{"gene":"ZMYND11","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":1995,"finding":"BS69/ZMYND11 specifically interacts with adenovirus 5 E1A (289R) protein, requiring the region unique to the large E1A protein for high-affinity binding, and co-immunoprecipitates with E1A in adenovirus-transformed 293 cells; BS69 specifically inhibits transactivation by the 289R E1A protein but not the 243R E1A protein.","method":"Yeast two-hybrid, co-immunoprecipitation, reporter gene transcription assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP in vivo and reporter assay with defined domain requirements, founding paper replicated by multiple subsequent studies","pmids":["7621829"],"is_preprint":false},{"year":2000,"finding":"BS69/ZMYND11 represses transcription at least in part through interaction with the co-repressor N-CoR; this interaction is mediated by the MYND domain in the BS69 C-terminus. Expression of E1A inhibits BS69-mediated repression.","method":"Co-immunoprecipitation, reporter gene transcription assay, domain deletion analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction mapped by domain deletions, transcriptional repression assay, single lab","pmids":["10734313"],"is_preprint":false},{"year":1998,"finding":"BRAM1, an alternatively spliced form of BS69/ZMYND11, localizes to the cytoplasm (whereas BS69 is nuclear) and specifically binds the BMP type IA receptor (BMPR-IA); the C-terminal half of BRAM1 is sufficient for BMPR-IA binding.","method":"Yeast two-hybrid, co-immunoprecipitation, subcellular localization by cell fractionation/imaging","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid and co-IP in mammalian cells with domain mapping, single lab","pmids":["9663660"],"is_preprint":false},{"year":2001,"finding":"The C-terminal MYND domain of BS69/ZMYND11 binds the Epstein-Barr virus oncoprotein EBNA2 and the Myc-related cellular protein MGA through a common PXLXP motif present in all three binding partners; viral proteins compete with MGA for BS69 binding in a PXLXP-dependent manner.","method":"Co-immunoprecipitation, GST pull-down, mutagenesis of PXLXP motif","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct binding mapped by mutagenesis and confirmed by pull-down; replicated in multiple subsequent structural studies","pmids":["11733528"],"is_preprint":false},{"year":2001,"finding":"BS69/ZMYND11 interacts with the carboxy-terminal negative regulatory domain of c-Myb and inhibits c-Myb transcriptional activity in a dose-dependent manner; the 289R E1A protein can inhibit BS69-mediated repression of c-Myb; direct in vitro interaction between BS69 and c-Myb was demonstrated.","method":"Yeast two-hybrid, in vitro binding, reporter gene assay, domain mapping","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro direct interaction plus cell-based reporter assay, domain mapping, single lab","pmids":["11244510"],"is_preprint":false},{"year":2002,"finding":"BRAM1 associates with EBV LMP1 (via the MYND domain of BRAM1 and the CTAR2 region of LMP1) both in vitro and in vivo, and interferes with LMP1-mediated NF-κB activation; BRAM1 also interferes with TNF-α-induced NF-κB activation by targeting IκBα molecules.","method":"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, confocal microscopy, reporter gene assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (pulldown, co-IP, confocal) in single lab","pmids":["12181323"],"is_preprint":false},{"year":2005,"finding":"EMSY binds directly to BS69/ZMYND11 via a conserved motif adjacent to its ENT domain; the crystal structure of EMSY residues 1–108 shows the HP1β/BS69-binding motif in an extended peptide conformation; HP1β chromoshadow domain (CSD) forms a complex with EMSY.","method":"Crystal structure (2.0 Å), NMR, biophysical analysis (ITC/analytical ultracentrifugation)","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — crystal structure from EMSY side, direct binding confirmed, but structural/functional characterization is of the EMSY-HP1 interaction; BS69 binding inferred from motif analysis rather than direct structural study of BS69 itself","pmids":["15947784"],"is_preprint":false},{"year":2005,"finding":"BS69/ZMYND11 inhibits ubiquitination of adenovirus E1A protein and stabilizes E1A in vivo; this inhibition requires the MYND domain, which mediates E1A binding; BS69 mutants lacking the MYND domain cannot bind E1A and cannot inhibit its ubiquitination.","method":"In vivo ubiquitination assay, co-immunoprecipitation, domain deletion mutagenesis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination assay plus domain mutagenesis, single lab","pmids":["16300738"],"is_preprint":false},{"year":2006,"finding":"BS69/ZMYND11 is a specific adaptor bridging EBV LMP1 and TRAF6 in the LMP1-induced JNK pathway; the MYND domain and a separate region of BS69 bind LMP1 and TRAF6 C-termini, respectively; LMP1 promotes BS69-TRAF6 complex formation; a fraction of LMP1 and BS69 co-localizes in membrane lipid rafts; knockdown of BS69 specifically inhibits LMP1-induced JNK activation but not TNF-α-induced JNK activation.","method":"Co-immunoprecipitation, siRNA knockdown, chimeric protein overexpression, lipid raft fractionation, JNK activation assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods including siRNA, chimeric rescue, co-IP and lipid raft fractionation, specific pathway assignment","pmids":["16382137"],"is_preprint":false},{"year":2006,"finding":"Full-length BS69/ZMYND11 is a nuclear protein that associates with chromatin and mitotic chromosomes; it interacts with chromatin remodeling factors including ATP-dependent helicases, histone deacetylases, and histone methyltransferases, as well as the E2F6 transcription factor.","method":"Endogenous antibody-based chromatin fractionation, co-immunoprecipitation, immunofluorescence","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — endogenous protein studied with validated antibody, multiple co-IP interactions, single lab","pmids":["16565076"],"is_preprint":false},{"year":2007,"finding":"BS69/ZMYND11 knockdown in primary human fibroblasts induces premature senescence via the p53-p21Cip1 pathway; BS69 forms complexes with both p53 and p400, and associates with the p21Cip1 promoter through p53; knockdown of p53 or p21Cip1, but not p16INK4a or Rb, rescues premature senescence induced by BS69 knockdown.","method":"RNA interference knockdown, senescence marker assays (SA-β-gal, SAHF), co-immunoprecipitation, chromatin immunoprecipitation, epistasis by double knockdown","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — pathway placement by genetic epistasis (double KD rescue), ChIP on p21 promoter, co-IP of complex, multiple orthogonal methods","pmids":["17721438"],"is_preprint":false},{"year":2009,"finding":"BS69/ZMYND11 negatively regulates LMP1-mediated NF-κB activation; BS69 manipulation decreases complex formation between LMP1 and TRADD, thus dampening IκBα degradation and IL-6 upregulation.","method":"Co-immunoprecipitation, siRNA-mediated knockdown, NF-κB reporter assay, IL-6 mRNA measurement","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic link via co-IP showing disruption of LMP1-TRADD complex, single lab","pmids":["19379743"],"is_preprint":false},{"year":2009,"finding":"BS69/ZMYND11 is SUMOylated; it interacts with SUMO E3 ligase PIAS1 and the SUMO E2 enzyme Ubc9 through distinct regions, and PIAS1 significantly enhances BS69 SUMO modification; the PHD domain is required for BS69 localization, sumoylation, and inhibitory function in muscle and neuronal differentiation.","method":"Co-immunoprecipitation, SUMO modification assay, domain deletion mutagenesis, differentiation reporter assay","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical SUMO assay with E3 ligase, domain mutagenesis, single lab","pmids":["19766626"],"is_preprint":false},{"year":2009,"finding":"BS69/ZMYND11 translocates from the nucleus to the cytoplasm upon dsRNA stimulation or TICAM-1 overexpression, is recruited to TICAM-1 signaling speckles, and positively regulates NF-κB/IRF-3 activation and IFN-β production downstream of TLR3-TICAM-1; knockdown of BS69 reduces IFN-β induction.","method":"Yeast two-hybrid, co-immunoprecipitation, confocal microscopy, siRNA knockdown, cytokine induction assay","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — nuclear-to-cytoplasmic translocation shown by confocal, co-IP interaction, and siRNA phenotype, single lab","pmids":["19795416"],"is_preprint":false},{"year":2010,"finding":"BS69/ZMYND11 directly interacts with LMP1/CTAR1 domain and with TRAF3 (a negative regulator of NF-κB); BS69 and TRAF3 cooperate to suppress LMP1/CTAR1-mediated NF-κB activation and IL-6 production; siRNA knockdown of TRAF3 impairs BS69-mediated suppression.","method":"Co-immunoprecipitation, siRNA knockdown, NF-κB reporter assay, IL-6 measurement","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP interaction mapped, genetic epistasis by double siRNA, single lab","pmids":["20138174"],"is_preprint":false},{"year":2013,"finding":"The BS69 MYND domain adopts a ββα fold with tandem zinc-binding sites in a cross-brace topology (characterized by homology modeling and mutational analysis); interactions of BS69 MYND with viral and cellular binding partners require distinct charged residues flanking the predicted MYND domain fold, suggesting a different binding mode from AML1/ETO.","method":"NMR structure determination (DEAF-1 MYND), homology modeling plus mutational analysis (BS69 MYND), NMR titration mapping","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — NMR structure of related MYND plus mutagenesis of BS69 MYND, single lab; BS69 itself not solved by NMR","pmids":["23372760"],"is_preprint":false},{"year":2014,"finding":"ZMYND11 specifically recognizes H3K36me3 on the histone variant H3.3 (H3.3K36me3) via its PWWP domain aromatic cage; H3.3-specific recognition additionally requires encapsulation of the H3.3-specific Ser31 residue in a composite pocket formed by the tandem bromo-PWWP domains. ZMYND11 co-localizes genome-wide with H3K36me3 and H3.3 in gene bodies and its chromatin occupancy requires pre-deposited H3.3K36me3. ZMYND11 functions as a transcription co-repressor by modulating RNA Pol II at the elongation stage.","method":"Crystal structure (bromo-PWWP-H3.3K36me3 peptide complex), ChIP-seq, RNA Pol II elongation assay, loss-of-function with tumor growth readout","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation, genome-wide ChIP-seq, multiple orthogonal methods, replicated by concurrent paper (PMID:25263594)","pmids":["24590075"],"is_preprint":false},{"year":2014,"finding":"BS69/ZMYND11 selectively recognizes H3.3K36me3 via its chromatin-binding PHD-BROMO-PWWP domains; it associates with U5 snRNP components of the spliceosome including EFTUD2; BS69 promotes intron retention by antagonizing EFTUD2 through physical interaction; this splicing regulatory function depends on BS69 binding to H3K36me3-decorated chromatin.","method":"Biochemical pulldown, co-immunoprecipitation, RNA-seq, genetic epistasis (BS69 KD + EFTUD2 overexpression), ChIP","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (co-IP, RNA-seq, rescue genetics, ChIP), novel function independently established, concurrent with PMID:24590075","pmids":["25263594"],"is_preprint":false},{"year":2014,"finding":"The cancer-testis antigen HCA587/MAGE-C2 interacts with BS69/ZMYND11 and promotes its ubiquitination and proteasomal degradation; knockdown of endogenous HCA587 increases BS69 protein levels; HCA587 overexpression enhances LMP1-induced IL-6 production consistent with loss of BS69 function.","method":"Mass spectrometry identification, co-immunoprecipitation, GST pull-down, ubiquitination assay, siRNA knockdown, IL-6 measurement","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination assay and co-IP confirmed by MS, single lab","pmids":["24866244"],"is_preprint":false},{"year":2016,"finding":"The C-terminal coiled-coil-MYND (CC-MYND) domains of BS69/ZMYND11 form a homodimer via coiled-coil self-association, which brings two MYND domains in close proximity to synergistically bind two PXLXP motifs in EBNA2 (CR7 and CR8); ectopic BS69 CC-MYND is recruited to viral promoters via EBNA2, inhibits EBNA2-mediated transactivation, and impairs lymphoblastoid cell line proliferation; MYND domain mutations that abolish EBNA2 binding also abolish inhibitory activity.","method":"Crystal structure, ITC, chromatin immunoprecipitation, reporter assay, cell proliferation assay, site-directed mutagenesis","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus ITC quantitative binding, mutagenesis, ChIP, and functional assay in single rigorous study","pmids":["26845565"],"is_preprint":false},{"year":2017,"finding":"ZMYND11 interacts with ETS2 (but not ETS1) through the ETS2 N-terminus and acts as a co-repressor to attenuate ETS2-mediated transcriptional activation, enabling ETS2 to suppress a cell migration gene expression program; this specific interaction accounts for the opposing functions of ETS1 (oncogenic) and ETS2 (tumor suppressive) at shared genomic binding sites.","method":"Co-immunoprecipitation, deletion mapping, ChIP-seq cistrome comparison, reporter gene assay, cell migration assay","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP interaction mapped, cistrome analysis, functional migration assay, single lab","pmids":["28119415"],"is_preprint":false},{"year":2018,"finding":"In zebrafish, the MYND domain of Bs69/Zmynd11 binds the kinase domain of Bmpr1a and interferes with Bmpr1a phosphorylation and activation of Smad1/5/8; cytoplasmic Mga antagonizes Bs69 by disrupting the Bs69-Bmpr1a association, thereby facilitating BMP signaling for ventral tailfin cell fate specification.","method":"TALEN/CRISPR-Cas9 loss-of-function, co-immunoprecipitation, phosphorylation assay (Smad1/5/8), domain mapping","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function plus biochemical co-IP and phosphorylation assay, single lab, zebrafish model","pmids":["30324105"],"is_preprint":false},{"year":2019,"finding":"Type 2 EBV EBNA2 contains a third conserved PXLXP motif absent in type 1 EBNA2, enabling it to bind an additional BS69 CC-MYND molecule; SAXS shows three BS69 CC-MYND dimers bound to two molecules of type 2 EBNA2 TAD; mutation of the third BS69-binding motif in type 2 EBNA2 improves B-cell growth and transcriptional activation, indicating that increased BS69 association restricts type 2 EBNA2 function.","method":"Pull-down, SAXS (low-resolution structure), molecular weight analysis, mutagenesis, B-cell growth assay, gene expression assay","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — SAXS structural data plus mutagenesis and functional rescue in single rigorous study","pmids":["31283782"],"is_preprint":false},{"year":2021,"finding":"The ZMYND11-MBTD1 (ZM) fusion protein recruits the NuA4/TIP60 histone acetyltransferase complex to cis-regulatory elements of pro-leukemic genes (Hoxa, Meis1, Myb, Myc, Sox4), sustaining active chromatin enriched in histone acetylation and devoid of repressive marks; both the TIP60 interaction and the H3K36me3-binding PWWP domain of ZMYND11 are required for ZM oncogenic function.","method":"Murine hematopoietic stem/progenitor cell transformation assay, in vivo AML model, ChIP-seq, systematic domain mutagenesis, co-immunoprecipitation, bromodomain inhibitor treatment","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic mutagenesis, co-IP, ChIP-seq, in vivo model, and pharmacological inhibition, multiple orthogonal methods in single study","pmids":["33594072"],"is_preprint":false},{"year":2022,"finding":"ZMYND11-MBTD1 fusion is stably incorporated into the endogenous NuA4/TIP60 complex, leading to its mislocalization to gene bodies normally occupied by ZMYND11; this causes increased chromatin acetylation and altered transcription (notably at the MYC oncogene) and alternative splicing; ZMYND11-MBTD1 favors MYC-driven pluripotency and self-renewal of hematopoietic stem/progenitor cells.","method":"Biochemical complex purification, ChIP-seq, RNA-seq, alternative splicing analysis, embryonic stem cell differentiation assay, hematopoietic progenitor self-renewal assay","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — biochemical purification plus genomics and functional assays in multiple cell systems, single lab but multiple orthogonal methods","pmids":["35705031"],"is_preprint":false},{"year":2024,"finding":"ZMYND11 binds arginine-194-methylated HNRNPA1 via its MYND domain, retaining HNRNPA1 in the nucleus and preventing stress granule formation in the cytoplasm; ZMYND11 counteracts HNRNPA1-driven increase in the PKM2/PKM1 ratio; PRMT5 inhibition disrupts ZMYND11 recognition of methylated HNRNPA1.","method":"Co-immunoprecipitation, domain mutagenesis (MYND), stress granule imaging, PKM2/PKM1 ratio assay, PRMT5 inhibitor treatment, in vitro tumor formation assay","journal":"Signal transduction and targeted therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with domain mapping, functional stress granule assay, pharmacological disruption, single lab","pmids":["39341825"],"is_preprint":false},{"year":2024,"finding":"USP53 deubiquitylase interacts with ZMYND11 and catalyzes its deubiquitination and stabilization; the USP53 Cys-box domain (aa 33-50) is required for enzyme activity but not for ZMYND11 binding; USP53 anti-tumor effects in breast cancer cells are partially mediated through ZMYND11.","method":"Co-immunoprecipitation, ubiquitination assay, domain deletion analysis, gain/loss-of-function rescue experiments, xenograft model","journal":"Biological procedures online","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus ubiquitination assay and rescue genetics, single lab","pmids":["39044157"],"is_preprint":false},{"year":2025,"finding":"ZMYND11 deficiency in mouse neurons causes aberrant upregulation of non-neuronal gene programs leading to reduced dendritic branching and spine density; ZMYND11 interacts with and inhibits histone methyltransferase KMT2A (MLL1); a ZRSID-associated ZMYND11 point mutation abolishes KMT2A interaction; gene expression changes from ZMYND11 loss are attenuated by KMT2A inhibitor revumenib.","method":"Neuronal-specific conditional knockout, co-immunoprecipitation, point mutagenesis, pharmacological KMT2A inhibition (revumenib), dendritic morphology assay, RNA-seq","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus mutagenesis of disease variant, conditional KO phenotype, pharmacological rescue; preprint, not yet peer-reviewed","pmids":["41279818"],"is_preprint":true},{"year":2025,"finding":"ZMYND11 deficiency in cortical neural stem cells upregulates latent developmental pathways impairing progenitor and neuron production; beyond chromatin, ZMYND11 controls a brain-specific RNA isoform switch involving the splicing regulator RBFOX2.","method":"Human pluripotent stem cell cortical differentiation model, ZMYND11 loss-of-function, RNA-seq, splicing isoform analysis","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — hPSC model with RNA-seq and splicing analysis, single study, functional neurogenesis readout","pmids":["41068108"],"is_preprint":false},{"year":2025,"finding":"Zmynd11 deficiency decreases Epha2 expression and disrupts PI3K signaling; under Zmynd11 deficiency, H3K36me3 modification on the Epha2 promoter abnormally increases while RNA Pol II binding decreases; restoration of PI3K signaling via exogenous Epha2 rescues aberrant neurogenesis caused by Zmynd11 depletion in vitro and in vivo.","method":"Mouse knockout model, ChIP (H3K36me3, Pol II), Epha2 rescue overexpression, neurosphere/neurogenesis assay","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, rescue genetics, in vivo KO, single lab","pmids":["40281637"],"is_preprint":false},{"year":2026,"finding":"Crystal structures of ZMYND11 winged helix (WH), PHD, and coiled-coil-MYND (CC-MYND) domains reveal intermolecular zinc finger bonds in the PHD domain and intermolecular disulfide bonds in the CC domain; oligomeric state of PHD is pH-dependent and redox state of CC impairs binding; Bromo-PWWP domains cooperate with the WH domain and PHD domain to bind nucleic acids and histones respectively; both PHD and CC-MYND domains interact with nucleic acid repair protein ALKBH6.","method":"Crystal structure determination, ITC, mutagenesis, co-immunoprecipitation (ALKBH6 interaction)","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple crystal structures plus ITC and co-IP; single lab but multiple orthogonal structural and biochemical methods","pmids":["41591843"],"is_preprint":false},{"year":2026,"finding":"Using CUT&Tag, ZMYND11 was found to robustly occupy promoter regions (not only gene bodies) in mouse ESCs and MEFs, with occupancy positively correlating with gene expression and Pol II occupancy; ZMYND11 deficiency reduces the Pol II pausing index, H3.3 occupancy, and H3K36me3 at genes, indicating impaired transcription initiation; ZMYND11 knockout induces transcriptomic changes, impairs cell proliferation, and aberrantly activates 2-cell-specific transcriptional programs via ROS accumulation.","method":"CUT&Tag, ChIP-seq comparison, Pol II pausing index analysis, RNA-seq, cell proliferation assay, ROS measurement","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CUT&Tag vs ChIP-seq comparison with functional KO, multiple genomic readouts, single lab","pmids":["42262664"],"is_preprint":false}],"current_model":"ZMYND11/BS69 is a multidomain chromatin reader (PHD-BROMO-PWWP tandem) that specifically recognizes H3.3K36me3 on the histone variant H3.3 in gene bodies and promoters, where it functions as a transcriptional co-repressor by restraining RNA Pol II elongation and stabilizing Pol II pausing at promoters; it additionally connects H3.3K36me3-marked chromatin to regulated pre-mRNA splicing (promoting intron retention by antagonizing EFTUD2 and controlling a RBFOX2-dependent brain-specific isoform switch); its MYND domain recruits co-repressors (N-CoR) and mediates binding to viral (E1A, EBNA2, LMP1) and cellular (c-Myb, MGA, ETS2, HNRNPA1-R194me, KMT2A) partners through PXLXP or arginine-methylation motifs; it is regulated post-translationally by PIAS1-mediated SUMOylation, MAGE-C2-driven ubiquitin-proteasomal degradation, and USP53-mediated deubiquitination/stabilization; in the nucleus it forms complexes with p53 and p400 to suppress the p53-p21Cip1 senescence pathway; its alternatively spliced cytoplasmic isoform BRAM1 binds and inhibits BMPR-IA to modulate BMP-Smad signaling; the oncogenic ZMYND11-MBTD1 fusion aberrantly recruits the NuA4/TIP60 acetyltransferase complex to gene bodies, driving leukemogenesis."},"narrative":{"mechanistic_narrative":"ZMYND11 (BS69/BRAM1) is a multidomain chromatin reader that couples a specific histone modification state to transcriptional repression, co-transcriptional splicing, and tumor suppression [PMID:24590075, PMID:25263594]. Through a tandem PHD-bromo-PWWP module it selectively recognizes H3K36me3 deposited on the histone variant H3.3, with H3.3 specificity enforced by encapsulation of the H3.3-unique Ser31 residue in a composite pocket formed across the bromo and PWWP domains [PMID:24590075]. At H3.3K36me3-marked gene bodies and promoters ZMYND11 acts as a transcriptional co-repressor, restraining RNA Pol II elongation, supporting Pol II pausing, and sustaining proper transcription initiation; its loss reduces the Pol II pausing index and disrupts H3.3/H3K36me3 occupancy at target genes [PMID:24590075, PMID:42262664]. The same H3K36me3-dependent chromatin engagement directs a splicing function: ZMYND11 associates with U5 snRNP components including EFTUD2 and promotes intron retention by antagonizing EFTUD2, and it governs a brain-specific RBFOX2-dependent isoform switch [PMID:25263594, PMID:41068108]. A second functional surface is the C-terminal coiled-coil-MYND module, which homodimerizes and recruits binding partners through PXLXP motifs or arginine-methylation marks: it binds the co-repressor N-CoR and the cellular repressors MGA, c-Myb, and ETS2, the methyl-mark on R194 of HNRNPA1, and the histone methyltransferase KMT2A, and it is also the docking site for viral oncoproteins (adenovirus E1A, EBV EBNA2 and LMP1) [PMID:10734313, PMID:11733528, PMID:11244510, PMID:26845565, PMID:28119415, PMID:39341825, PMID:41279818]. In the nucleus ZMYND11 forms complexes with p53 and p400 and associates with the p21Cip1 promoter through p53 to restrain the p53-p21Cip1 senescence pathway [PMID:17721438]. ZMYND11 protein abundance is set by competing modifications — PIAS1-enhanced SUMOylation, MAGE-C2/HCA587-driven ubiquitin-proteasomal degradation, and USP53-mediated deubiquitination and stabilization [PMID:19766626, PMID:24866244, PMID:39044157]. A distinct cytoplasmic splice isoform, BRAM1, binds the BMP type IA receptor through its MYND domain and inhibits BMPR-IA activation of Smad signaling [PMID:9663660, PMID:30324105]. Loss of ZMYND11 in neurons and neural progenitors derepresses non-neuronal and latent developmental gene programs and impairs neurogenesis, a defect linked to KMT2A inhibition and to Epha2/PI3K signaling, and a ZRSID-associated point mutation abolishes the ZMYND11-KMT2A interaction [PMID:41279818, PMID:41068108, PMID:40281637]. The oncogenic ZMYND11-MBTD1 fusion subverts these activities by stably incorporating into the NuA4/TIP60 acetyltransferase complex and mislocalizing it to ZMYND11-bound gene bodies and cis-regulatory elements, driving aberrant acetylation and MYC-driven self-renewal in leukemogenesis, dependent on both the TIP60 interaction and the H3K36me3-binding PWWP domain [PMID:33594072, PMID:35705031].","teleology":[{"year":1995,"claim":"Established ZMYND11/BS69 as a binding partner and functional antagonist of a viral oncoprotein, the first clue to its role in transcriptional control.","evidence":"Yeast two-hybrid, reciprocal co-IP, and reporter assay with adenovirus E1A in transformed cells","pmids":["7621829"],"confidence":"High","gaps":["No endogenous cellular function identified","Binding domain on BS69 not yet mapped","Mechanism of transactivation inhibition unknown"]},{"year":2000,"claim":"Defined a molecular basis for repression by showing the MYND domain recruits the co-repressor N-CoR, framing BS69 as a transcriptional co-repressor.","evidence":"Co-IP, domain deletion, and reporter repression assay","pmids":["10734313"],"confidence":"Medium","gaps":["Endogenous target genes not identified","Single lab","Link to chromatin not established"]},{"year":1998,"claim":"Revealed isoform-dependent compartmentalization: a cytoplasmic splice form (BRAM1) binds BMPR-IA, expanding the gene's reach beyond the nucleus.","evidence":"Yeast two-hybrid, co-IP, and fractionation/imaging in mammalian cells","pmids":["9663660"],"confidence":"Medium","gaps":["Functional consequence for BMP signaling not yet tested","Single lab","Regulation of isoform choice unknown"]},{"year":2001,"claim":"Identified the PXLXP motif as the common code recognized by the MYND domain, unifying viral (EBNA2) and cellular (MGA) partner recognition and explaining competition between them.","evidence":"Co-IP, GST pull-down, and PXLXP motif mutagenesis","pmids":["11733528","11244510"],"confidence":"High","gaps":["Structural basis of PXLXP recognition not resolved","Functional output of MGA/c-Myb repression in vivo unclear"]},{"year":2002,"claim":"Showed that the cytoplasmic BRAM1 isoform and MYND domain also intercept viral signaling, dampening LMP1- and TNF-driven NF-kB activation.","evidence":"Pull-down, co-IP, confocal, and NF-kB reporter assays","pmids":["12181323"],"confidence":"Medium","gaps":["Direct biochemical target in the IkBa pathway not defined","Single lab","Physiological relevance untested"]},{"year":2006,"claim":"Placed full-length BS69 on chromatin and mitotic chromosomes in association with remodelers, deacetylases and methyltransferases, anchoring its function to chromatin regulation.","evidence":"Endogenous chromatin fractionation, co-IP, immunofluorescence","pmids":["16565076"],"confidence":"Medium","gaps":["Histone mark recognized not yet identified","Direct vs indirect chromatin association unresolved","Specific complexes not purified"]},{"year":2006,"claim":"Demonstrated adaptor function in viral signaling by bridging LMP1 to TRAF6 to selectively drive JNK activation, distinct from TNF signaling.","evidence":"Co-IP, siRNA knockdown, chimeric rescue, lipid raft fractionation, JNK assay","pmids":["16382137"],"confidence":"High","gaps":["How a chromatin reader operates at membrane rafts mechanistically unclear","Relevance to nuclear function unconnected"]},{"year":2007,"claim":"Connected BS69 to senescence control, showing it forms p53/p400 complexes and restrains the p53-p21Cip1 pathway, an endogenous tumor-suppressive axis.","evidence":"RNAi, senescence markers, co-IP, ChIP on p21 promoter, double-knockdown epistasis","pmids":["17721438"],"confidence":"High","gaps":["Whether chromatin-reading is required for p53 regulation untested","Mechanism of p21 promoter repression not detailed"]},{"year":2009,"claim":"Defined post-translational control of BS69 abundance and localization via PIAS1-enhanced SUMOylation through a PHD-dependent mechanism.","evidence":"Co-IP, SUMO modification assay, domain mutagenesis, differentiation reporter","pmids":["19766626"],"confidence":"Medium","gaps":["SUMO acceptor sites not mapped","Functional consequence of SUMOylation for chromatin binding unclear","Single lab"]},{"year":2009,"claim":"Extended viral signaling roles, showing BS69 can both negatively regulate LMP1-NF-kB (via TRADD) and positively regulate antiviral TLR3-TICAM-1 signaling through nuclear-to-cytoplasmic translocation.","evidence":"Co-IP, siRNA, confocal translocation, NF-kB/IFN-b reporter and cytokine assays","pmids":["19379743","19795416"],"confidence":"Medium","gaps":["Signals triggering nucleocytoplasmic shuttling not defined","Reconciliation of opposing NF-kB outcomes unclear","Single labs"]},{"year":2013,"claim":"Resolved the MYND domain fold (bba cross-brace zinc topology) and showed partner binding requires distinct flanking charged residues, defining a binding mode distinct from AML1/ETO.","evidence":"NMR of related MYND, homology modeling and mutagenesis of BS69 MYND, NMR titration","pmids":["23372760"],"confidence":"Medium","gaps":["BS69 MYND not directly solved by NMR","Quantitative affinities not measured","Single lab"]},{"year":2014,"claim":"Defined the central molecular function: ZMYND11 reads H3.3K36me3 via PWWP with H3.3-Ser31-dependent specificity from the tandem bromo-PWWP, co-localizes with H3K36me3 in gene bodies, and represses transcription at the Pol II elongation step.","evidence":"Crystal structure of bromo-PWWP with H3.3K36me3 peptide, ChIP-seq, Pol II elongation and tumor-growth assays","pmids":["24590075"],"confidence":"High","gaps":["Mechanism by which reading restrains elongation not fully detailed","Effector recruited at elongation step not defined"]},{"year":2014,"claim":"Linked H3.3K36me3 reading to co-transcriptional splicing, showing ZMYND11 associates with U5 snRNP/EFTUD2 and promotes intron retention by antagonizing EFTUD2 in a chromatin-dependent manner.","evidence":"Pull-down, co-IP, RNA-seq, ChIP, and KD+EFTUD2-overexpression epistasis","pmids":["25263594"],"confidence":"High","gaps":["Direct EFTUD2 antagonism mechanism not structurally resolved","Scope of regulated splicing events incomplete"]},{"year":2014,"claim":"Identified an additional layer of abundance control: MAGE-C2/HCA587 promotes ZMYND11 ubiquitination and proteasomal degradation, with functional loss reflected in increased LMP1-driven IL-6.","evidence":"MS, co-IP, GST pull-down, ubiquitination assay, siRNA, IL-6 readout","pmids":["24866244"],"confidence":"Medium","gaps":["E3 ligase responsible not identified","Ubiquitination sites not mapped","Single lab"]},{"year":2016,"claim":"Explained MYND-mediated partner recognition architecturally: the CC-MYND module homodimerizes to engage two PXLXP motifs of EBNA2 with avidity, and this engagement inhibits EBNA2 transactivation and LCL proliferation.","evidence":"Crystal structure, ITC, ChIP, reporter and proliferation assays, mutagenesis","pmids":["26845565"],"confidence":"High","gaps":["Whether the same dimeric avidity applies to cellular partners untested at structural level"]},{"year":2017,"claim":"Showed selective co-repression of ETS2 (not ETS1) explains divergent tumor-suppressive versus oncogenic outcomes at shared ETS binding sites, suppressing a migration program.","evidence":"Co-IP, deletion mapping, ChIP-seq cistrome comparison, reporter and migration assays","pmids":["28119415"],"confidence":"Medium","gaps":["Structural basis of ETS2 selectivity unknown","Single lab","In vivo relevance untested"]},{"year":2018,"claim":"Established a conserved cytoplasmic mechanism in vivo: the MYND domain binds the Bmpr1a kinase domain to block Smad1/5/8 activation, with cytoplasmic Mga antagonizing this to tune BMP-dependent cell fate.","evidence":"Zebrafish CRISPR/TALEN loss-of-function, co-IP, Smad phosphorylation assay, domain mapping","pmids":["30324105"],"confidence":"Medium","gaps":["Conservation to mammalian BMP signaling not directly shown","Single lab","Isoform (BRAM1) contribution in vivo not delineated"]},{"year":2019,"claim":"Refined the host-restriction model, showing type 2 EBNA2 carries a third PXLXP motif binding an extra CC-MYND dimer, and that increased ZMYND11 association restricts EBNA2 function.","evidence":"Pull-down, SAXS, mutagenesis, B-cell growth and gene expression assays","pmids":["31283782"],"confidence":"High","gaps":["High-resolution structure of the trimeric assembly lacking","Quantitative cellular ZMYND11 stoichiometry unknown"]},{"year":2021,"claim":"Defined the leukemogenic mechanism of the ZMYND11-MBTD1 fusion: it recruits NuA4/TIP60 to pro-leukemic cis-regulatory elements, sustaining active acetylated chromatin, and requires both TIP60 interaction and the PWWP H3K36me3-reading domain.","evidence":"Murine HSPC transformation, in vivo AML model, ChIP-seq, systematic domain mutagenesis, co-IP, bromodomain inhibitor","pmids":["33594072"],"confidence":"High","gaps":["How fusion converts repressive reading into activation mechanistically incomplete","Therapeutic window not defined"]},{"year":2022,"claim":"Showed the fusion stably integrates into endogenous NuA4/TIP60 and mislocalizes it to ZMYND11-occupied gene bodies, driving MYC-centered acetylation, transcription, splicing changes, and HSPC self-renewal.","evidence":"Complex purification, ChIP-seq, RNA-seq, splicing analysis, ESC differentiation and self-renewal assays","pmids":["35705031"],"confidence":"High","gaps":["Direct MYC regulatory element causality not isolated","Single lab"]},{"year":2024,"claim":"Identified an arginine-methyl reading function: the MYND domain binds R194-methylated HNRNPA1 to retain it in the nucleus, restrain stress granule formation, and counter HNRNPA1-driven PKM2/PKM1 shift, disrupted by PRMT5 inhibition.","evidence":"Co-IP, MYND mutagenesis, stress granule imaging, PKM ratio assay, PRMT5 inhibitor, tumor formation assay","pmids":["39341825"],"confidence":"Medium","gaps":["Structural basis of methyl-arginine recognition by MYND not solved","Single lab","In vivo relevance of metabolic shift untested"]},{"year":2024,"claim":"Completed the abundance-control circuit by identifying USP53 as a deubiquitinase that stabilizes ZMYND11, partly mediating USP53 anti-tumor effects in breast cancer.","evidence":"Co-IP, ubiquitination assay, domain deletion, gain/loss rescue, xenograft","pmids":["39044157"],"confidence":"Medium","gaps":["Ubiquitin chain type removed not characterized","Counterbalancing E3 in this context not identified","Single lab"]},{"year":2025,"claim":"Connected ZMYND11 to neurodevelopmental disease mechanism: loss derepresses non-neuronal programs via failure to inhibit KMT2A, impairs dendritic morphology, and a ZRSID point mutation abolishes the KMT2A interaction, with revumenib attenuating the phenotype.","evidence":"Neuronal conditional knockout, co-IP, disease-variant mutagenesis, KMT2A inhibition, morphology, RNA-seq (preprint)","pmids":["41279818"],"confidence":"Medium","gaps":["Preprint, not peer-reviewed","Direct vs indirect KMT2A inhibition mechanism unresolved","Genotype-phenotype scope across ZRSID variants limited"]},{"year":2025,"claim":"Defined neurodevelopmental and neurogenic roles, showing ZMYND11 controls progenitor/neuron production through a brain-specific RBFOX2-dependent isoform switch and through Epha2/PI3K signaling coupled to H3K36me3 and Pol II occupancy.","evidence":"hPSC cortical differentiation, mouse KO, RNA-seq, splicing analysis, ChIP (H3K36me3, Pol II), Epha2 rescue, neurogenesis assays","pmids":["41068108","40281637"],"confidence":"Medium","gaps":["Direct targets of the RBFOX2 isoform switch not enumerated","Mechanism linking H3K36me3 gain to Pol II loss at Epha2 unclear","Two independent models, single labs each"]},{"year":2026,"claim":"Provided a structural and genomic refinement: crystal structures of WH, PHD, and CC-MYND domains reveal redox/pH-sensitive oligomerization and nucleic-acid/histone binding cooperation, and ZMYND11 robustly occupies promoters where its loss reduces Pol II pausing and H3.3/H3K36me3, with a new ALKBH6 interaction.","evidence":"Crystal structures, ITC, mutagenesis, co-IP (ALKBH6); CUT&Tag, ChIP-seq, pausing index, RNA-seq, ROS and proliferation assays","pmids":["41591843","42262664"],"confidence":"High","gaps":["Functional role of ALKBH6 interaction not established","Physiological relevance of redox-sensitive oligomerization unclear","How promoter occupancy reconciles with elongation control incomplete"]},{"year":null,"claim":"How ZMYND11's H3.3K36me3 reading is mechanistically converted into Pol II pausing/elongation control versus the activation imposed by the ZMYND11-MBTD1 fusion, and how its many partner interactions are coordinated in time and space, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of ZMYND11 engaging Pol II or pausing machinery","Effector linking reading to repression at elongation undefined","Integration of nuclear chromatin reading with cytoplasmic signaling roles unclear"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,4,10,16,20]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[16,17]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[30]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[2,8,21]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,8,17]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,9,10]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[9,16]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,5,13]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,16,31]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[9,16,23]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[17,28]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[23,24,27]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[10,31]}],"complexes":["NuA4/TIP60 acetyltransferase complex (via ZMYND11-MBTD1 fusion)","U5 snRNP/spliceosome","p53-p400 complex"],"partners":["EFTUD2","EBNA2","LMP1","MGA","ETS2","KMT2A","HNRNPA1","USP53"],"other_free_text":[]}},"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; MRD30","url":"https://www.omim.org/entry/616083"},{"mim_id":"608668","title":"ZINC FINGER MYND DOMAIN-CONTAINING PROTEIN 11; ZMYND11","url":"https://www.omim.org/entry/608668"},{"mim_id":"601128","title":"H3 HISTONE, FAMILY 3A; H3F3A","url":"https://www.omim.org/entry/601128"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ZMYND11"},"hgnc":{"alias_symbol":["BS69","BRAM1"],"prev_symbol":[]},"alphafold":{"accession":"Q15326","domains":[{"cath_id":"1.10.10.10","chopping":"3-94","consensus_level":"medium","plddt":89.2765,"start":3,"end":94},{"cath_id":"1.20.920.10","chopping":"151-257","consensus_level":"medium","plddt":90.2049,"start":151,"end":257},{"cath_id":"2.30.30.140","chopping":"261-358","consensus_level":"high","plddt":96.5035,"start":261,"end":358},{"cath_id":"-","chopping":"560-602","consensus_level":"medium","plddt":92.426,"start":560,"end":602},{"cath_id":"1.20.5","chopping":"500-558","consensus_level":"medium","plddt":92.5303,"start":500,"end":558}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15326","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15326-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15326-F1-predicted_aligned_error_v6.png","plddt_mean":82.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ZMYND11","jax_strain_url":"https://www.jax.org/strain/search?query=ZMYND11"},"sequence":{"accession":"Q15326","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15326.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15326/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15326"}},"corpus_meta":[{"pmid":"24590075","id":"PMC_24590075","title":"ZMYND11 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to enhance NF-kappaB activation and type I IFN induction.","date":"2009","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/19795416","citation_count":8,"is_preprint":false},{"pmid":"39044157","id":"PMC_39044157","title":"USP53 Affects the Proliferation and Apoptosis of Breast Cancer Cells by Regulating the Ubiquitination Level of ZMYND11.","date":"2024","source":"Biological procedures online","url":"https://pubmed.ncbi.nlm.nih.gov/39044157","citation_count":8,"is_preprint":false},{"pmid":"20425112","id":"PMC_20425112","title":"Analysis of copy number variations of BS69 in multiple types of hematological malignancies.","date":"2010","source":"Annals of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/20425112","citation_count":8,"is_preprint":false},{"pmid":"30324105","id":"PMC_30324105","title":"Mga Modulates Bmpr1a Activity by Antagonizing Bs69 in Zebrafish.","date":"2018","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/30324105","citation_count":7,"is_preprint":false},{"pmid":"30469473","id":"PMC_30469473","title":"The Transcriptional Repressor BS69 is a Conserved Target of the E1A Proteins from Several Human Adenovirus Species.","date":"2018","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/30469473","citation_count":7,"is_preprint":false},{"pmid":"34818214","id":"PMC_34818214","title":"Intragenic Deletion of the ZMYND11 Gene in 10p15.3 is Associated with Developmental Delay Phenotype: A Case Report.","date":"2021","source":"Cytogenetic and genome research","url":"https://pubmed.ncbi.nlm.nih.gov/34818214","citation_count":6,"is_preprint":false},{"pmid":"31262855","id":"PMC_31262855","title":"Regulation of BS69 Expression in Cancers.","date":"2019","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/31262855","citation_count":5,"is_preprint":false},{"pmid":"32512976","id":"PMC_32512976","title":"MicroRNA-196b promotes cell growth and metastasis of ovarian cancer by targeting ZMYND11.","date":"2020","source":"Minerva medica","url":"https://pubmed.ncbi.nlm.nih.gov/32512976","citation_count":5,"is_preprint":false},{"pmid":"16456708","id":"PMC_16456708","title":"Molecular cloning, expression and characterization of the zebrafish bram1 gene, a BMP receptor-associated molecule.","date":"2006","source":"Journal of biomedical science","url":"https://pubmed.ncbi.nlm.nih.gov/16456708","citation_count":5,"is_preprint":false},{"pmid":"20732415","id":"PMC_20732415","title":"The MYND domain-containing protein BRAM1 inhibits lymphotoxin beta receptor-mediated signaling through affecting receptor oligomerization.","date":"2010","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/20732415","citation_count":5,"is_preprint":false},{"pmid":"38397245","id":"PMC_38397245","title":"Further Delineation of Clinical Phenotype of ZMYND11 Variants in Patients with Neurodevelopmental Dysmorphic Syndrome.","date":"2024","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/38397245","citation_count":4,"is_preprint":false},{"pmid":"41068108","id":"PMC_41068108","title":"ZMYND11 functions in bimodal regulation of latent genes and brain-like splicing to safeguard corticogenesis.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/41068108","citation_count":3,"is_preprint":false},{"pmid":"38290943","id":"PMC_38290943","title":"Probing the biological consequences of a previously undescribed de novo mutation of ZMYND11 in a schizophrenia patient by CRISPR genome editing and induced pluripotent stem cell based in vitro disease-modeling.","date":"2024","source":"Schizophrenia research","url":"https://pubmed.ncbi.nlm.nih.gov/38290943","citation_count":3,"is_preprint":false},{"pmid":"37008727","id":"PMC_37008727","title":"Transgenic mice overexpressing mutant TDP-43 show aberrant splicing of neurological disorders-associated gene Zmynd11 prior to onset of motor symptoms.","date":"2023","source":"microPublication biology","url":"https://pubmed.ncbi.nlm.nih.gov/37008727","citation_count":3,"is_preprint":false},{"pmid":"39258225","id":"PMC_39258225","title":"Acute myeloid leukemia with a ZMYND11::MBTD1 fusion gene following chemotherapy and radiotherapy for breast cancer: A case report.","date":"2024","source":"Leukemia research reports","url":"https://pubmed.ncbi.nlm.nih.gov/39258225","citation_count":2,"is_preprint":false},{"pmid":"24795016","id":"PMC_24795016","title":"The putative tumor suppressor ZMYND11 recognizes H3.3K36me3.","date":"2014","source":"Cancer discovery","url":"https://pubmed.ncbi.nlm.nih.gov/24795016","citation_count":2,"is_preprint":false},{"pmid":"40281637","id":"PMC_40281637","title":"Zmynd11 is essential for neurogenesis by coordinating H3K36me3 modification of Epha2 and PI3K signaling pathway.","date":"2025","source":"Cell & bioscience","url":"https://pubmed.ncbi.nlm.nih.gov/40281637","citation_count":1,"is_preprint":false},{"pmid":"39464123","id":"PMC_39464123","title":"ZMYND11 Functions in Bimodal Regulation of Latent Genes and Brain-like Splicing to Safeguard Corticogenesis.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/39464123","citation_count":1,"is_preprint":false},{"pmid":"41279818","id":"PMC_41279818","title":"ZMYND11 Restrains KMT2A to Enable a Neuronal Developmental Program.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41279818","citation_count":0,"is_preprint":false},{"pmid":"40938895","id":"PMC_40938895","title":"ETS2 targets ZMYND11 to inhibit thyroid cancer progression via the mTOR signaling pathway.","date":"2025","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/40938895","citation_count":0,"is_preprint":false},{"pmid":"42262664","id":"PMC_42262664","title":"H3.3K36me3 Reader ZMYND11 Localizes to Gene Promoter and Regulates Transcription Initiation.","date":"2026","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/42262664","citation_count":0,"is_preprint":false},{"pmid":"41454826","id":"PMC_41454826","title":"ZMYND11::MBTD1 Fusion in Myeloid/NK Cell Precursor Leukemia: A Case Report With Literature Review and Diagnostic Implications.","date":"2025","source":"Pediatric blood & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/41454826","citation_count":0,"is_preprint":false},{"pmid":"42003802","id":"PMC_42003802","title":"A Complex Neurodevelopmental Phenotype Resembling a Chromatinopathy With Concurrent 7p Duplication and 10p Deletion Involving ZMYND11: A Case Report and Literature Review.","date":"2026","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/42003802","citation_count":0,"is_preprint":false},{"pmid":"41591843","id":"PMC_41591843","title":"Novel intermolecular zinc fingers and redox-driven conformational changes dictate tumor suppressor ZMYND11's role in cooperative recognition of diverse targets.","date":"2026","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/41591843","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.12.02.24316741","title":"Genetic Diversity and Expanded Phenotypes in Dystonia: Insights from Large-Scale Exome Sequencing","date":"2024-12-05","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.02.24316741","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":29801,"output_tokens":8378,"usd":0.107536,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":17978,"output_tokens":7864,"usd":0.143245,"stage2_stop_reason":"end_turn"},"total_usd":0.250781,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"BS69/ZMYND11 specifically interacts with adenovirus 5 E1A (289R) protein, requiring the region unique to the large E1A protein for high-affinity binding, and co-immunoprecipitates with E1A in adenovirus-transformed 293 cells; BS69 specifically inhibits transactivation by the 289R E1A protein but not the 243R E1A protein.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, reporter gene transcription assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP in vivo and reporter assay with defined domain requirements, founding paper replicated by multiple subsequent studies\",\n      \"pmids\": [\"7621829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"BS69/ZMYND11 represses transcription at least in part through interaction with the co-repressor N-CoR; this interaction is mediated by the MYND domain in the BS69 C-terminus. Expression of E1A inhibits BS69-mediated repression.\",\n      \"method\": \"Co-immunoprecipitation, reporter gene transcription assay, domain deletion analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction mapped by domain deletions, transcriptional repression assay, single lab\",\n      \"pmids\": [\"10734313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"BRAM1, an alternatively spliced form of BS69/ZMYND11, localizes to the cytoplasm (whereas BS69 is nuclear) and specifically binds the BMP type IA receptor (BMPR-IA); the C-terminal half of BRAM1 is sufficient for BMPR-IA binding.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, subcellular localization by cell fractionation/imaging\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid and co-IP in mammalian cells with domain mapping, single lab\",\n      \"pmids\": [\"9663660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The C-terminal MYND domain of BS69/ZMYND11 binds the Epstein-Barr virus oncoprotein EBNA2 and the Myc-related cellular protein MGA through a common PXLXP motif present in all three binding partners; viral proteins compete with MGA for BS69 binding in a PXLXP-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down, mutagenesis of PXLXP motif\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct binding mapped by mutagenesis and confirmed by pull-down; replicated in multiple subsequent structural studies\",\n      \"pmids\": [\"11733528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"BS69/ZMYND11 interacts with the carboxy-terminal negative regulatory domain of c-Myb and inhibits c-Myb transcriptional activity in a dose-dependent manner; the 289R E1A protein can inhibit BS69-mediated repression of c-Myb; direct in vitro interaction between BS69 and c-Myb was demonstrated.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding, reporter gene assay, domain mapping\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro direct interaction plus cell-based reporter assay, domain mapping, single lab\",\n      \"pmids\": [\"11244510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"BRAM1 associates with EBV LMP1 (via the MYND domain of BRAM1 and the CTAR2 region of LMP1) both in vitro and in vivo, and interferes with LMP1-mediated NF-κB activation; BRAM1 also interferes with TNF-α-induced NF-κB activation by targeting IκBα molecules.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, confocal microscopy, reporter gene assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (pulldown, co-IP, confocal) in single lab\",\n      \"pmids\": [\"12181323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"EMSY binds directly to BS69/ZMYND11 via a conserved motif adjacent to its ENT domain; the crystal structure of EMSY residues 1–108 shows the HP1β/BS69-binding motif in an extended peptide conformation; HP1β chromoshadow domain (CSD) forms a complex with EMSY.\",\n      \"method\": \"Crystal structure (2.0 Å), NMR, biophysical analysis (ITC/analytical ultracentrifugation)\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — crystal structure from EMSY side, direct binding confirmed, but structural/functional characterization is of the EMSY-HP1 interaction; BS69 binding inferred from motif analysis rather than direct structural study of BS69 itself\",\n      \"pmids\": [\"15947784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"BS69/ZMYND11 inhibits ubiquitination of adenovirus E1A protein and stabilizes E1A in vivo; this inhibition requires the MYND domain, which mediates E1A binding; BS69 mutants lacking the MYND domain cannot bind E1A and cannot inhibit its ubiquitination.\",\n      \"method\": \"In vivo ubiquitination assay, co-immunoprecipitation, domain deletion mutagenesis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assay plus domain mutagenesis, single lab\",\n      \"pmids\": [\"16300738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"BS69/ZMYND11 is a specific adaptor bridging EBV LMP1 and TRAF6 in the LMP1-induced JNK pathway; the MYND domain and a separate region of BS69 bind LMP1 and TRAF6 C-termini, respectively; LMP1 promotes BS69-TRAF6 complex formation; a fraction of LMP1 and BS69 co-localizes in membrane lipid rafts; knockdown of BS69 specifically inhibits LMP1-induced JNK activation but not TNF-α-induced JNK activation.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, chimeric protein overexpression, lipid raft fractionation, JNK activation assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods including siRNA, chimeric rescue, co-IP and lipid raft fractionation, specific pathway assignment\",\n      \"pmids\": [\"16382137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Full-length BS69/ZMYND11 is a nuclear protein that associates with chromatin and mitotic chromosomes; it interacts with chromatin remodeling factors including ATP-dependent helicases, histone deacetylases, and histone methyltransferases, as well as the E2F6 transcription factor.\",\n      \"method\": \"Endogenous antibody-based chromatin fractionation, co-immunoprecipitation, immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — endogenous protein studied with validated antibody, multiple co-IP interactions, single lab\",\n      \"pmids\": [\"16565076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"BS69/ZMYND11 knockdown in primary human fibroblasts induces premature senescence via the p53-p21Cip1 pathway; BS69 forms complexes with both p53 and p400, and associates with the p21Cip1 promoter through p53; knockdown of p53 or p21Cip1, but not p16INK4a or Rb, rescues premature senescence induced by BS69 knockdown.\",\n      \"method\": \"RNA interference knockdown, senescence marker assays (SA-β-gal, SAHF), co-immunoprecipitation, chromatin immunoprecipitation, epistasis by double knockdown\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — pathway placement by genetic epistasis (double KD rescue), ChIP on p21 promoter, co-IP of complex, multiple orthogonal methods\",\n      \"pmids\": [\"17721438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"BS69/ZMYND11 negatively regulates LMP1-mediated NF-κB activation; BS69 manipulation decreases complex formation between LMP1 and TRADD, thus dampening IκBα degradation and IL-6 upregulation.\",\n      \"method\": \"Co-immunoprecipitation, siRNA-mediated knockdown, NF-κB reporter assay, IL-6 mRNA measurement\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic link via co-IP showing disruption of LMP1-TRADD complex, single lab\",\n      \"pmids\": [\"19379743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"BS69/ZMYND11 is SUMOylated; it interacts with SUMO E3 ligase PIAS1 and the SUMO E2 enzyme Ubc9 through distinct regions, and PIAS1 significantly enhances BS69 SUMO modification; the PHD domain is required for BS69 localization, sumoylation, and inhibitory function in muscle and neuronal differentiation.\",\n      \"method\": \"Co-immunoprecipitation, SUMO modification assay, domain deletion mutagenesis, differentiation reporter assay\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical SUMO assay with E3 ligase, domain mutagenesis, single lab\",\n      \"pmids\": [\"19766626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"BS69/ZMYND11 translocates from the nucleus to the cytoplasm upon dsRNA stimulation or TICAM-1 overexpression, is recruited to TICAM-1 signaling speckles, and positively regulates NF-κB/IRF-3 activation and IFN-β production downstream of TLR3-TICAM-1; knockdown of BS69 reduces IFN-β induction.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, confocal microscopy, siRNA knockdown, cytokine induction assay\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — nuclear-to-cytoplasmic translocation shown by confocal, co-IP interaction, and siRNA phenotype, single lab\",\n      \"pmids\": [\"19795416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"BS69/ZMYND11 directly interacts with LMP1/CTAR1 domain and with TRAF3 (a negative regulator of NF-κB); BS69 and TRAF3 cooperate to suppress LMP1/CTAR1-mediated NF-κB activation and IL-6 production; siRNA knockdown of TRAF3 impairs BS69-mediated suppression.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, NF-κB reporter assay, IL-6 measurement\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP interaction mapped, genetic epistasis by double siRNA, single lab\",\n      \"pmids\": [\"20138174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The BS69 MYND domain adopts a ββα fold with tandem zinc-binding sites in a cross-brace topology (characterized by homology modeling and mutational analysis); interactions of BS69 MYND with viral and cellular binding partners require distinct charged residues flanking the predicted MYND domain fold, suggesting a different binding mode from AML1/ETO.\",\n      \"method\": \"NMR structure determination (DEAF-1 MYND), homology modeling plus mutational analysis (BS69 MYND), NMR titration mapping\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — NMR structure of related MYND plus mutagenesis of BS69 MYND, single lab; BS69 itself not solved by NMR\",\n      \"pmids\": [\"23372760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ZMYND11 specifically recognizes H3K36me3 on the histone variant H3.3 (H3.3K36me3) via its PWWP domain aromatic cage; H3.3-specific recognition additionally requires encapsulation of the H3.3-specific Ser31 residue in a composite pocket formed by the tandem bromo-PWWP domains. ZMYND11 co-localizes genome-wide with H3K36me3 and H3.3 in gene bodies and its chromatin occupancy requires pre-deposited H3.3K36me3. ZMYND11 functions as a transcription co-repressor by modulating RNA Pol II at the elongation stage.\",\n      \"method\": \"Crystal structure (bromo-PWWP-H3.3K36me3 peptide complex), ChIP-seq, RNA Pol II elongation assay, loss-of-function with tumor growth readout\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation, genome-wide ChIP-seq, multiple orthogonal methods, replicated by concurrent paper (PMID:25263594)\",\n      \"pmids\": [\"24590075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"BS69/ZMYND11 selectively recognizes H3.3K36me3 via its chromatin-binding PHD-BROMO-PWWP domains; it associates with U5 snRNP components of the spliceosome including EFTUD2; BS69 promotes intron retention by antagonizing EFTUD2 through physical interaction; this splicing regulatory function depends on BS69 binding to H3K36me3-decorated chromatin.\",\n      \"method\": \"Biochemical pulldown, co-immunoprecipitation, RNA-seq, genetic epistasis (BS69 KD + EFTUD2 overexpression), ChIP\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (co-IP, RNA-seq, rescue genetics, ChIP), novel function independently established, concurrent with PMID:24590075\",\n      \"pmids\": [\"25263594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The cancer-testis antigen HCA587/MAGE-C2 interacts with BS69/ZMYND11 and promotes its ubiquitination and proteasomal degradation; knockdown of endogenous HCA587 increases BS69 protein levels; HCA587 overexpression enhances LMP1-induced IL-6 production consistent with loss of BS69 function.\",\n      \"method\": \"Mass spectrometry identification, co-immunoprecipitation, GST pull-down, ubiquitination assay, siRNA knockdown, IL-6 measurement\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assay and co-IP confirmed by MS, single lab\",\n      \"pmids\": [\"24866244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The C-terminal coiled-coil-MYND (CC-MYND) domains of BS69/ZMYND11 form a homodimer via coiled-coil self-association, which brings two MYND domains in close proximity to synergistically bind two PXLXP motifs in EBNA2 (CR7 and CR8); ectopic BS69 CC-MYND is recruited to viral promoters via EBNA2, inhibits EBNA2-mediated transactivation, and impairs lymphoblastoid cell line proliferation; MYND domain mutations that abolish EBNA2 binding also abolish inhibitory activity.\",\n      \"method\": \"Crystal structure, ITC, chromatin immunoprecipitation, reporter assay, cell proliferation assay, site-directed mutagenesis\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus ITC quantitative binding, mutagenesis, ChIP, and functional assay in single rigorous study\",\n      \"pmids\": [\"26845565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ZMYND11 interacts with ETS2 (but not ETS1) through the ETS2 N-terminus and acts as a co-repressor to attenuate ETS2-mediated transcriptional activation, enabling ETS2 to suppress a cell migration gene expression program; this specific interaction accounts for the opposing functions of ETS1 (oncogenic) and ETS2 (tumor suppressive) at shared genomic binding sites.\",\n      \"method\": \"Co-immunoprecipitation, deletion mapping, ChIP-seq cistrome comparison, reporter gene assay, cell migration assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP interaction mapped, cistrome analysis, functional migration assay, single lab\",\n      \"pmids\": [\"28119415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In zebrafish, the MYND domain of Bs69/Zmynd11 binds the kinase domain of Bmpr1a and interferes with Bmpr1a phosphorylation and activation of Smad1/5/8; cytoplasmic Mga antagonizes Bs69 by disrupting the Bs69-Bmpr1a association, thereby facilitating BMP signaling for ventral tailfin cell fate specification.\",\n      \"method\": \"TALEN/CRISPR-Cas9 loss-of-function, co-immunoprecipitation, phosphorylation assay (Smad1/5/8), domain mapping\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function plus biochemical co-IP and phosphorylation assay, single lab, zebrafish model\",\n      \"pmids\": [\"30324105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Type 2 EBV EBNA2 contains a third conserved PXLXP motif absent in type 1 EBNA2, enabling it to bind an additional BS69 CC-MYND molecule; SAXS shows three BS69 CC-MYND dimers bound to two molecules of type 2 EBNA2 TAD; mutation of the third BS69-binding motif in type 2 EBNA2 improves B-cell growth and transcriptional activation, indicating that increased BS69 association restricts type 2 EBNA2 function.\",\n      \"method\": \"Pull-down, SAXS (low-resolution structure), molecular weight analysis, mutagenesis, B-cell growth assay, gene expression assay\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — SAXS structural data plus mutagenesis and functional rescue in single rigorous study\",\n      \"pmids\": [\"31283782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The ZMYND11-MBTD1 (ZM) fusion protein recruits the NuA4/TIP60 histone acetyltransferase complex to cis-regulatory elements of pro-leukemic genes (Hoxa, Meis1, Myb, Myc, Sox4), sustaining active chromatin enriched in histone acetylation and devoid of repressive marks; both the TIP60 interaction and the H3K36me3-binding PWWP domain of ZMYND11 are required for ZM oncogenic function.\",\n      \"method\": \"Murine hematopoietic stem/progenitor cell transformation assay, in vivo AML model, ChIP-seq, systematic domain mutagenesis, co-immunoprecipitation, bromodomain inhibitor treatment\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic mutagenesis, co-IP, ChIP-seq, in vivo model, and pharmacological inhibition, multiple orthogonal methods in single study\",\n      \"pmids\": [\"33594072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ZMYND11-MBTD1 fusion is stably incorporated into the endogenous NuA4/TIP60 complex, leading to its mislocalization to gene bodies normally occupied by ZMYND11; this causes increased chromatin acetylation and altered transcription (notably at the MYC oncogene) and alternative splicing; ZMYND11-MBTD1 favors MYC-driven pluripotency and self-renewal of hematopoietic stem/progenitor cells.\",\n      \"method\": \"Biochemical complex purification, ChIP-seq, RNA-seq, alternative splicing analysis, embryonic stem cell differentiation assay, hematopoietic progenitor self-renewal assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — biochemical purification plus genomics and functional assays in multiple cell systems, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"35705031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZMYND11 binds arginine-194-methylated HNRNPA1 via its MYND domain, retaining HNRNPA1 in the nucleus and preventing stress granule formation in the cytoplasm; ZMYND11 counteracts HNRNPA1-driven increase in the PKM2/PKM1 ratio; PRMT5 inhibition disrupts ZMYND11 recognition of methylated HNRNPA1.\",\n      \"method\": \"Co-immunoprecipitation, domain mutagenesis (MYND), stress granule imaging, PKM2/PKM1 ratio assay, PRMT5 inhibitor treatment, in vitro tumor formation assay\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with domain mapping, functional stress granule assay, pharmacological disruption, single lab\",\n      \"pmids\": [\"39341825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP53 deubiquitylase interacts with ZMYND11 and catalyzes its deubiquitination and stabilization; the USP53 Cys-box domain (aa 33-50) is required for enzyme activity but not for ZMYND11 binding; USP53 anti-tumor effects in breast cancer cells are partially mediated through ZMYND11.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, domain deletion analysis, gain/loss-of-function rescue experiments, xenograft model\",\n      \"journal\": \"Biological procedures online\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus ubiquitination assay and rescue genetics, single lab\",\n      \"pmids\": [\"39044157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZMYND11 deficiency in mouse neurons causes aberrant upregulation of non-neuronal gene programs leading to reduced dendritic branching and spine density; ZMYND11 interacts with and inhibits histone methyltransferase KMT2A (MLL1); a ZRSID-associated ZMYND11 point mutation abolishes KMT2A interaction; gene expression changes from ZMYND11 loss are attenuated by KMT2A inhibitor revumenib.\",\n      \"method\": \"Neuronal-specific conditional knockout, co-immunoprecipitation, point mutagenesis, pharmacological KMT2A inhibition (revumenib), dendritic morphology assay, RNA-seq\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus mutagenesis of disease variant, conditional KO phenotype, pharmacological rescue; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"41279818\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZMYND11 deficiency in cortical neural stem cells upregulates latent developmental pathways impairing progenitor and neuron production; beyond chromatin, ZMYND11 controls a brain-specific RNA isoform switch involving the splicing regulator RBFOX2.\",\n      \"method\": \"Human pluripotent stem cell cortical differentiation model, ZMYND11 loss-of-function, RNA-seq, splicing isoform analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — hPSC model with RNA-seq and splicing analysis, single study, functional neurogenesis readout\",\n      \"pmids\": [\"41068108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Zmynd11 deficiency decreases Epha2 expression and disrupts PI3K signaling; under Zmynd11 deficiency, H3K36me3 modification on the Epha2 promoter abnormally increases while RNA Pol II binding decreases; restoration of PI3K signaling via exogenous Epha2 rescues aberrant neurogenesis caused by Zmynd11 depletion in vitro and in vivo.\",\n      \"method\": \"Mouse knockout model, ChIP (H3K36me3, Pol II), Epha2 rescue overexpression, neurosphere/neurogenesis assay\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, rescue genetics, in vivo KO, single lab\",\n      \"pmids\": [\"40281637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Crystal structures of ZMYND11 winged helix (WH), PHD, and coiled-coil-MYND (CC-MYND) domains reveal intermolecular zinc finger bonds in the PHD domain and intermolecular disulfide bonds in the CC domain; oligomeric state of PHD is pH-dependent and redox state of CC impairs binding; Bromo-PWWP domains cooperate with the WH domain and PHD domain to bind nucleic acids and histones respectively; both PHD and CC-MYND domains interact with nucleic acid repair protein ALKBH6.\",\n      \"method\": \"Crystal structure determination, ITC, mutagenesis, co-immunoprecipitation (ALKBH6 interaction)\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple crystal structures plus ITC and co-IP; single lab but multiple orthogonal structural and biochemical methods\",\n      \"pmids\": [\"41591843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Using CUT&Tag, ZMYND11 was found to robustly occupy promoter regions (not only gene bodies) in mouse ESCs and MEFs, with occupancy positively correlating with gene expression and Pol II occupancy; ZMYND11 deficiency reduces the Pol II pausing index, H3.3 occupancy, and H3K36me3 at genes, indicating impaired transcription initiation; ZMYND11 knockout induces transcriptomic changes, impairs cell proliferation, and aberrantly activates 2-cell-specific transcriptional programs via ROS accumulation.\",\n      \"method\": \"CUT&Tag, ChIP-seq comparison, Pol II pausing index analysis, RNA-seq, cell proliferation assay, ROS measurement\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CUT&Tag vs ChIP-seq comparison with functional KO, multiple genomic readouts, single lab\",\n      \"pmids\": [\"42262664\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ZMYND11/BS69 is a multidomain chromatin reader (PHD-BROMO-PWWP tandem) that specifically recognizes H3.3K36me3 on the histone variant H3.3 in gene bodies and promoters, where it functions as a transcriptional co-repressor by restraining RNA Pol II elongation and stabilizing Pol II pausing at promoters; it additionally connects H3.3K36me3-marked chromatin to regulated pre-mRNA splicing (promoting intron retention by antagonizing EFTUD2 and controlling a RBFOX2-dependent brain-specific isoform switch); its MYND domain recruits co-repressors (N-CoR) and mediates binding to viral (E1A, EBNA2, LMP1) and cellular (c-Myb, MGA, ETS2, HNRNPA1-R194me, KMT2A) partners through PXLXP or arginine-methylation motifs; it is regulated post-translationally by PIAS1-mediated SUMOylation, MAGE-C2-driven ubiquitin-proteasomal degradation, and USP53-mediated deubiquitination/stabilization; in the nucleus it forms complexes with p53 and p400 to suppress the p53-p21Cip1 senescence pathway; its alternatively spliced cytoplasmic isoform BRAM1 binds and inhibits BMPR-IA to modulate BMP-Smad signaling; the oncogenic ZMYND11-MBTD1 fusion aberrantly recruits the NuA4/TIP60 acetyltransferase complex to gene bodies, driving leukemogenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ZMYND11 (BS69/BRAM1) is a multidomain chromatin reader that couples a specific histone modification state to transcriptional repression, co-transcriptional splicing, and tumor suppression [#16, #17]. Through a tandem PHD-bromo-PWWP module it selectively recognizes H3K36me3 deposited on the histone variant H3.3, with H3.3 specificity enforced by encapsulation of the H3.3-unique Ser31 residue in a composite pocket formed across the bromo and PWWP domains [#16]. At H3.3K36me3-marked gene bodies and promoters ZMYND11 acts as a transcriptional co-repressor, restraining RNA Pol II elongation, supporting Pol II pausing, and sustaining proper transcription initiation; its loss reduces the Pol II pausing index and disrupts H3.3/H3K36me3 occupancy at target genes [#16, #31]. The same H3K36me3-dependent chromatin engagement directs a splicing function: ZMYND11 associates with U5 snRNP components including EFTUD2 and promotes intron retention by antagonizing EFTUD2, and it governs a brain-specific RBFOX2-dependent isoform switch [#17, #28]. A second functional surface is the C-terminal coiled-coil-MYND module, which homodimerizes and recruits binding partners through PXLXP motifs or arginine-methylation marks: it binds the co-repressor N-CoR and the cellular repressors MGA, c-Myb, and ETS2, the methyl-mark on R194 of HNRNPA1, and the histone methyltransferase KMT2A, and it is also the docking site for viral oncoproteins (adenovirus E1A, EBV EBNA2 and LMP1) [#1, #3, #4, #19, #20, #25, #27]. In the nucleus ZMYND11 forms complexes with p53 and p400 and associates with the p21Cip1 promoter through p53 to restrain the p53-p21Cip1 senescence pathway [#10]. ZMYND11 protein abundance is set by competing modifications — PIAS1-enhanced SUMOylation, MAGE-C2/HCA587-driven ubiquitin-proteasomal degradation, and USP53-mediated deubiquitination and stabilization [#12, #18, #26]. A distinct cytoplasmic splice isoform, BRAM1, binds the BMP type IA receptor through its MYND domain and inhibits BMPR-IA activation of Smad signaling [#2, #21]. Loss of ZMYND11 in neurons and neural progenitors derepresses non-neuronal and latent developmental gene programs and impairs neurogenesis, a defect linked to KMT2A inhibition and to Epha2/PI3K signaling, and a ZRSID-associated point mutation abolishes the ZMYND11-KMT2A interaction [#27, #28, #29]. The oncogenic ZMYND11-MBTD1 fusion subverts these activities by stably incorporating into the NuA4/TIP60 acetyltransferase complex and mislocalizing it to ZMYND11-bound gene bodies and cis-regulatory elements, driving aberrant acetylation and MYC-driven self-renewal in leukemogenesis, dependent on both the TIP60 interaction and the H3K36me3-binding PWWP domain [#23, #24].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established ZMYND11/BS69 as a binding partner and functional antagonist of a viral oncoprotein, the first clue to its role in transcriptional control.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal co-IP, and reporter assay with adenovirus E1A in transformed cells\",\n      \"pmids\": [\"7621829\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No endogenous cellular function identified\", \"Binding domain on BS69 not yet mapped\", \"Mechanism of transactivation inhibition unknown\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Defined a molecular basis for repression by showing the MYND domain recruits the co-repressor N-CoR, framing BS69 as a transcriptional co-repressor.\",\n      \"evidence\": \"Co-IP, domain deletion, and reporter repression assay\",\n      \"pmids\": [\"10734313\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous target genes not identified\", \"Single lab\", \"Link to chromatin not established\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Revealed isoform-dependent compartmentalization: a cytoplasmic splice form (BRAM1) binds BMPR-IA, expanding the gene's reach beyond the nucleus.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, and fractionation/imaging in mammalian cells\",\n      \"pmids\": [\"9663660\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence for BMP signaling not yet tested\", \"Single lab\", \"Regulation of isoform choice unknown\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identified the PXLXP motif as the common code recognized by the MYND domain, unifying viral (EBNA2) and cellular (MGA) partner recognition and explaining competition between them.\",\n      \"evidence\": \"Co-IP, GST pull-down, and PXLXP motif mutagenesis\",\n      \"pmids\": [\"11733528\", \"11244510\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of PXLXP recognition not resolved\", \"Functional output of MGA/c-Myb repression in vivo unclear\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showed that the cytoplasmic BRAM1 isoform and MYND domain also intercept viral signaling, dampening LMP1- and TNF-driven NF-kB activation.\",\n      \"evidence\": \"Pull-down, co-IP, confocal, and NF-kB reporter assays\",\n      \"pmids\": [\"12181323\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical target in the IkBa pathway not defined\", \"Single lab\", \"Physiological relevance untested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Placed full-length BS69 on chromatin and mitotic chromosomes in association with remodelers, deacetylases and methyltransferases, anchoring its function to chromatin regulation.\",\n      \"evidence\": \"Endogenous chromatin fractionation, co-IP, immunofluorescence\",\n      \"pmids\": [\"16565076\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Histone mark recognized not yet identified\", \"Direct vs indirect chromatin association unresolved\", \"Specific complexes not purified\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrated adaptor function in viral signaling by bridging LMP1 to TRAF6 to selectively drive JNK activation, distinct from TNF signaling.\",\n      \"evidence\": \"Co-IP, siRNA knockdown, chimeric rescue, lipid raft fractionation, JNK assay\",\n      \"pmids\": [\"16382137\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a chromatin reader operates at membrane rafts mechanistically unclear\", \"Relevance to nuclear function unconnected\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Connected BS69 to senescence control, showing it forms p53/p400 complexes and restrains the p53-p21Cip1 pathway, an endogenous tumor-suppressive axis.\",\n      \"evidence\": \"RNAi, senescence markers, co-IP, ChIP on p21 promoter, double-knockdown epistasis\",\n      \"pmids\": [\"17721438\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether chromatin-reading is required for p53 regulation untested\", \"Mechanism of p21 promoter repression not detailed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined post-translational control of BS69 abundance and localization via PIAS1-enhanced SUMOylation through a PHD-dependent mechanism.\",\n      \"evidence\": \"Co-IP, SUMO modification assay, domain mutagenesis, differentiation reporter\",\n      \"pmids\": [\"19766626\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SUMO acceptor sites not mapped\", \"Functional consequence of SUMOylation for chromatin binding unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extended viral signaling roles, showing BS69 can both negatively regulate LMP1-NF-kB (via TRADD) and positively regulate antiviral TLR3-TICAM-1 signaling through nuclear-to-cytoplasmic translocation.\",\n      \"evidence\": \"Co-IP, siRNA, confocal translocation, NF-kB/IFN-b reporter and cytokine assays\",\n      \"pmids\": [\"19379743\", \"19795416\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signals triggering nucleocytoplasmic shuttling not defined\", \"Reconciliation of opposing NF-kB outcomes unclear\", \"Single labs\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved the MYND domain fold (bba cross-brace zinc topology) and showed partner binding requires distinct flanking charged residues, defining a binding mode distinct from AML1/ETO.\",\n      \"evidence\": \"NMR of related MYND, homology modeling and mutagenesis of BS69 MYND, NMR titration\",\n      \"pmids\": [\"23372760\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"BS69 MYND not directly solved by NMR\", \"Quantitative affinities not measured\", \"Single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the central molecular function: ZMYND11 reads H3.3K36me3 via PWWP with H3.3-Ser31-dependent specificity from the tandem bromo-PWWP, co-localizes with H3K36me3 in gene bodies, and represses transcription at the Pol II elongation step.\",\n      \"evidence\": \"Crystal structure of bromo-PWWP with H3.3K36me3 peptide, ChIP-seq, Pol II elongation and tumor-growth assays\",\n      \"pmids\": [\"24590075\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which reading restrains elongation not fully detailed\", \"Effector recruited at elongation step not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linked H3.3K36me3 reading to co-transcriptional splicing, showing ZMYND11 associates with U5 snRNP/EFTUD2 and promotes intron retention by antagonizing EFTUD2 in a chromatin-dependent manner.\",\n      \"evidence\": \"Pull-down, co-IP, RNA-seq, ChIP, and KD+EFTUD2-overexpression epistasis\",\n      \"pmids\": [\"25263594\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct EFTUD2 antagonism mechanism not structurally resolved\", \"Scope of regulated splicing events incomplete\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified an additional layer of abundance control: MAGE-C2/HCA587 promotes ZMYND11 ubiquitination and proteasomal degradation, with functional loss reflected in increased LMP1-driven IL-6.\",\n      \"evidence\": \"MS, co-IP, GST pull-down, ubiquitination assay, siRNA, IL-6 readout\",\n      \"pmids\": [\"24866244\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase responsible not identified\", \"Ubiquitination sites not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Explained MYND-mediated partner recognition architecturally: the CC-MYND module homodimerizes to engage two PXLXP motifs of EBNA2 with avidity, and this engagement inhibits EBNA2 transactivation and LCL proliferation.\",\n      \"evidence\": \"Crystal structure, ITC, ChIP, reporter and proliferation assays, mutagenesis\",\n      \"pmids\": [\"26845565\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the same dimeric avidity applies to cellular partners untested at structural level\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed selective co-repression of ETS2 (not ETS1) explains divergent tumor-suppressive versus oncogenic outcomes at shared ETS binding sites, suppressing a migration program.\",\n      \"evidence\": \"Co-IP, deletion mapping, ChIP-seq cistrome comparison, reporter and migration assays\",\n      \"pmids\": [\"28119415\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of ETS2 selectivity unknown\", \"Single lab\", \"In vivo relevance untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established a conserved cytoplasmic mechanism in vivo: the MYND domain binds the Bmpr1a kinase domain to block Smad1/5/8 activation, with cytoplasmic Mga antagonizing this to tune BMP-dependent cell fate.\",\n      \"evidence\": \"Zebrafish CRISPR/TALEN loss-of-function, co-IP, Smad phosphorylation assay, domain mapping\",\n      \"pmids\": [\"30324105\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Conservation to mammalian BMP signaling not directly shown\", \"Single lab\", \"Isoform (BRAM1) contribution in vivo not delineated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Refined the host-restriction model, showing type 2 EBNA2 carries a third PXLXP motif binding an extra CC-MYND dimer, and that increased ZMYND11 association restricts EBNA2 function.\",\n      \"evidence\": \"Pull-down, SAXS, mutagenesis, B-cell growth and gene expression assays\",\n      \"pmids\": [\"31283782\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"High-resolution structure of the trimeric assembly lacking\", \"Quantitative cellular ZMYND11 stoichiometry unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the leukemogenic mechanism of the ZMYND11-MBTD1 fusion: it recruits NuA4/TIP60 to pro-leukemic cis-regulatory elements, sustaining active acetylated chromatin, and requires both TIP60 interaction and the PWWP H3K36me3-reading domain.\",\n      \"evidence\": \"Murine HSPC transformation, in vivo AML model, ChIP-seq, systematic domain mutagenesis, co-IP, bromodomain inhibitor\",\n      \"pmids\": [\"33594072\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How fusion converts repressive reading into activation mechanistically incomplete\", \"Therapeutic window not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed the fusion stably integrates into endogenous NuA4/TIP60 and mislocalizes it to ZMYND11-occupied gene bodies, driving MYC-centered acetylation, transcription, splicing changes, and HSPC self-renewal.\",\n      \"evidence\": \"Complex purification, ChIP-seq, RNA-seq, splicing analysis, ESC differentiation and self-renewal assays\",\n      \"pmids\": [\"35705031\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct MYC regulatory element causality not isolated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified an arginine-methyl reading function: the MYND domain binds R194-methylated HNRNPA1 to retain it in the nucleus, restrain stress granule formation, and counter HNRNPA1-driven PKM2/PKM1 shift, disrupted by PRMT5 inhibition.\",\n      \"evidence\": \"Co-IP, MYND mutagenesis, stress granule imaging, PKM ratio assay, PRMT5 inhibitor, tumor formation assay\",\n      \"pmids\": [\"39341825\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of methyl-arginine recognition by MYND not solved\", \"Single lab\", \"In vivo relevance of metabolic shift untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Completed the abundance-control circuit by identifying USP53 as a deubiquitinase that stabilizes ZMYND11, partly mediating USP53 anti-tumor effects in breast cancer.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, domain deletion, gain/loss rescue, xenograft\",\n      \"pmids\": [\"39044157\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin chain type removed not characterized\", \"Counterbalancing E3 in this context not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected ZMYND11 to neurodevelopmental disease mechanism: loss derepresses non-neuronal programs via failure to inhibit KMT2A, impairs dendritic morphology, and a ZRSID point mutation abolishes the KMT2A interaction, with revumenib attenuating the phenotype.\",\n      \"evidence\": \"Neuronal conditional knockout, co-IP, disease-variant mutagenesis, KMT2A inhibition, morphology, RNA-seq (preprint)\",\n      \"pmids\": [\"41279818\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Direct vs indirect KMT2A inhibition mechanism unresolved\", \"Genotype-phenotype scope across ZRSID variants limited\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined neurodevelopmental and neurogenic roles, showing ZMYND11 controls progenitor/neuron production through a brain-specific RBFOX2-dependent isoform switch and through Epha2/PI3K signaling coupled to H3K36me3 and Pol II occupancy.\",\n      \"evidence\": \"hPSC cortical differentiation, mouse KO, RNA-seq, splicing analysis, ChIP (H3K36me3, Pol II), Epha2 rescue, neurogenesis assays\",\n      \"pmids\": [\"41068108\", \"40281637\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct targets of the RBFOX2 isoform switch not enumerated\", \"Mechanism linking H3K36me3 gain to Pol II loss at Epha2 unclear\", \"Two independent models, single labs each\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Provided a structural and genomic refinement: crystal structures of WH, PHD, and CC-MYND domains reveal redox/pH-sensitive oligomerization and nucleic-acid/histone binding cooperation, and ZMYND11 robustly occupies promoters where its loss reduces Pol II pausing and H3.3/H3K36me3, with a new ALKBH6 interaction.\",\n      \"evidence\": \"Crystal structures, ITC, mutagenesis, co-IP (ALKBH6); CUT&Tag, ChIP-seq, pausing index, RNA-seq, ROS and proliferation assays\",\n      \"pmids\": [\"41591843\", \"42262664\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of ALKBH6 interaction not established\", \"Physiological relevance of redox-sensitive oligomerization unclear\", \"How promoter occupancy reconciles with elongation control incomplete\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ZMYND11's H3.3K36me3 reading is mechanistically converted into Pol II pausing/elongation control versus the activation imposed by the ZMYND11-MBTD1 fusion, and how its many partner interactions are coordinated in time and space, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of ZMYND11 engaging Pol II or pausing machinery\", \"Effector linking reading to repression at elongation undefined\", \"Integration of nuclear chromatin reading with cytoplasmic signaling roles unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 4, 10, 16, 20]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [16, 17]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [30]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2, 8, 21]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 8, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 9, 10]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [9, 16]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 5, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 16, 31]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [9, 16, 23]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [17, 28]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [23, 24, 27]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [10, 31]}\n    ],\n    \"complexes\": [\n      \"NuA4/TIP60 acetyltransferase complex (via ZMYND11-MBTD1 fusion)\",\n      \"U5 snRNP/spliceosome\",\n      \"p53-p400 complex\"\n    ],\n    \"partners\": [\n      \"EFTUD2\",\n      \"EBNA2\",\n      \"LMP1\",\n      \"MGA\",\n      \"ETS2\",\n      \"KMT2A\",\n      \"HNRNPA1\",\n      \"USP53\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":10,"faith_pct":90.0}}