",\n      \"pmids\": [\"29057918\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define the full set of ATAC target genes across tissues\", \"Structural basis of acetyllysine recognition not resolved here\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed YEATS2 downstream of hypoxia signaling, addressing how its expression is controlled in the tumor microenvironment.\",\n      \"evidence\": \"ChIP for HIF1α binding to the YEATS2 HRE plus ectopic overexpression rescue and xenograft in pancreatic cancer\",\n      \"pmids\": [\"32749678\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether HIF1α regulation is direct in other cancer types untested at the time\", \"Does not connect hypoxic induction to a specific chromatin readout\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed a histone-reading-independent scaffolding role by showing YEATS2 directly binds and stabilizes TAK1 to maintain NF-κB activity.\",\n      \"evidence\": \"Co-IP, luciferase reporter, western blotting, and ectopic overexpression rescue in PDAC cells\",\n      \"pmids\": [\"34686948\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which YEATS2 stabilizes TAK1 protein not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Confirmed the YEATS2/TAK1/NF-κB axis as a druggable dependency by showing pharmacological depletion of YEATS2 collapses the pathway and is reversed by re-expression.\",\n      \"evidence\": \"Western blotting, luciferase reporter, ectopic overexpression rescue, and xenograft following cinobufacini treatment\",\n      \"pmids\": [\"36610152\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Drug specificity for YEATS2 not established\", \"Does not separate scaffolding from reader functions in NF-κB regulation\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended YEATS2 function to neurons, asking whether its transcriptional role affects an in vivo physiological program beyond cancer.\",\n      \"evidence\": \"Pan-neuronal RNAi in Drosophila with behavioral assays, qRT-PCR for TH, and L-DOPA pharmacological rescue\",\n      \"pmids\": [\"38128822\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TH regulation is direct via histone acylation reading not shown\", \"Mammalian neuronal relevance untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked YEATS2 loss to genome stability and senescence, clarifying a tumor-suppressive consequence of its depletion.\",\n      \"evidence\": \"Transcriptomics, western blotting (γ-H2A.X, p53/p21), knockdown, and xenograft in HCC\",\n      \"pmids\": [\"38619971\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct chromatin targets driving the DNA damage phenotype not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated YEATS2 reads crotonylation (H3K27cr) at a defined promoter, broadening its mark repertoire beyond acetylation.\",\n      \"evidence\": \"ChIP, Co-IP, knockdown/overexpression and in vivo metastasis model placing YEATS2 downstream of a LINC00887/SIRT3/GCN5 axis at the ETS1 locus\",\n      \"pmids\": [\"39349460\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"YEATS domain selectivity for crotonyl- vs acetyl-lysine not biochemically dissected here\", \"Single locus focus\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined O-GlcNAcylation at Thr604 as a regulatory switch controlling YEATS2 chromatin association and ATAC complex integrity.\",\n      \"evidence\": \"ETD mass spectrometry mapping the site, Co-IP for complex stabilization, ChIP for H3K9ac, and T604A mutagenesis with xenograft\",\n      \"pmids\": [\"40541806\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stimuli that regulate OGT-dependent modification of YEATS2 not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed YEATS2 recruits specific co-activators (TAF15/KAT5, p300) to deposit activating acylation at named target promoters, defining how it directs the mark to genes.\",\n      \"evidence\": \"Co-IP-MS, ChIP, and functional assays at IL6ST (ESCC) and SPARC (head and neck cancer), with crotonyl-CoA supply linked to GCDH\",\n      \"pmids\": [\"40040791\", \"40810390\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Determinants of locus-specific co-activator recruitment unknown\", \"Single lab per locus\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected a post-translational signal to RNA-guided targeting, showing TNF-α-induced YEATS-domain dephosphorylation enhances MYC eRNA binding and ATAC recruitment at MYC.\",\n      \"evidence\": \"RNA-protein interaction assay, phosphorylation assay, ChIP, and knockdown/overexpression in pancreatic cancer\",\n      \"pmids\": [\"40216980\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase/phosphatase controlling the YEATS domain tyrosine not identified\", \"Generality of eRNA-directed targeting beyond MYC untested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Reinforced the YEATS2–TAK1 scaffold in a new context (sorafenib resistance) and added structural support for direct binding.\",\n      \"evidence\": \"Reciprocal Co-IP, structural modeling/MD simulation, TAK1 inhibition epistasis, and drug-sensitivity assays in HCC\",\n      \"pmids\": [\"41962409\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural model is computational and not experimentally validated\", \"Binding interface residues unverified\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified transcription-factor partnering (NR2C2) and chromatin opening as the mechanism by which YEATS2 activates DNA-repair gene RAD50 to drive metastasis.\",\n      \"evidence\": \"ATAC-seq, ChIP, Co-IP, knockdown/overexpression, and in vivo metastasis model in prostate cancer\",\n      \"pmids\": [\"41708952\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether NR2C2 recruitment is direct or ATAC-dependent not fully separated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Linked mechanotransduction to YEATS2-driven metabolic reprogramming via KAT2A-dependent acetylation of the TGFBR2 promoter.\",\n      \"evidence\": \"Co-IP for KAT2A, ChIP at TGFBR2, RNA-seq, mass spectrometry, and in vitro/in vivo assays with HIF-1α as upstream inducer under matrix stiffness in HCC\",\n      \"pmids\": [\"41776086\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism converting matrix stiffness to HIF-1α activation not detailed\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined a downstream calcium-homeostasis effector mechanism for YEATS2 in neurons, explaining the dopaminergic phenotype.\",\n      \"evidence\": \"Transcriptomics, calcium imaging, Orai/SOCE and ryanodine-receptor genetic and pharmacological epistasis, and behavioral rescue in Drosophila\",\n      \"pmids\": [\"42109848\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether YEATS2 directly controls SOCE/GPCR genes via histone acylation reading not shown\", \"Mammalian conservation untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how YEATS2 selects between acetyl- versus crotonyl-lysine marks and distinct co-activators at individual promoters, and how its histone-reader and TAK1-scaffold activities are integrated within a single cell.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of YEATS domain mark selectivity validated\", \"Reader vs scaffold functions never tested side-by-side in one system\", \"No high-resolution structure of the YEATS2-ATAC assembly\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [0, 6, 8, 13]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 5, 13, 14]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 5, 12, 13]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [0, 4, 13]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 5, 13, 14]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 4, 6, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2, 12]}\n    ],\n    \"complexes\": [\"ATAC complex\"],\n    \"partners\": [\"TAK1\", \"OGT\", \"ZZZ3\", \"GCN5\", \"PCAF\", \"KAT5\", \"TAF15\", \"NR2C2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}