{"gene":"MEAF6","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2008,"finding":"MEAF6 (EAF6) is a core subunit of the tetrameric MOZ/MORF histone acetyltransferase complexes. BRPF proteins bridge MOZ/MORF with ING5 and EAF6 via the EPc homology domain. The association of BRPF1 with EAF6 alone is weak, but ING5 increases the affinity, forming a trimeric ING5-EAF6-BRPF1 core conserved from Drosophila to humans.","method":"Complex reconstitution, deletion mapping, co-immunoprecipitation, in vitro acetyltransferase assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted complexes in vitro with deletion mapping and acetyltransferase activity assays; multiple orthogonal methods in a single rigorous study","pmids":["18794358"],"is_preprint":false},{"year":2008,"finding":"EAF6 co-purifies with the HBO1 HAT complex consisting of HBO1, ING4/5, and EAF6, and this complex mediates histone H4 acetylation; Jade-1/1L positively regulates HBO1 HAT activity within this complex.","method":"Co-purification, co-immunoprecipitation, in vitro HAT assay with reconstituted oligonucleosome substrates, siRNA knockdown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — co-purification confirmed, in vitro reconstitution with nucleosomal substrates, siRNA knockdown with defined acetylation phenotype; multiple orthogonal methods","pmids":["18684714"],"is_preprint":false},{"year":2018,"finding":"Cryo-EM structure of the NuA4/TIP60 piccolo assembly (Esa1, Epl1, Yng2, and Eaf6) reveals that Eaf6 is part of the piccolo sub-module that packs against FAT and HEAT repeats of Tra1, with its association depending on the Eaf1 HSA region.","method":"Cryo-EM structure determination (7.6 Å resolution)","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structural determination with functional validation of assembly interactions; single study but high-resolution structural method","pmids":["29559617"],"is_preprint":false},{"year":2019,"finding":"MEAF6 is a native subunit of HBO1 complexes; in combination with BRPF scaffolding proteins, MEAF6-containing HBO1 complexes are the major acetyltransferases responsible for histone H4 acetylation in vivo. The choice of JADE vs BRPF as scaffold provides a regulatory switch governing H4 vs H3 substrate specificity.","method":"Complex purification, HAT activity assays, subunit composition analysis (review consolidating experimental data)","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — consolidates multiple experimental findings; not a primary experimental study but synthesizes replicated biochemical data","pmids":["31535175"],"is_preprint":false},{"year":2019,"finding":"The BRPF1 PZP domain requires both histone H3 tail binding and DNA binding for tight association with the nucleosome core particle (NCP) and for acetyltransferase function of the BRPF1-MORF-ING5-MEAF6 complex, confirming MEAF6 as an integral subunit of this functional complex.","method":"Crystal structure of BRPF1-PZP bound to H3 tail, NCP binding assays, acetyltransferase functional assays with mutagenesis","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus mutagenesis plus functional HAT assay on the BRPF1-MORF-ING5-MEAF6 complex; multiple orthogonal methods in one rigorous study","pmids":["31711755"],"is_preprint":false},{"year":2020,"finding":"MEAF6 is essential for cell proliferation; inducible Meaf6 knockout in mouse ES cells causes proliferation arrest. In the absence of Meaf6, KAT7/MYST2 increases its interaction with PHD-finger proteins (BRPF/JADE), indicating that MEAF6 modulates KAT7 complex assembly without being essential for HAT activity per se.","method":"Inducible knockout ES cells, proliferation assays, co-immunoprecipitation, histone acetylation analysis","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean inducible KO with specific cellular phenotype (proliferation arrest) plus Co-IP showing altered complex assembly; two orthogonal methods, single lab","pmids":["32918898"],"is_preprint":false},{"year":2017,"finding":"A splice variant of MEAF6 (MEAF6-1) is stimulated by neuronal RNA splicing factor SRRM4, and its upregulation promotes cell proliferation, anchorage-independent growth, invasion, and xenograft tumor growth, in part mediated by ID1 and ID3 genes.","method":"Splice variant identification, overexpression/knockdown assays, xenograft model, gene microarray","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays (proliferation, invasion, xenograft) with mechanistic follow-up via gene array identifying ID1/ID3 mediators; single lab","pmids":["28427194"],"is_preprint":false},{"year":2022,"finding":"miR-197-3p suppresses MEAF6 expression (by binding MEAF6 mRNA), and reduced MEAF6 leads to decreased histone H3 acetylation at the IL-6 promoter, thereby reducing IL-6 transcription; chromatin immunoprecipitation confirmed MEAF6-mediated histone H3 acetylation at the IL-6 promoter.","method":"miRNA target validation (molecular biology techniques), chromatin immunoprecipitation (ChIP) for histone acetylation at IL-6 promoter, Western blotting, in vivo mouse model","journal":"Leukemia research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with functional outcome plus miRNA-target validation and in vivo model; two orthogonal methods, single lab","pmids":["35074616"],"is_preprint":false},{"year":2021,"finding":"MEAF6 interacts with the cytoskeletal protein MACF1 and with E2F6 and TCF12 (transcriptional repressors of osteoblast differentiation); MACF1 knockdown was shown to alter cytoplasmic-nuclear localization of MEAF6-interacting repressors, suppressing osteoblast differentiation.","method":"Co-immunoprecipitation (MACF1 pulldown identifying MEAF6 and other partners), knockdown experiments, subcellular localization studies","journal":"Cell death and differentiation","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP identifying MEAF6 as an interactor of MACF1; mechanistic follow-up focused on MACF1, not MEAF6 specifically","pmids":["33664480"],"is_preprint":false},{"year":2025,"finding":"KAT6A (a MYST acetyltransferase) forms a 4-protein complex with BRPF1, ING4/5, and MEAF6 to acetylate H3K23; in this complex, BRPF1 shifts KAT6A substrate preference from H3K14 (preferred by uncomplexed KAT6A) to H3K23, with BRPF1 altering substrate selectivity by ~10^3-fold. A crystal structure of the KAT6A MYST domain with an H3K14-CoA bisubstrate inhibitor was determined.","method":"In vitro acetyltransferase assays with peptide substrates, crystal structure of MYST domain bound to bisubstrate inhibitor, reconstitution of 4-protein complex, steady-state kinetics","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus reconstituted complex acetyltransferase assays with mutagenesis-like dissection of substrate specificity; multiple orthogonal Tier 1 methods in one rigorous study","pmids":["39909374"],"is_preprint":false},{"year":2012,"finding":"MEAF6 (from chromosome 1p34) is fused in-frame to PHF1 (from 6p21) in endometrial stromal sarcoma via t(1;6)(p34;p21), producing a chimeric protein containing the histone acetyltransferase subunit NuA4 domain of MEAF6 and the tudor, PHD zinc finger, and MTF2 domains of PHF1.","method":"5'-RACE, RT-PCR, Sanger sequencing, karyotyping","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple molecular methods (RACE, RT-PCR, sequencing) confirming in-frame fusion and predicted protein domains; replicated in subsequent studies","pmids":["22761769"],"is_preprint":false},{"year":2025,"finding":"Removal of a microexon in meaf6 in zebrafish (via CRISPR) produced mild neural activity phenotypes in larval brain, indicating the MEAF6 microexon contributes to normal neural function.","method":"CRISPR/Cas9 microexon deletion in zebrafish, larval brain activity and morphology assessment","journal":"eLife","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single CRISPR deletion with mild phenotype, no mechanistic pathway placement for MEAF6 specifically","pmids":["41252186"],"is_preprint":false}],"current_model":"MEAF6 is a conserved small non-catalytic subunit of MYST-family histone acetyltransferase complexes (MOZ/MORF/KAT6A, HBO1/KAT7, and NuA4/TIP60), where it forms part of a trimeric core with ING4/5 and BRPF or JADE scaffold proteins; it is essential for cell proliferation and modulates KAT7 complex assembly (rather than being required for HAT activity itself), and in the context of KAT6A it participates in a 4-protein complex that shifts substrate specificity toward H3K23 acetylation, while a splice variant (MEAF6-1) promotes tumor cell proliferation and invasion partly through ID1/ID3, and MEAF6-mediated histone H3 acetylation at target promoters (e.g., IL-6) regulates gene expression downstream of miR-197-3p."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2008,"claim":"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","pmids":["18794358","18684714"],"confidence":"High","gaps":["Did not define an independent catalytic or regulatory function for EAF6 itself","Role of EAF6 in substrate specificity not addressed"]},{"year":2018,"claim":"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","pmids":["29559617"],"confidence":"High","gaps":["Resolution limited; atomic detail of Eaf6 contacts not resolved","Human complex architecture inferred from yeast ortholog"]},{"year":2019,"claim":"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","pmids":["31535175","31711755"],"confidence":"High","gaps":["MEAF6's specific contribution to substrate switching not isolated","How MEAF6 contacts the nucleosome directly remains undefined"]},{"year":2020,"claim":"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","pmids":["32918898"],"confidence":"High","gaps":["Molecular basis for altered KAT7-PHD interactions unresolved","Direct gene targets driving proliferation arrest not mapped"]},{"year":2025,"claim":"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","pmids":["39909374"],"confidence":"High","gaps":["MEAF6's individual energetic contribution to specificity not separated from BRPF1","No structure of the assembled 4-protein complex"]},{"year":2012,"claim":"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","pmids":["22761769"],"confidence":"Medium","gaps":["Functional consequence of the fusion protein not tested","Whether the MEAF6 portion confers HAT recruitment to PHF1 targets unknown"]},{"year":2017,"claim":"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","pmids":["28427194"],"confidence":"Medium","gaps":["Mechanism by which the variant alters complex function unresolved","Direct vs indirect regulation of ID1/ID3 not established"]},{"year":2022,"claim":"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","pmids":["35074616"],"confidence":"Medium","gaps":["Which acetyltransferase complex delivers MEAF6 to the IL-6 promoter unclear","Direct recruitment mechanism not defined"]},{"year":2021,"claim":"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","pmids":["33664480"],"confidence":"Low","gaps":["Single Co-IP centered on MACF1, not validated reciprocally for MEAF6","MEAF6-specific functional contribution not isolated"]},{"year":2025,"claim":"Indicated that a MEAF6 microexon contributes to normal neural function.","evidence":"CRISPR/Cas9 microexon deletion in zebrafish with larval brain activity assessment","pmids":["41252186"],"confidence":"Low","gaps":["Mild phenotype with no mechanistic pathway placement","Molecular role of the microexon in complex function unknown"]},{"year":null,"claim":"The distinct molecular contribution of MEAF6 itself—as opposed to its scaffold and ING partners—to substrate specificity and nucleosome engagement remains undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["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"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,4,9]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,7]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,1,9]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[7]}],"complexes":["MOZ/MORF (KAT6A/KAT6B) HAT complex","HBO1/KAT7 HAT complex","NuA4/TIP60 piccolo module","BRPF1-MORF-ING5-MEAF6 complex"],"partners":["BRPF1","ING5","ING4","KAT6A","HBO1","JADE1","MACF1","PHF1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9HAF1","full_name":"Chromatin modification-related protein MEAF6","aliases":["Esa1-associated factor 6 homolog","Protein EAF6 homolog","hEAF6","Sarcoma antigen NY-SAR-91"],"length_aa":191,"mass_kda":21.6,"function":"Component of the NuA4 histone acetyltransferase complex which is involved in transcriptional activation of select genes principally by acetylation of nucleosomal histone H4 and H2A (PubMed:14966270). This modification may both alter nucleosome - DNA interactions and promote interaction of the modified histones with other proteins which positively regulate transcription (PubMed:14966270). Component of HBO1 complexes, which specifically mediate acetylation of histone H3 at 'Lys-14' (H3K14ac), and have reduced activity toward histone H4 (PubMed:16387653, PubMed:24065767). Component of the MOZ/MORF complex which has a histone H3 acetyltransferase activity (PubMed:18794358)","subcellular_location":"Nucleus, nucleolus; Chromosome, centromere, kinetochore","url":"https://www.uniprot.org/uniprotkb/Q9HAF1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MEAF6","classification":"Not Classified","n_dependent_lines":362,"n_total_lines":1208,"dependency_fraction":0.2996688741721854},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CSNK2B","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"NUMA1","stoichiometry":0.2},{"gene":"PARP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/MEAF6","total_profiled":1310},"omim":[{"mim_id":"617333","title":"INTELLECTUAL DEVELOPMENTAL DISORDER WITH DYSMORPHIC FACIES AND PTOSIS; IDDDFP","url":"https://www.omim.org/entry/617333"},{"mim_id":"611001","title":"MYST/ESA1-ASSOCIATED FACTOR 6; MEAF6","url":"https://www.omim.org/entry/611001"},{"mim_id":"602410","title":"BROMODOMAIN- AND PHD FINGER-CONTAINING PROTEIN; BRPF1","url":"https://www.omim.org/entry/602410"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nuclear bodies","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MEAF6"},"hgnc":{"alias_symbol":["NY-SAR-91","FLJ11730","Eaf6","CENP-28"],"prev_symbol":["C1orf149"]},"alphafold":{"accession":"Q9HAF1","domains":[{"cath_id":"-","chopping":"15-103","consensus_level":"high","plddt":89.4029,"start":15,"end":103}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HAF1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HAF1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HAF1-F1-predicted_aligned_error_v6.png","plddt_mean":70.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MEAF6","jax_strain_url":"https://www.jax.org/strain/search?query=MEAF6"},"sequence":{"accession":"Q9HAF1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9HAF1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9HAF1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HAF1"}},"corpus_meta":[{"pmid":"18794358","id":"PMC_18794358","title":"Molecular 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BRPF proteins bridge MOZ/MORF with ING5 and EAF6 via the EPc homology domain. The association of BRPF1 with EAF6 alone is weak, but ING5 increases the affinity, forming a trimeric ING5-EAF6-BRPF1 core conserved from Drosophila to humans.\",\n      \"method\": \"Complex reconstitution, deletion mapping, co-immunoprecipitation, in vitro acetyltransferase assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted complexes in vitro with deletion mapping and acetyltransferase activity assays; multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"18794358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"EAF6 co-purifies with the HBO1 HAT complex consisting of HBO1, ING4/5, and EAF6, and this complex mediates histone H4 acetylation; Jade-1/1L positively regulates HBO1 HAT activity within this complex.\",\n      \"method\": \"Co-purification, co-immunoprecipitation, in vitro HAT assay with reconstituted oligonucleosome substrates, siRNA knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — co-purification confirmed, in vitro reconstitution with nucleosomal substrates, siRNA knockdown with defined acetylation phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"18684714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cryo-EM structure of the NuA4/TIP60 piccolo assembly (Esa1, Epl1, Yng2, and Eaf6) reveals that Eaf6 is part of the piccolo sub-module that packs against FAT and HEAT repeats of Tra1, with its association depending on the Eaf1 HSA region.\",\n      \"method\": \"Cryo-EM structure determination (7.6 Å resolution)\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structural determination with functional validation of assembly interactions; single study but high-resolution structural method\",\n      \"pmids\": [\"29559617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MEAF6 is a native subunit of HBO1 complexes; in combination with BRPF scaffolding proteins, MEAF6-containing HBO1 complexes are the major acetyltransferases responsible for histone H4 acetylation in vivo. The choice of JADE vs BRPF as scaffold provides a regulatory switch governing H4 vs H3 substrate specificity.\",\n      \"method\": \"Complex purification, HAT activity assays, subunit composition analysis (review consolidating experimental data)\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — consolidates multiple experimental findings; not a primary experimental study but synthesizes replicated biochemical data\",\n      \"pmids\": [\"31535175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The BRPF1 PZP domain requires both histone H3 tail binding and DNA binding for tight association with the nucleosome core particle (NCP) and for acetyltransferase function of the BRPF1-MORF-ING5-MEAF6 complex, confirming MEAF6 as an integral subunit of this functional complex.\",\n      \"method\": \"Crystal structure of BRPF1-PZP bound to H3 tail, NCP binding assays, acetyltransferase functional assays with mutagenesis\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus mutagenesis plus functional HAT assay on the BRPF1-MORF-ING5-MEAF6 complex; multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"31711755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MEAF6 is essential for cell proliferation; inducible Meaf6 knockout in mouse ES cells causes proliferation arrest. In the absence of Meaf6, KAT7/MYST2 increases its interaction with PHD-finger proteins (BRPF/JADE), indicating that MEAF6 modulates KAT7 complex assembly without being essential for HAT activity per se.\",\n      \"method\": \"Inducible knockout ES cells, proliferation assays, co-immunoprecipitation, histone acetylation analysis\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean inducible KO with specific cellular phenotype (proliferation arrest) plus Co-IP showing altered complex assembly; two orthogonal methods, single lab\",\n      \"pmids\": [\"32918898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A splice variant of MEAF6 (MEAF6-1) is stimulated by neuronal RNA splicing factor SRRM4, and its upregulation promotes cell proliferation, anchorage-independent growth, invasion, and xenograft tumor growth, in part mediated by ID1 and ID3 genes.\",\n      \"method\": \"Splice variant identification, overexpression/knockdown assays, xenograft model, gene microarray\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays (proliferation, invasion, xenograft) with mechanistic follow-up via gene array identifying ID1/ID3 mediators; single lab\",\n      \"pmids\": [\"28427194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"miR-197-3p suppresses MEAF6 expression (by binding MEAF6 mRNA), and reduced MEAF6 leads to decreased histone H3 acetylation at the IL-6 promoter, thereby reducing IL-6 transcription; chromatin immunoprecipitation confirmed MEAF6-mediated histone H3 acetylation at the IL-6 promoter.\",\n      \"method\": \"miRNA target validation (molecular biology techniques), chromatin immunoprecipitation (ChIP) for histone acetylation at IL-6 promoter, Western blotting, in vivo mouse model\",\n      \"journal\": \"Leukemia research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with functional outcome plus miRNA-target validation and in vivo model; two orthogonal methods, single lab\",\n      \"pmids\": [\"35074616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MEAF6 interacts with the cytoskeletal protein MACF1 and with E2F6 and TCF12 (transcriptional repressors of osteoblast differentiation); MACF1 knockdown was shown to alter cytoplasmic-nuclear localization of MEAF6-interacting repressors, suppressing osteoblast differentiation.\",\n      \"method\": \"Co-immunoprecipitation (MACF1 pulldown identifying MEAF6 and other partners), knockdown experiments, subcellular localization studies\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP identifying MEAF6 as an interactor of MACF1; mechanistic follow-up focused on MACF1, not MEAF6 specifically\",\n      \"pmids\": [\"33664480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KAT6A (a MYST acetyltransferase) forms a 4-protein complex with BRPF1, ING4/5, and MEAF6 to acetylate H3K23; in this complex, BRPF1 shifts KAT6A substrate preference from H3K14 (preferred by uncomplexed KAT6A) to H3K23, with BRPF1 altering substrate selectivity by ~10^3-fold. A crystal structure of the KAT6A MYST domain with an H3K14-CoA bisubstrate inhibitor was determined.\",\n      \"method\": \"In vitro acetyltransferase assays with peptide substrates, crystal structure of MYST domain bound to bisubstrate inhibitor, reconstitution of 4-protein complex, steady-state kinetics\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus reconstituted complex acetyltransferase assays with mutagenesis-like dissection of substrate specificity; multiple orthogonal Tier 1 methods in one rigorous study\",\n      \"pmids\": [\"39909374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MEAF6 (from chromosome 1p34) is fused in-frame to PHF1 (from 6p21) in endometrial stromal sarcoma via t(1;6)(p34;p21), producing a chimeric protein containing the histone acetyltransferase subunit NuA4 domain of MEAF6 and the tudor, PHD zinc finger, and MTF2 domains of PHF1.\",\n      \"method\": \"5'-RACE, RT-PCR, Sanger sequencing, karyotyping\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple molecular methods (RACE, RT-PCR, sequencing) confirming in-frame fusion and predicted protein domains; replicated in subsequent studies\",\n      \"pmids\": [\"22761769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Removal of a microexon in meaf6 in zebrafish (via CRISPR) produced mild neural activity phenotypes in larval brain, indicating the MEAF6 microexon contributes to normal neural function.\",\n      \"method\": \"CRISPR/Cas9 microexon deletion in zebrafish, larval brain activity and morphology assessment\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single CRISPR deletion with mild phenotype, no mechanistic pathway placement for MEAF6 specifically\",\n      \"pmids\": [\"41252186\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MEAF6 is a conserved small non-catalytic subunit of MYST-family histone acetyltransferase complexes (MOZ/MORF/KAT6A, HBO1/KAT7, and NuA4/TIP60), where it forms part of a trimeric core with ING4/5 and BRPF or JADE scaffold proteins; it is essential for cell proliferation and modulates KAT7 complex assembly (rather than being required for HAT activity itself), and in the context of KAT6A it participates in a 4-protein complex that shifts substrate specificity toward H3K23 acetylation, while a splice variant (MEAF6-1) promotes tumor cell proliferation and invasion partly through ID1/ID3, and MEAF6-mediated histone H3 acetylation at target promoters (e.g., IL-6) regulates gene expression downstream of miR-197-3p.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #1]. 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\\u2013EAF6\\u2013BRPF1 core, with ING5 stabilizing the otherwise weak BRPF1\\u2013EAF6 association; this conserved core supports nucleosomal histone H4 acetylation [#0, #1, #3]. MEAF6 is an integral subunit of the functional BRPF1\\u2013MORF\\u2013ING5\\u2013MEAF6 complex that engages the nucleosome core particle through the BRPF1 PZP domain [#4], and in the KAT6A complex with BRPF1 and ING4/5 it participates in acetylation directed toward H3K23, a specificity dictated by BRPF1 [#9]. Functionally, MEAF6 is required for cell proliferation\\u2014its loss arrests proliferation in mouse ES cells\\u2014and it modulates KAT7 complex assembly by tuning the enzyme's interaction with PHD-finger scaffolds rather than being strictly required for HAT catalysis [#5]. At target promoters MEAF6 directs histone H3 acetylation to regulate gene expression, exemplified by control of IL-6 transcription downstream of miR-197-3p [#7]. A recurrent t(1;6) translocation fuses the MEAF6 NuA4-domain region in-frame to PHF1 in endometrial stromal sarcoma [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"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.\",\n      \"evidence\": \"Complex reconstitution, deletion mapping, co-IP and in vitro HAT assays for MOZ/MORF; co-purification and reconstituted nucleosomal HAT assays for HBO1\",\n      \"pmids\": [\"18794358\", \"18684714\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define an independent catalytic or regulatory function for EAF6 itself\", \"Role of EAF6 in substrate specificity not addressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed Eaf6 structurally within the NuA4/TIP60 piccolo sub-module, showing how it packs against the larger assembly via Tra1 and Eaf1.\",\n      \"evidence\": \"Cryo-EM structure of the yeast NuA4/TIP60 complex at 7.6 \\u00c5\",\n      \"pmids\": [\"29559617\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Resolution limited; atomic detail of Eaf6 contacts not resolved\", \"Human complex architecture inferred from yeast ortholog\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"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.\",\n      \"evidence\": \"Complex purification and HAT assays (review consolidating data); crystal structure of BRPF1-PZP on H3 tail plus NCP-binding and HAT functional assays\",\n      \"pmids\": [\"31535175\", \"31711755\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"MEAF6's specific contribution to substrate switching not isolated\", \"How MEAF6 contacts the nucleosome directly remains undefined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"Inducible Meaf6 knockout in mouse ES cells with proliferation assays, co-IP, and histone acetylation analysis\",\n      \"pmids\": [\"32918898\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis for altered KAT7-PHD interactions unresolved\", \"Direct gene targets driving proliferation arrest not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined how MEAF6 within the KAT6A\\u2013BRPF1\\u2013ING4/5 complex contributes to H3K23-directed acetylation, with BRPF1 reprogramming KAT6A substrate preference ~1000-fold from H3K14.\",\n      \"evidence\": \"Reconstituted 4-protein complex acetyltransferase assays, steady-state kinetics, and crystal structure of the KAT6A MYST domain with bisubstrate inhibitor\",\n      \"pmids\": [\"39909374\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"MEAF6's individual energetic contribution to specificity not separated from BRPF1\", \"No structure of the assembled 4-protein complex\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linked MEAF6 to disease by identifying an in-frame MEAF6-PHF1 fusion in endometrial stromal sarcoma, implicating its chromatin-modifying domain in oncogenic chimeras.\",\n      \"evidence\": \"5'-RACE, RT-PCR, Sanger sequencing, and karyotyping of tumor samples\",\n      \"pmids\": [\"22761769\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the fusion protein not tested\", \"Whether the MEAF6 portion confers HAT recruitment to PHF1 targets unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified a splice variant (MEAF6-1) regulated by SRRM4 as pro-tumorigenic, acting partly through ID1/ID3.\",\n      \"evidence\": \"Splice variant identification, overexpression/knockdown, xenograft model, and gene microarray\",\n      \"pmids\": [\"28427194\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which the variant alters complex function unresolved\", \"Direct vs indirect regulation of ID1/ID3 not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"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.\",\n      \"evidence\": \"miRNA target validation, ChIP for histone acetylation at IL-6 promoter, Western blot, and an in vivo mouse model\",\n      \"pmids\": [\"35074616\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which acetyltransferase complex delivers MEAF6 to the IL-6 promoter unclear\", \"Direct recruitment mechanism not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Reported MEAF6 as an interactor of cytoskeletal MACF1 and of repressors E2F6/TCF12, raising a possible cytoplasmic-nuclear shuttling role in osteoblast differentiation.\",\n      \"evidence\": \"Co-IP via MACF1 pulldown, knockdown, and subcellular localization studies\",\n      \"pmids\": [\"33664480\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP centered on MACF1, not validated reciprocally for MEAF6\", \"MEAF6-specific functional contribution not isolated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Indicated that a MEAF6 microexon contributes to normal neural function.\",\n      \"evidence\": \"CRISPR/Cas9 microexon deletion in zebrafish with larval brain activity assessment\",\n      \"pmids\": [\"41252186\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Mild phenotype with no mechanistic pathway placement\", \"Molecular role of the microexon in complex function unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The distinct molecular contribution of MEAF6 itself\\u2014as opposed to its scaffold and ING partners\\u2014to substrate specificity and nucleosome engagement remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 4, 9]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 1, 9]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"complexes\": [\n      \"MOZ/MORF (KAT6A/KAT6B) HAT complex\",\n      \"HBO1/KAT7 HAT complex\",\n      \"NuA4/TIP60 piccolo module\",\n      \"BRPF1-MORF-ING5-MEAF6 complex\"\n    ],\n    \"partners\": [\n      \"BRPF1\",\n      \"ING5\",\n      \"ING4\",\n      \"KAT6A\",\n      \"HBO1\",\n      \"JADE1\",\n      \"MACF1\",\n      \"PHF1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}