MEAF6

MEAF6 (EAF6) is a small, conserved, non-catalytic subunit shared across MYST-family histone acetyltransferase complexes, where it functions as a structural core component rather than an enzymatic one (PMID:18794358, PMID:18684714). In the MOZ/MORF and HBO1/KAT7 complexes it assembles with ING4/5 and a PHD-finger scaffold (BRPF or JADE) into a trimeric ING5–EAF6–BRPF1 core, with ING5 stabilizing the otherwise weak BRPF1–EAF6 association; this conserved core supports nucleosomal histone H4 acetylation (PMID:18794358, PMID:18684714, PMID:31535175). MEAF6 is an integral subunit of the functional BRPF1–MORF–ING5–MEAF6 complex that engages the nucleosome core particle through the BRPF1 PZP domain (PMID:31711755), and in the KAT6A complex with BRPF1 and ING4/5 it participates in acetylation directed toward H3K23, a specificity dictated by BRPF1 (PMID:39909374). Functionally, MEAF6 is required for cell proliferation—its loss arrests proliferation in mouse ES cells—and it modulates KAT7 complex assembly by tuning the enzyme's interaction with PHD-finger scaffolds rather than being strictly required for HAT catalysis (PMID:32918898). At target promoters MEAF6 directs histone H3 acetylation to regulate gene expression, exemplified by control of IL-6 transcription downstream of miR-197-3p (PMID:35074616). A recurrent t(1;6) translocation fuses the MEAF6 NuA4-domain region in-frame to PHF1 in endometrial stromal sarcoma (PMID:22761769).

1. 2008 High

   Established MEAF6/EAF6 as a conserved core subunit of MYST acetyltransferase complexes and defined how it is incorporated, answering how this small protein joins the MOZ/MORF and HBO1 machinery.

   Evidence Complex reconstitution, deletion mapping, co-IP and in vitro HAT assays for MOZ/MORF; co-purification and reconstituted nucleosomal HAT assays for HBO1

   PMID:18684714 PMID:18794358

   Open questions at the time

   • Did not define an independent catalytic or regulatory function for EAF6 itself
   • Role of EAF6 in substrate specificity not addressed
2. 2018 High

   Placed Eaf6 structurally within the NuA4/TIP60 piccolo sub-module, showing how it packs against the larger assembly via Tra1 and Eaf1.

   Evidence Cryo-EM structure of the yeast NuA4/TIP60 complex at 7.6 Å

   PMID:29559617

   Open questions at the time

   • Resolution limited; atomic detail of Eaf6 contacts not resolved
   • Human complex architecture inferred from yeast ortholog
3. 2019 High

   Confirmed MEAF6 as an integral, in vivo subunit of functional HBO1/MORF complexes and showed scaffold choice (JADE vs BRPF) governs H3 vs H4 substrate specificity.

   Evidence Complex purification and HAT assays (review consolidating data); crystal structure of BRPF1-PZP on H3 tail plus NCP-binding and HAT functional assays

   PMID:31535175 PMID:31711755

   Open questions at the time

   • MEAF6's specific contribution to substrate switching not isolated
   • How MEAF6 contacts the nucleosome directly remains undefined
4. 2020 High

   Demonstrated that MEAF6 is essential for proliferation and acts by modulating KAT7 complex assembly rather than being required for catalysis, distinguishing a regulatory role from an enzymatic one.

   Evidence Inducible Meaf6 knockout in mouse ES cells with proliferation assays, co-IP, and histone acetylation analysis

   PMID:32918898

   Open questions at the time

   • Molecular basis for altered KAT7-PHD interactions unresolved
   • Direct gene targets driving proliferation arrest not mapped
5. 2025 High

   Defined how MEAF6 within the KAT6A–BRPF1–ING4/5 complex contributes to H3K23-directed acetylation, with BRPF1 reprogramming KAT6A substrate preference ~1000-fold from H3K14.

   Evidence Reconstituted 4-protein complex acetyltransferase assays, steady-state kinetics, and crystal structure of the KAT6A MYST domain with bisubstrate inhibitor

   PMID:39909374

   Open questions at the time

   • MEAF6's individual energetic contribution to specificity not separated from BRPF1
   • No structure of the assembled 4-protein complex
6. 2012 Medium

   Linked MEAF6 to disease by identifying an in-frame MEAF6-PHF1 fusion in endometrial stromal sarcoma, implicating its chromatin-modifying domain in oncogenic chimeras.

   Evidence 5'-RACE, RT-PCR, Sanger sequencing, and karyotyping of tumor samples

   PMID:22761769

   Open questions at the time

   • Functional consequence of the fusion protein not tested
   • Whether the MEAF6 portion confers HAT recruitment to PHF1 targets unknown
7. 2017 Medium

   Identified a splice variant (MEAF6-1) regulated by SRRM4 as pro-tumorigenic, acting partly through ID1/ID3.

   Evidence Splice variant identification, overexpression/knockdown, xenograft model, and gene microarray

   PMID:28427194

   Open questions at the time

   • Mechanism by which the variant alters complex function unresolved
   • Direct vs indirect regulation of ID1/ID3 not established
8. 2022 Medium

   Connected MEAF6 to specific promoter regulation, showing miR-197-3p suppression of MEAF6 reduces H3 acetylation at the IL-6 promoter and IL-6 transcription.

   Evidence miRNA target validation, ChIP for histone acetylation at IL-6 promoter, Western blot, and an in vivo mouse model

   PMID:35074616

   Open questions at the time

   • Which acetyltransferase complex delivers MEAF6 to the IL-6 promoter unclear
   • Direct recruitment mechanism not defined
9. 2021 Low

   Reported MEAF6 as an interactor of cytoskeletal MACF1 and of repressors E2F6/TCF12, raising a possible cytoplasmic-nuclear shuttling role in osteoblast differentiation.

   Evidence Co-IP via MACF1 pulldown, knockdown, and subcellular localization studies

   PMID:33664480

   Open questions at the time

   • Single Co-IP centered on MACF1, not validated reciprocally for MEAF6
   • MEAF6-specific functional contribution not isolated
10. 2025 Low

    Indicated that a MEAF6 microexon contributes to normal neural function.

    Evidence CRISPR/Cas9 microexon deletion in zebrafish with larval brain activity assessment

    PMID:41252186

    Open questions at the time

    • Mild phenotype with no mechanistic pathway placement
    • Molecular role of the microexon in complex function unknown

• The distinct molecular contribution of MEAF6 itself—as opposed to its scaffold and ING partners—to substrate specificity and nucleosome engagement remains undefined.
• No isolated structure-function dissection of MEAF6's nucleosome contacts
• Genome-wide direct targets of MEAF6-containing complexes not mapped
• Mechanism by which MEAF6 modulates scaffold selection unresolved