{"gene":"ZMYND11","run_date":"2026-04-28T23:00:24","timeline":{"discoveries":[{"year":2014,"finding":"ZMYND11 specifically recognizes H3K36me3 on histone variant H3.3 (H3.3K36me3) through its tandem bromo-PWWP domains; the PWWP domain provides an aromatic cage for trimethyl-lysine binding, while the H3.3-specific Ser31 residue is encapsulated in a composite pocket formed by the bromo-PWWP domains together.","method":"Structural studies (crystal structure), chromatin immunoprecipitation followed by sequencing (ChIP-seq), in vitro binding assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with functional validation and ChIP-seq genome-wide co-localization, single rigorous paper with multiple orthogonal methods","pmids":["24590075"],"is_preprint":false},{"year":2014,"finding":"ZMYND11 functions as an unconventional transcriptional co-repressor by modulating RNA polymerase II at the elongation stage; genome-wide occupancy requires pre-deposition of H3.3K36me3 in gene bodies.","method":"ChIP-seq, RNA polymerase II elongation assays, loss-of-function experiments in cancer cells","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1–2 — ChIP-seq genome-wide analysis plus functional elongation assays with loss-of-function, moderate-to-strong evidence in a single rigorous study","pmids":["24590075"],"is_preprint":false},{"year":2014,"finding":"ZMYND11 (BS69) associates with RNA splicing regulators including U5 snRNP components (e.g., EFTUD2) and promotes intron retention by antagonizing EFTUD2 through physical interaction; this regulation also depends on binding to H3K36me3-decorated chromatin.","method":"Co-immunoprecipitation, RNA sequencing, biochemical and genetic epistasis experiments","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, RNA-seq, and genetic rescue experiments across multiple orthogonal methods","pmids":["25263594"],"is_preprint":false},{"year":1995,"finding":"BS69 (ZMYND11) was identified as a nuclear phosphoprotein that interacts specifically with the conserved region 3 (CR3) of the adenovirus 5 289R E1A protein and inhibits E1A-mediated transcriptional transactivation; interaction was confirmed by co-immunoprecipitation in adenovirus-transformed 293 cells.","method":"Co-immunoprecipitation, transactivation reporter assays, yeast two-hybrid","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP in vivo plus functional transactivation assays; foundational discovery paper with high citation count","pmids":["7621829"],"is_preprint":false},{"year":2000,"finding":"BS69 mediates transcriptional repression at least in part through interaction with the co-repressor N-CoR via its MYND domain; expression of E1A inhibits repression mediated by BS69.","method":"Co-immunoprecipitation, transcriptional reporter assays, domain deletion analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and reporter assays, single lab with two orthogonal methods","pmids":["10734313"],"is_preprint":false},{"year":2001,"finding":"The C-terminal MYND domain of BS69 binds to viral (E1A, EBNA2) and cellular (MGA) proteins through a conserved PXLXP motif; viral proteins compete with MGA for BS69 MYND binding in a PXLXP-dependent manner.","method":"GST pulldown, yeast two-hybrid, co-immunoprecipitation, mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro GST pulldown plus mutagenesis of PXLXP motif and competition assays; multiple orthogonal methods","pmids":["11733528"],"is_preprint":false},{"year":2001,"finding":"BS69 interacts with the carboxyl terminus of c-Myb via its MYND domain and inhibits c-Myb transcriptional activity in a dose-dependent manner; direct interaction was demonstrated in vitro, and 289R E1A can relieve BS69-mediated repression of c-Myb.","method":"Yeast two-hybrid, in vitro GST pulldown, transcriptional reporter assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro pulldown and reporter assays, single lab with two orthogonal methods","pmids":["11244510"],"is_preprint":false},{"year":1998,"finding":"BRAM1, an alternatively spliced isoform of BS69/ZMYND11, is localized to the cytoplasm (unlike nuclear BS69) and specifically binds to BMPR-IA (BMP type IA receptor) via its C-terminal half.","method":"Yeast two-hybrid, co-immunoprecipitation in mammalian cells, subcellular localization by cell fractionation/immunofluorescence","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 — yeast two-hybrid confirmed by Co-IP; direct localization experiment demonstrating cytoplasmic vs. nuclear isoform difference","pmids":["9663660"],"is_preprint":false},{"year":2006,"finding":"BS69's MYND domain acts as a specific adaptor bridging EBV LMP1 and TRAF6 to activate the JNK pathway; the MYND domain binds LMP1 C-terminus while a separate region binds TRAF6; LMP1 promotes the BS69-TRAF6 complex, and knockdown of BS69 specifically inhibits LMP1-induced JNK activation but not TNF-alpha-induced JNK activation.","method":"Co-immunoprecipitation, siRNA knockdown, JNK kinase assays, chimeric protein rescue","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, siRNA knockdown with specific phenotypic readout, and chimeric protein rescue; multiple orthogonal methods","pmids":["16382137"],"is_preprint":false},{"year":2006,"finding":"BS69 associates with chromatin remodeling factors including ATP-dependent helicases, histone deacetylases, histone methyltransferases, and the transcription factor E2F6; BS69 is nuclear and associates with chromatin and mitotic chromosomes.","method":"Endogenous protein immunoprecipitation, mass spectrometry, chromatin fractionation, immunofluorescence","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — endogenous protein IP with MS identification and direct localization by fractionation; single lab","pmids":["16565076"],"is_preprint":false},{"year":2007,"finding":"BS69 is involved in cellular senescence through the p53-p21Cip1 pathway; knockdown of BS69 in primary fibroblasts elevates p21Cip1 and induces premature senescence that is bypassed by knockdown of p53 or p21Cip1 (but not p16 or Rb); BS69 forms complexes with p53 and p400 and associates with the p21Cip1 promoter via p53.","method":"siRNA knockdown, double knockdown epistasis, chromatin immunoprecipitation, co-immunoprecipitation, senescence assays","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis by double knockdown, ChIP for promoter association, Co-IP for complex formation; multiple orthogonal methods","pmids":["17721438"],"is_preprint":false},{"year":2009,"finding":"BS69 undergoes SUMO modification; it interacts with SUMO E3 ligase PIAS1 and SUMO E2 enzyme Ubc9 through distinct domains, and PIAS1 significantly increases BS69 SUMOylation; the PHD domain is required for proper localization, sumoylation, and function of BS69.","method":"Co-immunoprecipitation, in vivo SUMOylation assay, domain mutant analysis, immunofluorescence","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and in vivo sumoylation assay with domain mutagenesis; single lab with multiple methods","pmids":["19766626"],"is_preprint":false},{"year":2009,"finding":"BS69 negatively regulates LMP1-mediated NF-κB activation by decreasing complex formation between LMP1 and TRADD; manipulation of BS69 expression modulates IκBα degradation and IL-6 production.","method":"siRNA knockdown, overexpression, co-immunoprecipitation, NF-κB reporter assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 — IP showing disrupted LMP1-TRADD complex plus functional NF-κB reporter; single lab","pmids":["19379743"],"is_preprint":false},{"year":2009,"finding":"BS69 translocates from the nucleus to the cytoplasm upon dsRNA stimulation or TICAM-1 overexpression, where it is incorporated into the TICAM-1 signalosome complex and acts as a positive regulator of NF-κB and IRF-3 activation and IFN-β induction.","method":"Yeast two-hybrid, co-immunoprecipitation, confocal microscopy, siRNA knockdown, reporter assays","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP, live confocal imaging of translocation, and siRNA knockdown with IFN-β readout; single lab","pmids":["19795416"],"is_preprint":false},{"year":2010,"finding":"BS69 directly interacts with the LMP1/CTAR1 domain and with TRAF3, and BS69-mediated suppression of LMP1/CTAR1-induced NF-κB activation requires TRAF3.","method":"Co-immunoprecipitation, siRNA knockdown, NF-κB reporter assays","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP demonstrating direct interaction plus epistatic siRNA knockdown; single lab","pmids":["20138174"],"is_preprint":false},{"year":2013,"finding":"The BS69 MYND domain folds as a ββα zinc binding domain (C4-C2HC topology); mutational analysis of charged residues flanking the MYND fold reveals they are required for binding to viral (E1A, EBNA2) and cellular partners, suggesting a distinct binding mode from related MYND domains.","method":"NMR structure (DEAF-1 MYND), homology modeling, mutagenesis, NMR titration binding assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1 — NMR structure with mutagenesis binding validation; moderate evidence as BS69 itself modeled by homology","pmids":["23372760"],"is_preprint":false},{"year":2016,"finding":"The BS69/ZMYND11 coiled-coil domain self-associates to bring two MYND domains into proximity, enhancing binding to EBNA2 PXLXP motifs; the CC-MYND homodimer synergistically binds the two PXLXP motifs in EBNA2 CR7 and CR8; EBNA2 also down-regulates BS69 expression in EBV-infected B cells.","method":"Crystal structure of CC-MYND/EBNA2 complex, ITC binding analysis, mutagenesis, reporter assays, ectopic expression experiments","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with ITC binding quantification and mutagenesis abolishing interaction; strong mechanistic evidence","pmids":["26845565"],"is_preprint":false},{"year":2017,"finding":"ZMYND11 specifically interacts with ETS2 (but not ETS1) through the ETS2 N-terminus and attenuates ETS2 transcriptional activation, causing ETS2 to repress rather than activate a cell migration gene expression program; this interaction underlies the context-dependent oncogenic vs. tumor-suppressive function of ETS2.","method":"Co-immunoprecipitation, ETS1/ETS2 cistrome comparison (ChIP-seq), deletion mapping, reporter assays","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and ChIP-seq with functional reporter assays; single lab but multiple methods","pmids":["28119415"],"is_preprint":false},{"year":2019,"finding":"Type 2 EBV EBNA2 contains a third PXLXP motif that allows binding of an additional BS69 CC-MYND dimer; SAXS shows three BS69CC-MYND dimers bind two molecules of type 2 EBNA2 TAD; mutation of the third BS69-binding motif in type 2 EBNA2 improved B-cell growth and transcriptional activation.","method":"Pull-down assays, small-angle X-ray scattering (SAXS), mutagenesis, transcriptional and B-cell growth assays","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1 — SAXS structural analysis with mutagenesis and functional validation in B-cell growth assay","pmids":["31283782"],"is_preprint":false},{"year":2014,"finding":"MAGE-C2/HCA587 interacts with BS69 and promotes its ubiquitination and proteasomal degradation; knockdown of HCA587 increases BS69 protein levels, and overexpression of HCA587 enhances LMP1-induced NF-κB activation consistent with reduced BS69 levels.","method":"Co-immunoprecipitation, mass spectrometry, GST pulldown, ubiquitination assay, proteasome inhibitor treatment","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP/MS identification with ubiquitination assay and functional NF-κB readout; single lab","pmids":["24866244"],"is_preprint":false},{"year":2005,"finding":"BS69 inhibits ubiquitination of adenovirus E1A protein through its MYND domain; BS69 binding to E1A protects E1A from proteasomal degradation; MYND domain mutants that cannot bind E1A fail to inhibit E1A ubiquitination.","method":"In vivo ubiquitination assay, proteasome inhibitor experiments, MYND domain mutagenesis, co-immunoprecipitation","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo ubiquitination assay with domain mutagenesis; single lab","pmids":["16300738"],"is_preprint":false},{"year":2021,"finding":"The ZMYND11-MBTD1 fusion oncoprotein recruits the NuA4/TIP60 histone acetyltransferase complex to cis-regulatory elements of pro-leukemic genes via the ZMYND11 PWWP domain's H3K36me3 binding, sustaining active chromatin enriched in histone acetylation; both TIP60 interaction and the PWWP H3K36me3-binding are required for oncogenesis.","method":"ChIP-seq, ATAC-seq, systematic mutagenesis, co-immunoprecipitation, in vivo leukemia model, gene expression profiling","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 — systematic mutagenesis, ChIP-seq, and in vivo leukemia model with multiple orthogonal methods; strong mechanistic evidence","pmids":["33594072"],"is_preprint":false},{"year":2022,"finding":"ZMYND11-MBTD1 is stably incorporated into the endogenous NuA4/TIP60 complex, mislocalizing it to the bodies of genes normally bound by ZMYND11; this leads to increased chromatin acetylation and altered gene transcription including on MYC, and alternative splicing changes.","method":"Biochemical co-purification/Co-IP, ChIP-seq, RNA-seq, comparison to individual fusion partners","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — Co-IP showing stable incorporation into endogenous complex, ChIP-seq for mislocalization, RNA-seq for functional consequences; multiple methods","pmids":["35705031"],"is_preprint":false},{"year":2024,"finding":"ZMYND11 exhibits a non-canonical function as a nonhistone methylation reader: its MYND domain recognizes arginine-194-methylated HNRNPA1, retaining HNRNPA1 in the nucleus and preventing stress granule formation in the cytoplasm; ZMYND11 also counteracts HNRNPA1-driven increases in PKM2/PKM1 ratio; PRMT5 inhibition disrupts the ZMYND11-HNRNPA1 interaction.","method":"Co-immunoprecipitation, domain mutagenesis, subcellular fractionation, in vitro and in vivo tumor assays, pharmacological PRMT5 inhibition","journal":"Signal transduction and targeted therapy","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP with domain mutagenesis and subcellular localization experiments plus functional rescue; single lab","pmids":["39341825"],"is_preprint":false},{"year":2024,"finding":"USP53 deubiquitinase interacts with ZMYND11 via co-immunoprecipitation and catalyzes its deubiquitination and stabilization; the USP53 Cys-box domain (aa 33-50) is required for enzyme activity but not for ZMYND11 binding; loss of USP53 reduces ZMYND11 protein levels and promotes breast cancer cell growth.","method":"Co-immunoprecipitation, deubiquitination assay, loss-of-function and rescue experiments","journal":"Biological procedures online","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP with in vivo deubiquitination assay and functional rescue; single lab","pmids":["39044157"],"is_preprint":false},{"year":2025,"finding":"ZMYND11 interacts with and inhibits the histone methyltransferase KMT2A (MLL1); a ZRSID-associated ZMYND11 point mutation abrogates this interaction; neuronal deletion of ZMYND11 causes upregulation of non-neuronal gene programs and reduced dendritic branching, effects attenuated by KMT2A inhibition with revumenib.","method":"Co-immunoprecipitation, point mutagenesis, degron-tagged mouse model, RNA-seq, dendritic morphology assay, pharmacological KMT2A inhibition","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP with disease-associated mutagenesis plus in vivo degron model and pharmacological rescue; preprint, single lab","pmids":["41279818"],"is_preprint":true},{"year":2025,"finding":"ZMYND11 regulates a brain-specific RNA isoform switch involving the splicing regulator RBFOX2; ZMYND11-deficient cortical neural stem cells upregulate inappropriate developmental pathways impairing neurogenesis, and similar splicing dysregulation is seen with other chromatin-related ASD risk genes.","method":"Human pluripotent stem cell differentiation model, RNA-seq, loss-of-function","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — human stem cell model with RNA-seq identifying RBFOX2-related isoform switch; single lab","pmids":["41068108"],"is_preprint":false},{"year":2026,"finding":"Crystal structures of ZMYND11 WH, PHD, and CC-MYND domains reveal intermolecular zinc fingers (PHD domain) and redox-driven intermolecular disulfide bonds (CC-MYND domain) that regulate oligomeric state and substrate binding; the Bromo-PWWP domains cooperate with WH to bind nucleic acids and with PHD to bind histones; PHD and CC-MYND domains also interact with nucleic acid repair protein ALKBH6.","method":"Crystal structure determination, ITC, mutagenesis, co-immunoprecipitation","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 — multiple crystal structures with functional binding assays and Co-IP; rigorous structural and biochemical characterization","pmids":["41591843"],"is_preprint":false},{"year":2025,"finding":"In mouse neurons, ZMYND11 deficiency leads to upregulation of non-neuronal gene programs, reduced dendritic branching and spine density, and hyperactivity/abnormal motor behavior; Zmynd11 deficiency in embryos impairs neurogenesis by decreasing Epha2 expression, increasing H3K36me3 on the Epha2 promoter, and disrupting PI3K signaling; restoration of PI3K via Epha2 rescues neurogenesis defects.","method":"Conditional neuronal knockout mouse, degron model, ChIP for H3K36me3, RNA Pol II ChIP, Epha2 rescue experiments, behavioral assays","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo mouse knockout with ChIP and molecular rescue; single lab","pmids":["40281637"],"is_preprint":false}],"current_model":"ZMYND11 is a multidomain chromatin reader that specifically recognizes H3.3K36me3 via its tandem bromo-PWWP domains, localizes to gene bodies genome-wide, and acts as a transcriptional co-repressor by modulating RNA polymerase II elongation; it additionally regulates pre-mRNA splicing (promoting intron retention via antagonism of spliceosome component EFTUD2 and controlling a brain-specific RBFOX2-dependent isoform switch), suppresses cellular senescence through the p53-p21Cip1 pathway, modulates NF-κB and JNK signaling through its MYND domain interactions with viral (LMP1) and cellular (TRAF6, TRAF3) proteins, undergoes SUMO modification via PIAS1 and is stabilized by the deubiquitinase USP53, inhibits the histone methyltransferase KMT2A, and reads arginine-methylated non-histone substrates (e.g., HNRNPA1-R194me) to control stress granule formation and tumor suppression."},"narrative":{"teleology":[{"year":1995,"claim":"The initial identification of BS69/ZMYND11 as a nuclear phosphoprotein that binds adenovirus E1A CR3 and inhibits E1A-mediated transactivation established it as a transcriptional repressor.","evidence":"Co-IP from adenovirus-transformed 293 cells plus transactivation reporter assays and yeast two-hybrid","pmids":["7621829"],"confidence":"High","gaps":["Endogenous target genes unknown","Mechanism of repression unresolved","Physiological relevance beyond viral context unclear"]},{"year":1998,"claim":"Discovery of the cytoplasmic isoform BRAM1, which binds BMP receptor IA, revealed that alternative splicing generates isoforms with distinct subcellular localization and potentially different signaling functions.","evidence":"Yeast two-hybrid with Co-IP in mammalian cells; subcellular fractionation and immunofluorescence","pmids":["9663660"],"confidence":"Medium","gaps":["Functional consequence of BRAM1–BMPR-IA interaction on BMP signaling not demonstrated","Tissue-specific expression of isoforms not characterized"]},{"year":2001,"claim":"Mapping the MYND domain as the binding interface for a conserved PXLXP motif shared by viral (E1A, EBNA2) and cellular (MGA) partners established a general recognition mechanism and revealed that viral oncoproteins hijack a host protein–protein interaction surface.","evidence":"GST pulldown, yeast two-hybrid, Co-IP, and PXLXP mutagenesis with competition assays; interaction with N-CoR via MYND domain and repression of c-Myb","pmids":["11733528","10734313","11244510"],"confidence":"High","gaps":["Structural basis of MYND–PXLXP recognition not yet determined","Full complement of cellular PXLXP partners unknown"]},{"year":2006,"claim":"Demonstration that BS69 bridges EBV LMP1 to TRAF6 to specifically activate JNK signaling, and association with chromatin-remodeling complexes and E2F6, broadened its role from simple repressor to a signal-transduction adaptor and chromatin organizer.","evidence":"Reciprocal Co-IP, siRNA knockdown with JNK kinase assay and chimeric rescue; endogenous IP–mass spectrometry and chromatin fractionation","pmids":["16382137","16565076"],"confidence":"High","gaps":["Structural mechanism of TRAF6 bridging unclear","Whether chromatin-associated complexes are functionally distinct from signaling complexes not tested"]},{"year":2007,"claim":"Linking BS69 to cellular senescence through the p53–p21Cip1 pathway provided the first endogenous physiological function, showing that BS69 forms complexes with p53 and p400 on the p21 promoter to suppress premature senescence.","evidence":"siRNA and double-knockdown epistasis, ChIP at p21 promoter, Co-IP with p53 and p400, senescence assays in primary fibroblasts","pmids":["17721438"],"confidence":"High","gaps":["Whether BS69 directly represses p21 transcription or acts through p400 remodeling not resolved","Relevance to in vivo aging or tumor suppression not tested"]},{"year":2009,"claim":"Multiple studies established that BS69 modulates NF-κB signaling (both LMP1-induced and TICAM-1/dsRNA-induced pathways) and undergoes SUMO modification by PIAS1, revealing post-translational regulation and context-dependent pro- or anti-inflammatory roles.","evidence":"Co-IP, NF-κB and IFN-β reporter assays, siRNA, confocal imaging of nuclear-cytoplasmic translocation; in vivo SUMOylation assay with domain mutagenesis","pmids":["19379743","19795416","19766626"],"confidence":"Medium","gaps":["How SUMOylation affects BS69 transcriptional or signaling activity not determined","Opposing effects on NF-κB in different contexts not mechanistically reconciled"]},{"year":2014,"claim":"Crystal structure and ChIP-seq demonstrated that ZMYND11 is a histone-variant-specific reader recognizing H3.3K36me3 through a composite bromo-PWWP pocket encapsulating H3.3 Ser31, and that this recognition directs it to gene bodies to modulate Pol II elongation and RNA splicing (intron retention via EFTUD2 antagonism), establishing its core chromatin-based mechanism.","evidence":"Crystal structure, ChIP-seq, in vitro binding assays, RNA-seq, Co-IP with U5 snRNP/EFTUD2, genetic epistasis","pmids":["24590075","25263594"],"confidence":"High","gaps":["How H3.3K36me3 binding is mechanistically linked to Pol II pausing/elongation not fully elucidated","Genome-wide determinants of which genes are repressed vs. spliced unclear"]},{"year":2016,"claim":"Crystal structure of the CC-MYND homodimer bound to EBNA2 PXLXP motifs revealed that coiled-coil-mediated dimerization brings two MYND domains into proximity for synergistic bivalent binding, providing a structural explanation for high-affinity target recognition.","evidence":"Crystal structure of CC-MYND/EBNA2 complex, ITC binding quantification, mutagenesis, reporter assays","pmids":["26845565"],"confidence":"High","gaps":["Whether dimerization similarly enhances binding to all cellular PXLXP partners untested","Regulation of dimer formation not addressed"]},{"year":2021,"claim":"Studies of the ZMYND11-MBTD1 leukemia fusion showed that the ZMYND11 PWWP domain's H3K36me3 reading function is co-opted to mislocalize the NuA4/TIP60 acetyltransferase complex to gene bodies, driving aberrant chromatin acetylation and pro-leukemic gene expression.","evidence":"ChIP-seq, ATAC-seq, systematic mutagenesis, Co-IP, in vivo leukemia model; biochemical co-purification confirming stable incorporation into endogenous NuA4/TIP60","pmids":["33594072","35705031"],"confidence":"High","gaps":["Whether wild-type ZMYND11 normally opposes NuA4/TIP60 at gene bodies not tested","Patient-relevant therapeutic vulnerabilities not fully defined"]},{"year":2024,"claim":"Discovery that the MYND domain reads arginine-methylated HNRNPA1 (R194me, deposited by PRMT5) extended ZMYND11 from a histone reader to a nonhistone methylation reader, linking it to stress granule suppression and PKM splicing regulation in tumor suppression.","evidence":"Co-IP, domain mutagenesis, subcellular fractionation, in vitro and in vivo tumor assays, pharmacological PRMT5 inhibition","pmids":["39341825"],"confidence":"Medium","gaps":["Breadth of nonhistone methylated substrates recognized by MYND domain unknown","In vivo relevance of stress granule regulation not confirmed in animal models"]},{"year":2025,"claim":"ZMYND11 was shown to inhibit the histone methyltransferase KMT2A, regulate RBFOX2-dependent brain-specific splicing, and control neurogenesis via EPHA2-PI3K signaling; neuronal loss causes dendritic defects and behavioral abnormalities linked to neurodevelopmental disorder (ZRSID).","evidence":"Co-IP with disease-associated mutagenesis, degron-tagged and conditional knockout mouse models, RNA-seq, ChIP, pharmacological KMT2A inhibition with revumenib, human cortical organoid differentiation","pmids":["41279818","41068108","40281637"],"confidence":"Medium","gaps":["Precise molecular mechanism of KMT2A inhibition not structurally resolved","Whether splicing and KMT2A-regulation are independent or linked pathways unclear","PMID:41279818 is a preprint awaiting peer review"]},{"year":2026,"claim":"Comprehensive structural characterization revealed that PHD domain intermolecular zinc fingers and CC-MYND redox-driven disulfide bonds regulate oligomeric state and substrate binding, with the WH domain contributing to nucleic acid binding and PHD/CC-MYND domains interacting with the nucleic acid repair protein ALKBH6.","evidence":"Multiple crystal structures, ITC, mutagenesis, Co-IP","pmids":["41591843"],"confidence":"High","gaps":["Functional significance of ALKBH6 interaction not established in cells","How redox sensing regulates ZMYND11 function in vivo unknown"]},{"year":null,"claim":"Major unresolved questions include how ZMYND11's chromatin-reading, splicing-regulatory, signaling-adaptor, and nonhistone-reader functions are coordinated in different cell types, the full repertoire of arginine-methylated substrates, and the precise molecular mechanism by which H3.3K36me3 binding is transduced into Pol II elongation control.","evidence":"","pmids":[],"confidence":"Low","gaps":["Integration of chromatin, splicing, and signaling functions not mechanistically unified","Structural basis of Pol II elongation modulation unknown","Complete interactome of arginine-methylated nonhistone substrates not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[0,1,21,27]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,3,4,6,10,17]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[8,14]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,25]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[27]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,7,9,11]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[9]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[7,13]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,4,6,17]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,9,21,22]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[2,26]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,12,13,14]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[26,28]}],"complexes":["NuA4/TIP60 (via ZMYND11-MBTD1 fusion)"],"partners":["EFTUD2","EBNA2","TRAF6","TRAF3","KMT2A","HNRNPA1","PIAS1","USP53"],"other_free_text":[]},"mechanistic_narrative":"ZMYND11 (BS69) is a multidomain chromatin reader and transcriptional co-repressor that couples histone variant–specific recognition to regulation of transcription elongation, RNA splicing, and signaling. Its tandem bromo-PWWP domains form a composite pocket that specifically recognizes H3.3K36me3 via the H3.3-unique Ser31 residue, directing ZMYND11 to active gene bodies where it modulates RNA polymerase II elongation and promotes intron retention by antagonizing the spliceosome component EFTUD2 [PMID:24590075, PMID:25263594]. The C-terminal MYND domain, which folds as a ββα zinc-binding module and functions as a homodimer via the coiled-coil region, serves as a protein–protein interaction hub that engages PXLXP-motif partners (E1A, EBNA2, MGA), co-repressor N-CoR, TRAF6/TRAF3 to modulate NF-κB and JNK signaling, the histone methyltransferase KMT2A whose inhibition it mediates, and arginine-methylated nonhistone substrates such as HNRNPA1 to control stress granule formation [PMID:11733528, PMID:26845565, PMID:16382137, PMID:39341825, PMID:41279818]. ZMYND11 suppresses cellular senescence through the p53–p21Cip1 axis, regulates brain-specific RBFOX2-dependent splicing programs essential for neurogenesis and dendritic morphogenesis, and its loss in neurons causes upregulation of non-neuronal genes and behavioral abnormalities [PMID:17721438, PMID:41068108, PMID:40281637]."},"prefetch_data":{"uniprot":{"accession":"Q15326","full_name":"Zinc finger MYND domain-containing protein 11","aliases":["Adenovirus 5 E1A-binding protein","Bone morphogenetic protein receptor-associated molecule 1","Protein BS69"],"length_aa":602,"mass_kda":71.0,"function":"Chromatin reader that specifically recognizes and binds histone H3.3 trimethylated at 'Lys-36' (H3.3K36me3) and regulates RNA polymerase II elongation. Does not bind other histone H3 subtypes (H3.1 or H3.2) (By similarity). Colocalizes with highly expressed genes and functions as a transcription corepressor by modulating RNA polymerase II at the elongation stage. Binds non-specifically to dsDNA (PubMed:24675531). Acts as a tumor-suppressor by repressing a transcriptional program essential for tumor cell growth (Microbial infection) Inhibits Epstein-Barr virus EBNA2-mediated transcriptional activation and host cell proliferation, through direct interaction","subcellular_location":"Nucleus; Chromosome","url":"https://www.uniprot.org/uniprotkb/Q15326/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ZMYND11","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DYNLL1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ZMYND11","total_profiled":1310},"omim":[{"mim_id":"616083","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 30, WITH SPEECH DELAY AND BEHAVIORAL ABNORMALITIES; 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immunoprecipitation followed by sequencing (ChIP-seq), in vitro binding assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional validation and ChIP-seq genome-wide co-localization, single rigorous paper with multiple orthogonal methods\",\n      \"pmids\": [\"24590075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ZMYND11 functions as an unconventional transcriptional co-repressor by modulating RNA polymerase II at the elongation stage; genome-wide occupancy requires pre-deposition of H3.3K36me3 in gene bodies.\",\n      \"method\": \"ChIP-seq, RNA polymerase II elongation assays, loss-of-function experiments in cancer cells\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — ChIP-seq genome-wide analysis plus functional elongation assays with loss-of-function, moderate-to-strong evidence in a single rigorous study\",\n      \"pmids\": [\"24590075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ZMYND11 (BS69) associates with RNA splicing regulators including U5 snRNP components (e.g., EFTUD2) and promotes intron retention by antagonizing EFTUD2 through physical interaction; this regulation also depends on binding to H3K36me3-decorated chromatin.\",\n      \"method\": \"Co-immunoprecipitation, RNA sequencing, biochemical and genetic epistasis experiments\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, RNA-seq, and genetic rescue experiments across multiple orthogonal methods\",\n      \"pmids\": [\"25263594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"BS69 (ZMYND11) was identified as a nuclear phosphoprotein that interacts specifically with the conserved region 3 (CR3) of the adenovirus 5 289R E1A protein and inhibits E1A-mediated transcriptional transactivation; interaction was confirmed by co-immunoprecipitation in adenovirus-transformed 293 cells.\",\n      \"method\": \"Co-immunoprecipitation, transactivation reporter assays, yeast two-hybrid\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP in vivo plus functional transactivation assays; foundational discovery paper with high citation count\",\n      \"pmids\": [\"7621829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"BS69 mediates transcriptional repression at least in part through interaction with the co-repressor N-CoR via its MYND domain; expression of E1A inhibits repression mediated by BS69.\",\n      \"method\": \"Co-immunoprecipitation, transcriptional reporter assays, domain deletion analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and reporter assays, single lab with two orthogonal methods\",\n      \"pmids\": [\"10734313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The C-terminal MYND domain of BS69 binds to viral (E1A, EBNA2) and cellular (MGA) proteins through a conserved PXLXP motif; viral proteins compete with MGA for BS69 MYND binding in a PXLXP-dependent manner.\",\n      \"method\": \"GST pulldown, yeast two-hybrid, co-immunoprecipitation, mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro GST pulldown plus mutagenesis of PXLXP motif and competition assays; multiple orthogonal methods\",\n      \"pmids\": [\"11733528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"BS69 interacts with the carboxyl terminus of c-Myb via its MYND domain and inhibits c-Myb transcriptional activity in a dose-dependent manner; direct interaction was demonstrated in vitro, and 289R E1A can relieve BS69-mediated repression of c-Myb.\",\n      \"method\": \"Yeast two-hybrid, in vitro GST pulldown, transcriptional reporter assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro pulldown and reporter assays, single lab with two orthogonal methods\",\n      \"pmids\": [\"11244510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"BRAM1, an alternatively spliced isoform of BS69/ZMYND11, is localized to the cytoplasm (unlike nuclear BS69) and specifically binds to BMPR-IA (BMP type IA receptor) via its C-terminal half.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation in mammalian cells, subcellular localization by cell fractionation/immunofluorescence\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — yeast two-hybrid confirmed by Co-IP; direct localization experiment demonstrating cytoplasmic vs. nuclear isoform difference\",\n      \"pmids\": [\"9663660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"BS69's MYND domain acts as a specific adaptor bridging EBV LMP1 and TRAF6 to activate the JNK pathway; the MYND domain binds LMP1 C-terminus while a separate region binds TRAF6; LMP1 promotes the BS69-TRAF6 complex, and knockdown of BS69 specifically inhibits LMP1-induced JNK activation but not TNF-alpha-induced JNK activation.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, JNK kinase assays, chimeric protein rescue\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, siRNA knockdown with specific phenotypic readout, and chimeric protein rescue; multiple orthogonal methods\",\n      \"pmids\": [\"16382137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"BS69 associates with chromatin remodeling factors including ATP-dependent helicases, histone deacetylases, histone methyltransferases, and the transcription factor E2F6; BS69 is nuclear and associates with chromatin and mitotic chromosomes.\",\n      \"method\": \"Endogenous protein immunoprecipitation, mass spectrometry, chromatin fractionation, immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — endogenous protein IP with MS identification and direct localization by fractionation; single lab\",\n      \"pmids\": [\"16565076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"BS69 is involved in cellular senescence through the p53-p21Cip1 pathway; knockdown of BS69 in primary fibroblasts elevates p21Cip1 and induces premature senescence that is bypassed by knockdown of p53 or p21Cip1 (but not p16 or Rb); BS69 forms complexes with p53 and p400 and associates with the p21Cip1 promoter via p53.\",\n      \"method\": \"siRNA knockdown, double knockdown epistasis, chromatin immunoprecipitation, co-immunoprecipitation, senescence assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis by double knockdown, ChIP for promoter association, Co-IP for complex formation; multiple orthogonal methods\",\n      \"pmids\": [\"17721438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"BS69 undergoes SUMO modification; it interacts with SUMO E3 ligase PIAS1 and SUMO E2 enzyme Ubc9 through distinct domains, and PIAS1 significantly increases BS69 SUMOylation; the PHD domain is required for proper localization, sumoylation, and function of BS69.\",\n      \"method\": \"Co-immunoprecipitation, in vivo SUMOylation assay, domain mutant analysis, immunofluorescence\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and in vivo sumoylation assay with domain mutagenesis; single lab with multiple methods\",\n      \"pmids\": [\"19766626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"BS69 negatively regulates LMP1-mediated NF-κB activation by decreasing complex formation between LMP1 and TRADD; manipulation of BS69 expression modulates IκBα degradation and IL-6 production.\",\n      \"method\": \"siRNA knockdown, overexpression, co-immunoprecipitation, NF-κB reporter assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — IP showing disrupted LMP1-TRADD complex plus functional NF-κB reporter; single lab\",\n      \"pmids\": [\"19379743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"BS69 translocates from the nucleus to the cytoplasm upon dsRNA stimulation or TICAM-1 overexpression, where it is incorporated into the TICAM-1 signalosome complex and acts as a positive regulator of NF-κB and IRF-3 activation and IFN-β induction.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, confocal microscopy, siRNA knockdown, reporter assays\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, live confocal imaging of translocation, and siRNA knockdown with IFN-β readout; single lab\",\n      \"pmids\": [\"19795416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"BS69 directly interacts with the LMP1/CTAR1 domain and with TRAF3, and BS69-mediated suppression of LMP1/CTAR1-induced NF-κB activation requires TRAF3.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, NF-κB reporter assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP demonstrating direct interaction plus epistatic siRNA knockdown; single lab\",\n      \"pmids\": [\"20138174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The BS69 MYND domain folds as a ββα zinc binding domain (C4-C2HC topology); mutational analysis of charged residues flanking the MYND fold reveals they are required for binding to viral (E1A, EBNA2) and cellular partners, suggesting a distinct binding mode from related MYND domains.\",\n      \"method\": \"NMR structure (DEAF-1 MYND), homology modeling, mutagenesis, NMR titration binding assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure with mutagenesis binding validation; moderate evidence as BS69 itself modeled by homology\",\n      \"pmids\": [\"23372760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The BS69/ZMYND11 coiled-coil domain self-associates to bring two MYND domains into proximity, enhancing binding to EBNA2 PXLXP motifs; the CC-MYND homodimer synergistically binds the two PXLXP motifs in EBNA2 CR7 and CR8; EBNA2 also down-regulates BS69 expression in EBV-infected B cells.\",\n      \"method\": \"Crystal structure of CC-MYND/EBNA2 complex, ITC binding analysis, mutagenesis, reporter assays, ectopic expression experiments\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with ITC binding quantification and mutagenesis abolishing interaction; strong mechanistic evidence\",\n      \"pmids\": [\"26845565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ZMYND11 specifically interacts with ETS2 (but not ETS1) through the ETS2 N-terminus and attenuates ETS2 transcriptional activation, causing ETS2 to repress rather than activate a cell migration gene expression program; this interaction underlies the context-dependent oncogenic vs. tumor-suppressive function of ETS2.\",\n      \"method\": \"Co-immunoprecipitation, ETS1/ETS2 cistrome comparison (ChIP-seq), deletion mapping, reporter assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and ChIP-seq with functional reporter assays; single lab but multiple methods\",\n      \"pmids\": [\"28119415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Type 2 EBV EBNA2 contains a third PXLXP motif that allows binding of an additional BS69 CC-MYND dimer; SAXS shows three BS69CC-MYND dimers bind two molecules of type 2 EBNA2 TAD; mutation of the third BS69-binding motif in type 2 EBNA2 improved B-cell growth and transcriptional activation.\",\n      \"method\": \"Pull-down assays, small-angle X-ray scattering (SAXS), mutagenesis, transcriptional and B-cell growth assays\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — SAXS structural analysis with mutagenesis and functional validation in B-cell growth assay\",\n      \"pmids\": [\"31283782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MAGE-C2/HCA587 interacts with BS69 and promotes its ubiquitination and proteasomal degradation; knockdown of HCA587 increases BS69 protein levels, and overexpression of HCA587 enhances LMP1-induced NF-κB activation consistent with reduced BS69 levels.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, GST pulldown, ubiquitination assay, proteasome inhibitor treatment\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP/MS identification with ubiquitination assay and functional NF-κB readout; single lab\",\n      \"pmids\": [\"24866244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"BS69 inhibits ubiquitination of adenovirus E1A protein through its MYND domain; BS69 binding to E1A protects E1A from proteasomal degradation; MYND domain mutants that cannot bind E1A fail to inhibit E1A ubiquitination.\",\n      \"method\": \"In vivo ubiquitination assay, proteasome inhibitor experiments, MYND domain mutagenesis, co-immunoprecipitation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo ubiquitination assay with domain mutagenesis; single lab\",\n      \"pmids\": [\"16300738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The ZMYND11-MBTD1 fusion oncoprotein recruits the NuA4/TIP60 histone acetyltransferase complex to cis-regulatory elements of pro-leukemic genes via the ZMYND11 PWWP domain's H3K36me3 binding, sustaining active chromatin enriched in histone acetylation; both TIP60 interaction and the PWWP H3K36me3-binding are required for oncogenesis.\",\n      \"method\": \"ChIP-seq, ATAC-seq, systematic mutagenesis, co-immunoprecipitation, in vivo leukemia model, gene expression profiling\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — systematic mutagenesis, ChIP-seq, and in vivo leukemia model with multiple orthogonal methods; strong mechanistic evidence\",\n      \"pmids\": [\"33594072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ZMYND11-MBTD1 is stably incorporated into the endogenous NuA4/TIP60 complex, mislocalizing it to the bodies of genes normally bound by ZMYND11; this leads to increased chromatin acetylation and altered gene transcription including on MYC, and alternative splicing changes.\",\n      \"method\": \"Biochemical co-purification/Co-IP, ChIP-seq, RNA-seq, comparison to individual fusion partners\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP showing stable incorporation into endogenous complex, ChIP-seq for mislocalization, RNA-seq for functional consequences; multiple methods\",\n      \"pmids\": [\"35705031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZMYND11 exhibits a non-canonical function as a nonhistone methylation reader: its MYND domain recognizes arginine-194-methylated HNRNPA1, retaining HNRNPA1 in the nucleus and preventing stress granule formation in the cytoplasm; ZMYND11 also counteracts HNRNPA1-driven increases in PKM2/PKM1 ratio; PRMT5 inhibition disrupts the ZMYND11-HNRNPA1 interaction.\",\n      \"method\": \"Co-immunoprecipitation, domain mutagenesis, subcellular fractionation, in vitro and in vivo tumor assays, pharmacological PRMT5 inhibition\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with domain mutagenesis and subcellular localization experiments plus functional rescue; single lab\",\n      \"pmids\": [\"39341825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP53 deubiquitinase interacts with ZMYND11 via co-immunoprecipitation and catalyzes its deubiquitination and stabilization; the USP53 Cys-box domain (aa 33-50) is required for enzyme activity but not for ZMYND11 binding; loss of USP53 reduces ZMYND11 protein levels and promotes breast cancer cell growth.\",\n      \"method\": \"Co-immunoprecipitation, deubiquitination assay, loss-of-function and rescue experiments\",\n      \"journal\": \"Biological procedures online\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with in vivo deubiquitination assay and functional rescue; single lab\",\n      \"pmids\": [\"39044157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZMYND11 interacts with and inhibits the histone methyltransferase KMT2A (MLL1); a ZRSID-associated ZMYND11 point mutation abrogates this interaction; neuronal deletion of ZMYND11 causes upregulation of non-neuronal gene programs and reduced dendritic branching, effects attenuated by KMT2A inhibition with revumenib.\",\n      \"method\": \"Co-immunoprecipitation, point mutagenesis, degron-tagged mouse model, RNA-seq, dendritic morphology assay, pharmacological KMT2A inhibition\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with disease-associated mutagenesis plus in vivo degron model and pharmacological rescue; preprint, single lab\",\n      \"pmids\": [\"41279818\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZMYND11 regulates a brain-specific RNA isoform switch involving the splicing regulator RBFOX2; ZMYND11-deficient cortical neural stem cells upregulate inappropriate developmental pathways impairing neurogenesis, and similar splicing dysregulation is seen with other chromatin-related ASD risk genes.\",\n      \"method\": \"Human pluripotent stem cell differentiation model, RNA-seq, loss-of-function\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — human stem cell model with RNA-seq identifying RBFOX2-related isoform switch; single lab\",\n      \"pmids\": [\"41068108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Crystal structures of ZMYND11 WH, PHD, and CC-MYND domains reveal intermolecular zinc fingers (PHD domain) and redox-driven intermolecular disulfide bonds (CC-MYND domain) that regulate oligomeric state and substrate binding; the Bromo-PWWP domains cooperate with WH to bind nucleic acids and with PHD to bind histones; PHD and CC-MYND domains also interact with nucleic acid repair protein ALKBH6.\",\n      \"method\": \"Crystal structure determination, ITC, mutagenesis, co-immunoprecipitation\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple crystal structures with functional binding assays and Co-IP; rigorous structural and biochemical characterization\",\n      \"pmids\": [\"41591843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In mouse neurons, ZMYND11 deficiency leads to upregulation of non-neuronal gene programs, reduced dendritic branching and spine density, and hyperactivity/abnormal motor behavior; Zmynd11 deficiency in embryos impairs neurogenesis by decreasing Epha2 expression, increasing H3K36me3 on the Epha2 promoter, and disrupting PI3K signaling; restoration of PI3K via Epha2 rescues neurogenesis defects.\",\n      \"method\": \"Conditional neuronal knockout mouse, degron model, ChIP for H3K36me3, RNA Pol II ChIP, Epha2 rescue experiments, behavioral assays\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo mouse knockout with ChIP and molecular rescue; single lab\",\n      \"pmids\": [\"40281637\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ZMYND11 is a multidomain chromatin reader that specifically recognizes H3.3K36me3 via its tandem bromo-PWWP domains, localizes to gene bodies genome-wide, and acts as a transcriptional co-repressor by modulating RNA polymerase II elongation; it additionally regulates pre-mRNA splicing (promoting intron retention via antagonism of spliceosome component EFTUD2 and controlling a brain-specific RBFOX2-dependent isoform switch), suppresses cellular senescence through the p53-p21Cip1 pathway, modulates NF-κB and JNK signaling through its MYND domain interactions with viral (LMP1) and cellular (TRAF6, TRAF3) proteins, undergoes SUMO modification via PIAS1 and is stabilized by the deubiquitinase USP53, inhibits the histone methyltransferase KMT2A, and reads arginine-methylated non-histone substrates (e.g., HNRNPA1-R194me) to control stress granule formation and tumor suppression.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ZMYND11 (BS69) is a multidomain chromatin reader and transcriptional co-repressor that couples histone variant–specific recognition to regulation of transcription elongation, RNA splicing, and signaling. Its tandem bromo-PWWP domains form a composite pocket that specifically recognizes H3.3K36me3 via the H3.3-unique Ser31 residue, directing ZMYND11 to active gene bodies where it modulates RNA polymerase II elongation and promotes intron retention by antagonizing the spliceosome component EFTUD2 [PMID:24590075, PMID:25263594]. The C-terminal MYND domain, which folds as a ββα zinc-binding module and functions as a homodimer via the coiled-coil region, serves as a protein–protein interaction hub that engages PXLXP-motif partners (E1A, EBNA2, MGA), co-repressor N-CoR, TRAF6/TRAF3 to modulate NF-κB and JNK signaling, the histone methyltransferase KMT2A whose inhibition it mediates, and arginine-methylated nonhistone substrates such as HNRNPA1 to control stress granule formation [PMID:11733528, PMID:26845565, PMID:16382137, PMID:39341825, PMID:41279818]. ZMYND11 suppresses cellular senescence through the p53–p21Cip1 axis, regulates brain-specific RBFOX2-dependent splicing programs essential for neurogenesis and dendritic morphogenesis, and its loss in neurons causes upregulation of non-neuronal genes and behavioral abnormalities [PMID:17721438, PMID:41068108, PMID:40281637].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"The initial identification of BS69/ZMYND11 as a nuclear phosphoprotein that binds adenovirus E1A CR3 and inhibits E1A-mediated transactivation established it as a transcriptional repressor.\",\n      \"evidence\": \"Co-IP from adenovirus-transformed 293 cells plus transactivation reporter assays and yeast two-hybrid\",\n      \"pmids\": [\"7621829\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous target genes unknown\", \"Mechanism of repression unresolved\", \"Physiological relevance beyond viral context unclear\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Discovery of the cytoplasmic isoform BRAM1, which binds BMP receptor IA, revealed that alternative splicing generates isoforms with distinct subcellular localization and potentially different signaling functions.\",\n      \"evidence\": \"Yeast two-hybrid with Co-IP in mammalian cells; subcellular fractionation and immunofluorescence\",\n      \"pmids\": [\"9663660\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of BRAM1–BMPR-IA interaction on BMP signaling not demonstrated\", \"Tissue-specific expression of isoforms not characterized\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Mapping the MYND domain as the binding interface for a conserved PXLXP motif shared by viral (E1A, EBNA2) and cellular (MGA) partners established a general recognition mechanism and revealed that viral oncoproteins hijack a host protein–protein interaction surface.\",\n      \"evidence\": \"GST pulldown, yeast two-hybrid, Co-IP, and PXLXP mutagenesis with competition assays; interaction with N-CoR via MYND domain and repression of c-Myb\",\n      \"pmids\": [\"11733528\", \"10734313\", \"11244510\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of MYND–PXLXP recognition not yet determined\", \"Full complement of cellular PXLXP partners unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstration that BS69 bridges EBV LMP1 to TRAF6 to specifically activate JNK signaling, and association with chromatin-remodeling complexes and E2F6, broadened its role from simple repressor to a signal-transduction adaptor and chromatin organizer.\",\n      \"evidence\": \"Reciprocal Co-IP, siRNA knockdown with JNK kinase assay and chimeric rescue; endogenous IP–mass spectrometry and chromatin fractionation\",\n      \"pmids\": [\"16382137\", \"16565076\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural mechanism of TRAF6 bridging unclear\", \"Whether chromatin-associated complexes are functionally distinct from signaling complexes not tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Linking BS69 to cellular senescence through the p53–p21Cip1 pathway provided the first endogenous physiological function, showing that BS69 forms complexes with p53 and p400 on the p21 promoter to suppress premature senescence.\",\n      \"evidence\": \"siRNA and double-knockdown epistasis, ChIP at p21 promoter, Co-IP with p53 and p400, senescence assays in primary fibroblasts\",\n      \"pmids\": [\"17721438\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether BS69 directly represses p21 transcription or acts through p400 remodeling not resolved\", \"Relevance to in vivo aging or tumor suppression not tested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Multiple studies established that BS69 modulates NF-κB signaling (both LMP1-induced and TICAM-1/dsRNA-induced pathways) and undergoes SUMO modification by PIAS1, revealing post-translational regulation and context-dependent pro- or anti-inflammatory roles.\",\n      \"evidence\": \"Co-IP, NF-κB and IFN-β reporter assays, siRNA, confocal imaging of nuclear-cytoplasmic translocation; in vivo SUMOylation assay with domain mutagenesis\",\n      \"pmids\": [\"19379743\", \"19795416\", \"19766626\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How SUMOylation affects BS69 transcriptional or signaling activity not determined\", \"Opposing effects on NF-κB in different contexts not mechanistically reconciled\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Crystal structure and ChIP-seq demonstrated that ZMYND11 is a histone-variant-specific reader recognizing H3.3K36me3 through a composite bromo-PWWP pocket encapsulating H3.3 Ser31, and that this recognition directs it to gene bodies to modulate Pol II elongation and RNA splicing (intron retention via EFTUD2 antagonism), establishing its core chromatin-based mechanism.\",\n      \"evidence\": \"Crystal structure, ChIP-seq, in vitro binding assays, RNA-seq, Co-IP with U5 snRNP/EFTUD2, genetic epistasis\",\n      \"pmids\": [\"24590075\", \"25263594\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How H3.3K36me3 binding is mechanistically linked to Pol II pausing/elongation not fully elucidated\", \"Genome-wide determinants of which genes are repressed vs. spliced unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Crystal structure of the CC-MYND homodimer bound to EBNA2 PXLXP motifs revealed that coiled-coil-mediated dimerization brings two MYND domains into proximity for synergistic bivalent binding, providing a structural explanation for high-affinity target recognition.\",\n      \"evidence\": \"Crystal structure of CC-MYND/EBNA2 complex, ITC binding quantification, mutagenesis, reporter assays\",\n      \"pmids\": [\"26845565\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether dimerization similarly enhances binding to all cellular PXLXP partners untested\", \"Regulation of dimer formation not addressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Studies of the ZMYND11-MBTD1 leukemia fusion showed that the ZMYND11 PWWP domain's H3K36me3 reading function is co-opted to mislocalize the NuA4/TIP60 acetyltransferase complex to gene bodies, driving aberrant chromatin acetylation and pro-leukemic gene expression.\",\n      \"evidence\": \"ChIP-seq, ATAC-seq, systematic mutagenesis, Co-IP, in vivo leukemia model; biochemical co-purification confirming stable incorporation into endogenous NuA4/TIP60\",\n      \"pmids\": [\"33594072\", \"35705031\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether wild-type ZMYND11 normally opposes NuA4/TIP60 at gene bodies not tested\", \"Patient-relevant therapeutic vulnerabilities not fully defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Discovery that the MYND domain reads arginine-methylated HNRNPA1 (R194me, deposited by PRMT5) extended ZMYND11 from a histone reader to a nonhistone methylation reader, linking it to stress granule suppression and PKM splicing regulation in tumor suppression.\",\n      \"evidence\": \"Co-IP, domain mutagenesis, subcellular fractionation, in vitro and in vivo tumor assays, pharmacological PRMT5 inhibition\",\n      \"pmids\": [\"39341825\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Breadth of nonhistone methylated substrates recognized by MYND domain unknown\", \"In vivo relevance of stress granule regulation not confirmed in animal models\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"ZMYND11 was shown to inhibit the histone methyltransferase KMT2A, regulate RBFOX2-dependent brain-specific splicing, and control neurogenesis via EPHA2-PI3K signaling; neuronal loss causes dendritic defects and behavioral abnormalities linked to neurodevelopmental disorder (ZRSID).\",\n      \"evidence\": \"Co-IP with disease-associated mutagenesis, degron-tagged and conditional knockout mouse models, RNA-seq, ChIP, pharmacological KMT2A inhibition with revumenib, human cortical organoid differentiation\",\n      \"pmids\": [\"41279818\", \"41068108\", \"40281637\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Precise molecular mechanism of KMT2A inhibition not structurally resolved\", \"Whether splicing and KMT2A-regulation are independent or linked pathways unclear\", \"PMID:41279818 is a preprint awaiting peer review\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Comprehensive structural characterization revealed that PHD domain intermolecular zinc fingers and CC-MYND redox-driven disulfide bonds regulate oligomeric state and substrate binding, with the WH domain contributing to nucleic acid binding and PHD/CC-MYND domains interacting with the nucleic acid repair protein ALKBH6.\",\n      \"evidence\": \"Multiple crystal structures, ITC, mutagenesis, Co-IP\",\n      \"pmids\": [\"41591843\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional significance of ALKBH6 interaction not established in cells\", \"How redox sensing regulates ZMYND11 function in vivo unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major unresolved questions include how ZMYND11's chromatin-reading, splicing-regulatory, signaling-adaptor, and nonhistone-reader functions are coordinated in different cell types, the full repertoire of arginine-methylated substrates, and the precise molecular mechanism by which H3.3K36me3 binding is transduced into Pol II elongation control.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Integration of chromatin, splicing, and signaling functions not mechanistically unified\", \"Structural basis of Pol II elongation modulation unknown\", \"Complete interactome of arginine-methylated nonhistone substrates not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [0, 1, 21, 27]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 3, 4, 6, 10, 17]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [8, 14]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 25]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [27]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 7, 9, 11]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [7, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 4, 6, 17]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 9, 21, 22]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [2, 26]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 12, 13, 14]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [26, 28]}\n    ],\n    \"complexes\": [\n      \"NuA4/TIP60 (via ZMYND11-MBTD1 fusion)\"\n    ],\n    \"partners\": [\n      \"EFTUD2\",\n      \"EBNA2\",\n      \"TRAF6\",\n      \"TRAF3\",\n      \"KMT2A\",\n      \"HNRNPA1\",\n      \"PIAS1\",\n      \"USP53\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}