YEATS2

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).

1. 2017 High

   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

   PMID:29057918

   Open questions at the time

   • Does not define the full set of ATAC target genes across tissues
   • Structural basis of acetyllysine recognition not resolved here
2. 2020 Medium

   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

   PMID:32749678

   Open questions at the time

   • Whether HIF1α regulation is direct in other cancer types untested at the time
   • Does not connect hypoxic induction to a specific chromatin readout
3. 2021 Medium

   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

   PMID:34686948

   Open questions at the time

   • Mechanism by which YEATS2 stabilizes TAK1 protein not defined
   • Single lab
4. 2022 Medium

   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

   PMID:36610152

   Open questions at the time

   • Drug specificity for YEATS2 not established
   • Does not separate scaffolding from reader functions in NF-κB regulation
5. 2023 Medium

   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

   PMID:38128822

   Open questions at the time

   • Whether TH regulation is direct via histone acylation reading not shown
   • Mammalian neuronal relevance untested
6. 2024 Medium

   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

   PMID:38619971

   Open questions at the time

   • Direct chromatin targets driving the DNA damage phenotype not mapped
   • Single lab
7. 2024 Medium

   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

   PMID:39349460

   Open questions at the time

   • YEATS domain selectivity for crotonyl- vs acetyl-lysine not biochemically dissected here
   • Single locus focus
8. 2025 High

   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

   PMID:40541806

   Open questions at the time

   • Stimuli that regulate OGT-dependent modification of YEATS2 not defined
   • Single lab
9. 2025 Medium

   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

   PMID:40040791 PMID:40810390

   Open questions at the time

   • Determinants of locus-specific co-activator recruitment unknown
   • Single lab per locus
10. 2025 Medium

    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

    PMID:40216980

    Open questions at the time

    • Kinase/phosphatase controlling the YEATS domain tyrosine not identified
    • Generality of eRNA-directed targeting beyond MYC untested
11. 2026 Medium

    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

    PMID:41962409

    Open questions at the time

    • Structural model is computational and not experimentally validated
    • Binding interface residues unverified
12. 2026 Medium

    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

    PMID:41708952

    Open questions at the time

    • Whether NR2C2 recruitment is direct or ATAC-dependent not fully separated
    • Single lab
13. 2026 Medium

    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

    PMID:41776086

    Open questions at the time

    • Mechanism converting matrix stiffness to HIF-1α activation not detailed
    • Single lab
14. 2026 Medium

    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

    PMID:42109848

    Open questions at the time

    • Whether YEATS2 directly controls SOCE/GPCR genes via histone acylation reading not shown
    • Mammalian conservation untested

• 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.
• 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