YEATS2

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).

1. 2017 High

   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

   PMID:29057918

   Open questions at the time

   • 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
2. 2020 Medium

   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

   PMID:32749678

   Open questions at the time

   • 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
3. 2021 Medium

   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

   PMID:34686948

   Open questions at the time

   • 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
4. 2022 Medium

   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

   PMID:36610152

   Open questions at the time

   • Whether YEATS2 directly prevents TAK1 degradation or acts through an intermediary was not resolved
   • In vivo confirmation limited to xenograft with pharmacological perturbation
5. 2023 Medium

   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

   PMID:38128822

   Open questions at the time

   • 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
6. 2024 Medium

   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

   PMID:38619971

   Open questions at the time

   • 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
7. 2024 Medium

   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

   PMID:39349460

   Open questions at the time

   • 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
8. 2025 High

   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

   PMID:40541806

   Open questions at the time

   • 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
9. 2025 Medium

   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

   PMID:40216980

   Open questions at the time

   • 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
10. 2025 Medium

    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

    PMID:40040791

    Open questions at the time

    • 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
11. 2025 Medium

    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

    PMID:40810390

    Open questions at the time

    • 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
12. 2026 Medium

    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

    PMID:41708952

    Open questions at the time

    • 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
13. 2026 Medium

    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

    PMID:41962409

    Open questions at the time

    • The binding interface between YEATS2 and TAK1 lacks crystallographic validation
    • Whether YEATS2–TAK1 interaction is constitutive or signal-regulated was not addressed

• 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.
• 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