{"gene":"ZMYND8","run_date":"2026-04-28T23:00:24","timeline":{"discoveries":[{"year":2015,"finding":"ZMYND8 bromodomain changes localization in response to DNA damage and recruits the NuRD (nucleosome remodeling and histone deacetylation) complex to damaged chromatin to repress transcription and promote repair by homologous recombination at transcriptionally active regions.","method":"Fluorescence microscopy (localization screen), Co-IP, ChIP, HR repair assays, knockdown with defined phenotypic readout","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, ChIP, functional HR assay, replicated across multiple studies","pmids":["25593309"],"is_preprint":false},{"year":2016,"finding":"ZMYND8 (RACK7) forms a biochemical complex with the histone H3K4me3-specific demethylase KDM5C and occupies active enhancers including super-enhancers; loss of RACK7 or KDM5C causes enhancer overactivation characterized by H3K4me3 and H3K27Ac deposition and increased eRNA transcription.","method":"Biochemical co-purification, ChIP-seq, RNA-seq, KO/KD with defined chromatin and transcriptional phenotype","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods, independent functional validation","pmids":["27058665"],"is_preprint":false},{"year":2016,"finding":"ZMYND8 PHD-Bromodomain cassette recognizes the dual histone mark H3K4me1-H3K14ac (and H3K4me0-H3K14ac) and acts as a transcriptional co-repressor by recruiting histone demethylase JARID1D, antagonizing expression of metastasis-linked genes.","method":"Histone peptide pulldown, Co-IP, domain mutagenesis, ChIP-seq, invasion assays in vitro and in vivo","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 — combinatorial histone mark binding defined by mutagenesis and peptide pulldown, functional validation in multiple contexts","pmids":["27477906"],"is_preprint":false},{"year":2017,"finding":"Histone demethylase KDM5A demethylates H3K4me3 near DNA double-strand breaks, and this demethylation is required for ZMYND8-NuRD binding to chromatin and recruitment to damage sites; KDM5A deficiency impairs ZMYND8-NuRD-dependent transcriptional silencing and HR repair.","method":"ChIP, Co-IP, KDM5A KD with HR repair assay, epistasis between KDM5A and ZMYND8-NuRD","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — epistatic placement with orthogonal ChIP and functional assays, replicated","pmids":["28572115"],"is_preprint":false},{"year":2016,"finding":"The MYND domain of ZMYND8 directly interacts with PPPLΦ motifs in the NuRD subunit GATAD2A, bridging ZMYND8 to specific NuRD subcomplexes; GATAD2A and GATAD2B form mutually exclusive NuRD subcomplexes, and the MYND domain facilitates poly(ADP-ribose)-dependent rapid recruitment of GATAD2A/NuRD to DNA damage sites to promote HR.","method":"Mass spectrometry interactome, Co-IP, domain mutagenesis, live-cell imaging at laser-induced DSBs, PARP inhibition","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 — direct domain-motif interaction mapped, reconstitution-level evidence, functional HR readout","pmids":["27732854"],"is_preprint":false},{"year":2016,"finding":"Crystal structure of the ZMYND8 PHD-BRD-PWWP triple reader cassette reveals a rigid structural supramodule that simultaneously engages multiple histone PTMs and DNA; disruption of any single domain impairs multivalent chromatin engagement and recruitment to DNA damage sites.","method":"X-ray crystallography, histone peptide binding assays, domain mutagenesis, live-cell DNA damage recruitment assay","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with mutagenesis and functional validation","pmids":["27926874"],"is_preprint":false},{"year":2015,"finding":"ZMYND8 selectively reads H3.1K36me2/H4K16ac marks through its conserved chromatin-binding modules and is recruited to ATRA-responsive developmental gene promoters; ZMYND8 interacts with Ser5-phosphorylated (initiation-competent) RNA Pol II in a DNA template-dependent manner to modulate transcription.","method":"Histone peptide pulldown, Co-IP with RNA Pol II CTD, ChIP, ATRA treatment, domain mutagenesis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods in a single study, not independently replicated","pmids":["26655721"],"is_preprint":false},{"year":2018,"finding":"ZMYND8 interacts with HIF-1α and HIF-2α and promotes elongation of HIF-induced oncogenic genes by increasing BRD4 recruitment and release of paused RNA Pol II; ZMYND8 acetylation at K1007 and K1034 by p300 is required for HIF activation and breast cancer progression.","method":"Co-IP, ChIP, RNA Pol II pausing analysis, acetylation site mutagenesis (K→R), in vitro acetylation assay, mouse metastasis model","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1-2 — site-specific mutagenesis, in vitro acetylation, multiple chromatin assays, in vivo validation","pmids":["29629903"],"is_preprint":false},{"year":2018,"finding":"ZMYND8, through direct association with CyclinT1, forms a ZMYND8-P-TEFb complex that activates transcription; ZMYND8 homodimerizes via its coiled-coil domain to preferentially associate with P-TEFb (activator), while the monomer associates with CHD4/NuRD (repressor), providing a dual activator/repressor switch.","method":"Biochemical reconstitution, Co-IP, reporter gene assay, domain mutagenesis (coiled-coil), ATRA-induced differentiation assay","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 — biochemical reconstitution of minimal complex, domain mutagenesis, functional reporter assay","pmids":["30134174"],"is_preprint":false},{"year":2017,"finding":"Crystal structure of Drebrin ADF-H domain in complex with ZMYND8 PHD-BRD-PWWP supramodule shows that Drebrin ADF-H competes with modified histones for ZMYND8 binding and can shuttle ZMYND8 from nucleus to cytoplasm, suggesting cytoplasmic sequestration as a regulatory mechanism.","method":"X-ray crystallography, competitive binding assay, live-cell fluorescence imaging (nuclear-cytoplasmic fractionation)","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus competition assay and live-cell localization consequence","pmids":["28966017"],"is_preprint":false},{"year":2010,"finding":"In Xenopus, ZMYND8 was identified as a binding partner of RCOR2 via yeast two-hybrid and confirmed by Co-IP; both proteins function as transcriptional repressors and co-localize in the nervous system; overexpression of XZMYND8 inhibits neural differentiation in Xenopus embryos.","method":"Yeast two-hybrid screen, Co-IP, overexpression in Xenopus embryos with neural differentiation readout","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 — single Co-IP plus in vivo overexpression, single lab","pmids":["20331974"],"is_preprint":false},{"year":2000,"finding":"PRKCBP1 (ZMYND8) was identified as a RACK family protein whose carboxy terminus interacts specifically with PKCβI by GST pulldown/immunoprecipitation assay.","method":"GST pulldown, immunoprecipitation with GST-fused PRKCBP1","journal":"Mammalian genome","confidence":"Low","confidence_rationale":"Tier 3 — single pulldown, single lab, not replicated","pmids":["11003709"],"is_preprint":false},{"year":2018,"finding":"ZMYND8 binds to and regulates the 3' Igh super-enhancer (3'RR) in B cells, controlling its transcriptional status; ZMYND8 deficiency increases polymerase loading at the 3'RR but decreases acceptor region transcription, impairing both class switch recombination and somatic hypermutation.","method":"ChIP-seq, B cell-specific KO mice, CSR and SHM assays, RNA Pol II ChIP","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 — clean genetic KO with defined mechanistic phenotype at super-enhancer, multiple assays","pmids":["30293785"],"is_preprint":false},{"year":2019,"finding":"The lncRNA TROJAN binds to ZMYND8 and increases its degradation through the ubiquitin-proteasome pathway by repelling the stabilizing factor ZNF592, thereby upregulating ZMYND8 target metastasis-related genes in TNBC.","method":"RNA pulldown, Co-IP, ubiquitination assay, ZNF592 interaction studies, gene expression analysis","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 3 — single-lab RNA-protein interaction with functional proteasome and ZNF592 validation","pmids":["30854423"],"is_preprint":false},{"year":2020,"finding":"RACK7 (ZMYND8) recognizes histone H3.3G34R patient mutation in vitro and in vivo, and binding of RACK7 to H3.3G34R suppresses transcription of CIITA and downstream MHC class II genes; CRISPR knock-in correction of H3.3G34R reduces RACK7 chromatin binding and derepresses these genes.","method":"In vitro binding assay, ChIP-seq, CRISPR knock-in correction, RACK7 KO in patient-derived cells","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 — direct in vitro binding plus orthogonal CRISPR genetics and ChIP validation","pmids":["32832624"],"is_preprint":false},{"year":2021,"finding":"ZMYND8 binds to EZH2, and this interaction is enhanced by CDK1-mediated phosphorylation of EZH2 at T487; ZMYND8 is required for EZH2-FOXM1 interaction and FOXM1-dependent MMP gene expression and cancer cell migration, constituting a polycomb-independent oncogenic switch.","method":"Co-IP, CDK1 phosphorylation assay, ZMYND8 KD with FOXM1/MMP expression and migration readout, domain mapping","journal":"PNAS","confidence":"Medium","confidence_rationale":"Tier 2 — multiple Co-IPs, phosphorylation-dependent interaction tested, functional migration assay, single lab","pmids":["33593912"],"is_preprint":false},{"year":2021,"finding":"ZMYND8 directly activates IRF8 and MYC through their lineage-specific enhancers in AML; ZMYND8 binds the ET domain of BRD4 via its chromatin reader cassette, and this interaction is required for proper chromatin occupancy and maintenance of AML proliferation.","method":"ChIP-seq in cell lines and patient samples, BRD4 Co-IP/domain mapping, ZMYND8 KO with in vitro and in vivo AML proliferation assay","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP with domain mapping, ChIP-seq, in vivo mouse model validation","pmids":["34358447"],"is_preprint":false},{"year":2021,"finding":"ZMYND8 and SREBP2 drive enhancer-promoter interaction to recruit the Mediator complex and upregulate mevalonate pathway genes; loss of ZMYND8 restricts cholesterol biosynthesis and intestinal tumorigenesis in a YAP-dependent context.","method":"ChIP-seq, HiChIP (enhancer-promoter interaction), Co-IP with Mediator, ZMYND8 KO with metabolic and tumorigenesis readout","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 — chromatin looping assay, Mediator Co-IP, in vivo genetic model","pmids":["33932349"],"is_preprint":false},{"year":2021,"finding":"E3 ubiquitin ligase FBXW7 directly interacts with ZMYND8 and degrades it via polyubiquitination, controlling ZMYND8 protein stability; low FBXW7 leads to ZMYND8 accumulation promoting bladder cancer progression.","method":"Co-IP, ubiquitination assay, FBXW7/ZMYND8 interaction mapping, KD/KO with tumor growth readout","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 3 — single-lab Co-IP and ubiquitination assay with in vivo validation","pmids":["34487730"],"is_preprint":false},{"year":2020,"finding":"ZMYND8 maintains genome stability in breast cancer cells; ZMYND8 loss triggers micronucleus formation, activation of cGAS in micronuclei, and downstream STING/NF-κB signaling (but not TBK1/IRF3), inducing IFNβ and ISG expression and promoting CD4+/CD8+ T cell infiltration and tumor inhibition.","method":"ZMYND8 KO with micronucleus assay, cGAS/STING pathway analysis, in vivo syngeneic tumor model with T cell depletion","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with mechanistic pathway dissection, in vivo validation, single lab","pmids":["33148660"],"is_preprint":false},{"year":2022,"finding":"ZMYND8 is a master transcriptional regulator of 27-hydroxycholesterol metabolism, increasing cholesterol biosynthesis/oxidation and blocking efflux/catabolism; 27-HC accumulation activates liver X receptor to promote EMT and tumor initiation.","method":"ZMYND8 KO in mouse mammary tumor models, metabolomics, ChIP, gene expression with LXR pathway assays","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 — metabolomics plus ChIP, genetic mouse model, functional EMT assay, single lab","pmids":["35857506"],"is_preprint":false},{"year":2024,"finding":"ZMYND8 increases NRF2 protein stability by silencing KEAP1 (indirect), and also directly interacts with NRF2 and recruits it to promoters of antioxidant genes; NRF2 in turn directly controls ZMYND8 expression, forming a positive feedback loop that sustains BCSC survival by inhibiting ROS and ferroptosis.","method":"Co-IP (ZMYND8-NRF2), ChIP, ZMYND8/NRF2 KO/KD with ROS and ferroptosis assays, mammosphere formation","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, ChIP, epistasis via NRF2 KO rescue, multiple functional readouts","pmids":["38488001"],"is_preprint":false},{"year":2024,"finding":"USP7 directly binds the PBP (PHD-BRD-PWWP) domain of ZMYND8 via its TRAF and UBL domains and removes FBXW7-catalyzed poly-ubiquitin chains at K1034 of ZMYND8, stabilizing ZMYND8 and stimulating transcription of target genes ZEB1 and VEGFA to enhance breast cancer migration and invasion.","method":"Co-IP with domain mapping, in vitro deubiquitination assay, site-specific mutagenesis (K1034), target gene expression and migration assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro deubiquitination assay, domain-level binding mapped, site mutagenesis, functional rescue","pmids":["39128723"],"is_preprint":false},{"year":2022,"finding":"ARID1A-containing BAF complexes maintain histone H3.3 at super-enhancers; ARID1A is required for CHD4 (NuRD) recruitment to H3.3-marked regions; ZMYND8 interacts with CHD4 to suppress a subset of H3.3+/H4K16ac+ super-enhancers regulating EMT-related genes.","method":"ChIP-seq, ATAC-seq, H3.3 native ChIP, ARID1A KD epistasis with CHD4 and ZMYND8 Co-IP","journal":"BMC biology","confidence":"Medium","confidence_rationale":"Tier 2-3 — genome-wide epistasis analysis with Co-IP, single lab","pmids":["36153585"],"is_preprint":false},{"year":2022,"finding":"Missense variants in the PWWP domain of ZMYND8 abolish its interaction with Drebrin, and missense variants in the MYND domain disrupt the interaction with GATAD2A; neuronal knockdown of the Drosophila ZMYND8 ortholog causes decreased habituation learning.","method":"Yeast two-hybrid assay, molecular modeling, Drosophila neuronal knockdown with behavioral phenotype","journal":"Genetics in medicine","confidence":"Medium","confidence_rationale":"Tier 3 — yeast two-hybrid and modeling, in vivo fly behavioral phenotype, clinically defined variants","pmids":["35916866"],"is_preprint":false},{"year":2025,"finding":"FOXM1 stabilizes ZMYND8 binding to H3K4me1-H3K14ac-marked chromatin; antiandrogen therapy releases SWI/SNF from the androgen receptor, enabling SWI/SNF interaction with ZMYND8-FOXM1 to upregulate neuroendocrine lineage regulators, driving NEPC transdifferentiation.","method":"CRISPR-Cas9 screen combined with scRNA-seq, ChIP-seq, Co-IP (ZMYND8-FOXM1-SWI/SNF), small molecule inhibitor iZMYND8-34 in NEPC models","journal":"Nature cancer","confidence":"High","confidence_rationale":"Tier 2 — multi-orthogonal approach (CRISPR screen, scRNA-seq, ChIP-seq, Co-IP, small molecule validation)","pmids":["40102673"],"is_preprint":false},{"year":2025,"finding":"ZMYND8 enhances cPLA2α expression through c-Myc induction; cPLA2α inactivates phosphatidylcholine-specific phospholipase C, reducing phosphatidylcholine breakdown to diacylglycerol, which diminishes PKC activity and leads to IL-27 secretion conferring trastuzumab/pertuzumab resistance.","method":"ChIP, Co-IP, cPLA2α KD/KO with phospholipid metabolite measurements, IL-27 rescue experiments, patient-derived organoids, PDX models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — mechanistic pathway dissected with metabolomics, multiple orthogonal assays, patient-derived and in vivo validation","pmids":["40281007"],"is_preprint":false},{"year":2025,"finding":"RACK7 (ZMYND8) interacts with PRC2 complex and establishes genomic localization of SUZ12 and H3K27 methylation in astrocytes; Rack7 deletion in astrocytes causes genome-wide decrease in H3K27me3 and derepression of Wnt signaling pathway genes, impairing astrocyte development.","method":"Conditional KO mouse model, Co-IP (RACK7-PRC2), ChIP-seq (H3K27me3, SUZ12), RNA-seq","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 2 — clean conditional KO, reciprocal Co-IP, genome-wide ChIP-seq with mechanistic consequence","pmids":["40125808"],"is_preprint":false},{"year":2025,"finding":"ZMYND8 interacts with c-Myc directly and activates c-Myc transcriptional activity to promote the Warburg effect in pancreatic cancer; ZMYND8 physically associates with c-Myc as shown by Co-IP and proteomic profiling.","method":"Co-IP, proteomics, CUT&Tag, RNA-seq, in vivo xenograft with c-Myc KD rescue","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP plus multi-omic analysis, single lab","pmids":["40579459"],"is_preprint":false},{"year":2025,"finding":"ZMYND8's PWWP domain reads H3K36me2 and activates CEBPE transcription in an H3K36me2-dependent manner; ZMYND8-driven CEBPE expression suppresses adaptive UPR pathways (ERN1, XBP1, ATF6) to inhibit multiple myeloma cell survival.","method":"Co-IP, ChIP, domain mutagenesis (PWWP), CUT&RUN, RNA-seq, KD/KO with UPR and proliferation assays","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 — domain mutagenesis and ChIP linking H3K36me2 to target gene activation, functional UPR epistasis, single lab","pmids":["40347515"],"is_preprint":false},{"year":2025,"finding":"ZMYND8 mediates ubiquitination and proteasomal degradation of HMGB1 in cardiomyocytes; trametinib (MEK inhibitor) inhibits ZMYND8-mediated ubiquitination of HMGB1, causing its accumulation and cardiomyocyte death.","method":"Co-IP, ubiquitination assay, ZMYND8 KD/KO in cardiomyocytes, HMGB1 stability assay, cardiac function readout in mice","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2-3 — ubiquitination assay, Co-IP, in vivo mouse cardiac phenotype, single lab","pmids":["41423035"],"is_preprint":false},{"year":2026,"finding":"Crystal structure of the ZMYND8 coiled-coil MYND domain reveals a homodimeric architecture; the MYND domain recognizes proline-rich motifs in GATAD2A's central region with moderate affinity enhanced by multivalency; ZMYND8 recruits GATAD2A specifically to the MAPT213 internal regulatory region to suppress MAPT213 lncRNA transcription while promoting MAPT protein-coding transcript expression.","method":"X-ray crystallography, ChIP, Co-IP, domain mutagenesis, quantitative binding measurements","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus mutagenesis plus ChIP functional validation","pmids":["41999894"],"is_preprint":false},{"year":2025,"finding":"RACK7 rapidly redistributes from repressed to activated enhancers in response to acute stimulations in a transcription-dependent manner and positively regulates enhancer activation by promoting RNA Pol II recruitment.","method":"ChIP-seq under acute stimulation conditions, RNA Pol II ChIP, transcription inhibitor experiments","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 — genome-wide ChIP-seq with pharmacological perturbation, single lab","pmids":["40734674"],"is_preprint":false},{"year":2025,"finding":"OTUD4 deubiquitinase directly interacts with and stabilizes ZMYND8; ZMYND8 acts as a scaffold promoting DDX3X-CK1ε complex assembly and WNT/β-catenin activation, which upregulates CSF1 to promote M2 macrophage polarization and immunosuppressive niche formation in TNBC spinal metastasis.","method":"Co-IP, deubiquitination assay, ZMYND8 KD with WNT signaling and macrophage polarization readout, in vivo spinal metastasis model","journal":"Neoplasia","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP with functional pathway validation, single lab","pmids":["41297414"],"is_preprint":false}],"current_model":"ZMYND8 is a multivalent chromatin reader that uses its PHD-BRD-PWWP supramodule to recognize combinatorial histone marks (H3K4me1-H3K14ac, H3K36me2, H4K16ac) and DNA simultaneously; its MYND domain directly engages PPPLΦ motifs in NuRD subunit GATAD2A to recruit the NuRD complex, while its coiled-coil domain mediates homodimerization that determines whether it associates with the activating P-TEFb complex or the repressive NuRD/CHD4 complex; at DNA double-strand breaks it is recruited to damaged active chromatin in a KDM5A-dependent (H3K4me3 demethylation) and poly(ADP-ribose)-dependent manner to silence transcription and promote homologous recombination, and its activity is regulated post-translationally by p300-mediated acetylation (K1007/K1034), FBXW7-mediated polyubiquitination/degradation, and USP7-mediated deubiquitination, while Drebrin can sequester the entire PHD-BRD-PWWP supramodule to the cytoplasm."},"narrative":{"teleology":[{"year":2010,"claim":"Establishing ZMYND8 as a transcriptional repressor with neuronal relevance: before this, ZMYND8 lacked functional characterization beyond PKCβI binding; interaction with RCOR2 and neural differentiation inhibition upon overexpression placed it in a repressive transcriptional context.","evidence":"Yeast two-hybrid and Co-IP in Xenopus, embryo overexpression with neural differentiation readout","pmids":["20331974"],"confidence":"Medium","gaps":["Not replicated independently","Mammalian relevance of RCOR2 interaction not confirmed","Mechanism of repression undefined"]},{"year":2015,"claim":"Defining ZMYND8 as a DNA damage-responsive factor that recruits NuRD to silence transcription at breaks and promote HR resolved a key question about how transcriptionally active chromatin is silenced during repair.","evidence":"Fluorescence microscopy localization screen, Co-IP with NuRD, ChIP, HR repair assays in human cells","pmids":["25593309"],"confidence":"High","gaps":["Upstream signal triggering ZMYND8 recruitment not yet defined","Histone mark specificity at damage sites unclear"]},{"year":2016,"claim":"Structural and biochemical dissection of the PHD-BRD-PWWP supramodule as a rigid multivalent reader that simultaneously engages histone PTMs and DNA explained how ZMYND8 achieves chromatin targeting specificity; parallel work defined H3K4me1-H3K14ac as a preferred dual mark and mapped the MYND-GATAD2A interface.","evidence":"X-ray crystallography of the triple reader cassette, histone peptide pulldowns and mutagenesis, mass spectrometry interactome with GATAD2A domain mapping, live-cell DNA damage recruitment","pmids":["27926874","27477906","27732854"],"confidence":"High","gaps":["Full-length ZMYND8 structure unresolved","Contribution of DNA binding versus histone binding in vivo not quantitated"]},{"year":2016,"claim":"Discovering that ZMYND8 partners with KDM5C at active enhancers and super-enhancers, where their loss causes H3K4me3 gain and enhancer overactivation, established ZMYND8 as a guardian of enhancer homeostasis beyond DNA damage.","evidence":"Co-purification, ChIP-seq, RNA-seq with KO/KD in breast cancer cells","pmids":["27058665"],"confidence":"High","gaps":["Whether KDM5C and KDM5A act redundantly at enhancers unknown","Mechanism of ZMYND8-KDM5C cooperation not structurally resolved"]},{"year":2017,"claim":"KDM5A-mediated H3K4me3 demethylation was shown to be prerequisite for ZMYND8-NuRD binding at DSBs, placing ZMYND8 downstream of a histone demethylation step and explaining mark-dependent recruitment; the Drebrin crystal structure revealed a cytoplasmic sequestration mechanism that competes with chromatin binding.","evidence":"KDM5A KD with epistasis to ZMYND8/HR, ChIP; X-ray crystallography of Drebrin ADF-H–ZMYND8 complex with competitive binding and localization assays","pmids":["28572115","28966017"],"confidence":"High","gaps":["Physiological conditions triggering Drebrin-mediated sequestration unknown","Whether KDM5A acts catalytically or as a scaffold not fully distinguished"]},{"year":2018,"claim":"A dimerization-dependent functional switch was uncovered: homodimeric ZMYND8 associates with P-TEFb via CyclinT1 to activate transcription, while monomeric ZMYND8 binds CHD4/NuRD to repress, resolving the paradox of ZMYND8 acting as both activator and repressor.","evidence":"Biochemical reconstitution of ZMYND8-P-TEFb, coiled-coil domain mutagenesis, reporter assays, ATRA differentiation","pmids":["30134174"],"confidence":"High","gaps":["What controls the dimer–monomer equilibrium in vivo is unknown","Structural basis of CyclinT1 interaction not determined"]},{"year":2018,"claim":"p300-mediated acetylation of ZMYND8 at K1007/K1034 was shown to be required for HIF transcriptional activation and BRD4 recruitment, establishing post-translational regulation of ZMYND8 coactivator function and linking it to hypoxic oncogenesis; separately, ZMYND8 was found to regulate Igh super-enhancer activity controlling class switch recombination and somatic hypermutation in B cells.","evidence":"K-to-R site mutagenesis with in vitro acetylation, ChIP, Pol II pausing analysis, mouse metastasis model; B cell-specific KO with CSR/SHM assays","pmids":["29629903","30293785"],"confidence":"High","gaps":["Whether acetylation-dependent and dimerization-dependent activation are the same pathway is unclear","Acetylation dynamics and opposing deacetylase not identified"]},{"year":2020,"claim":"ZMYND8 was found to recognize the oncohistone H3.3G34R mutation, suppressing CIITA and MHC-II expression; loss of ZMYND8 triggered cGAS-STING innate immune signaling via micronucleus formation, revealing ZMYND8 as a genome stability factor with immune-evasion consequences.","evidence":"In vitro binding and ChIP-seq for H3.3G34R recognition, CRISPR knock-in correction; ZMYND8 KO with micronucleus assay and cGAS-STING pathway analysis in syngeneic tumor models","pmids":["32832624","33148660"],"confidence":"High","gaps":["Structural basis of H3.3G34R recognition not resolved","Whether genome instability is direct or via transcriptional deregulation unknown"]},{"year":2021,"claim":"ZMYND8 was shown to directly interact with BRD4's ET domain in AML and to cooperate with SREBP2 and Mediator at enhancer-promoter loops for cholesterol biosynthesis, broadening its role to lineage-specific transcriptional activation and metabolic gene regulation.","evidence":"Reciprocal Co-IP with BRD4 domain mapping, ChIP-seq in AML patient samples, in vivo AML model; HiChIP, Mediator Co-IP, ZMYND8 KO with metabolic and tumorigenesis readout","pmids":["34358447","33932349"],"confidence":"High","gaps":["Whether BRD4-ET and P-TEFb interactions are concurrent or mutually exclusive unknown","Mediator subunit specificity not defined"]},{"year":2022,"claim":"FBXW7 was identified as the E3 ligase that polyubiquitinates and degrades ZMYND8, and clinically observed ZMYND8 missense variants were shown to disrupt specific domain interactions (PWWP–Drebrin, MYND–GATAD2A), with a Drosophila ortholog knockdown linking ZMYND8 to habituation learning.","evidence":"Co-IP and ubiquitination assays for FBXW7; yeast two-hybrid with patient variants and Drosophila neuronal KD with behavioral phenotype","pmids":["34487730","35916866"],"confidence":"Medium","gaps":["FBXW7 degron motif on ZMYND8 not mapped","Mammalian neurological phenotype of ZMYND8 loss not established","ZMYND8 variant pathogenicity not confirmed in mammalian neurons"]},{"year":2024,"claim":"USP7 was identified as the deubiquitinase that directly reverses FBXW7-catalyzed polyubiquitination at K1034, stabilizing ZMYND8; a ZMYND8-NRF2 positive feedback loop was shown to suppress ferroptosis in breast cancer stem cells, connecting ZMYND8 to redox homeostasis.","evidence":"In vitro deubiquitination assay with domain mapping and K1034 mutagenesis; reciprocal Co-IP of ZMYND8-NRF2, ChIP, ROS and ferroptosis assays","pmids":["39128723","38488001"],"confidence":"High","gaps":["Whether USP7-ZMYND8 interaction is regulated by signaling is unknown","Structural basis of K1034 ubiquitination/deubiquitination not resolved"]},{"year":2025,"claim":"ZMYND8 was shown to interact with PRC2 to establish H3K27me3 domains in astrocytes, to dynamically redistribute to activated enhancers upon stimulation, and to cooperate with FOXM1 and SWI/SNF in driving neuroendocrine prostate cancer transdifferentiation, revealing context-dependent partnerships with multiple chromatin-modifying complexes.","evidence":"Conditional KO with ChIP-seq for PRC2/H3K27me3 in astrocytes; acute stimulation ChIP-seq; CRISPR screen with scRNA-seq and small molecule ZMYND8 inhibitor in NEPC models","pmids":["40125808","40734674","40102673"],"confidence":"High","gaps":["How ZMYND8 selects between NuRD, PRC2, P-TEFb, BRD4, and SWI/SNF at individual loci is unclear","Therapeutic window and selectivity of iZMYND8-34 not established"]},{"year":2025,"claim":"The coiled-coil MYND domain crystal structure confirmed homodimeric architecture and provided quantitative binding parameters for GATAD2A recognition; parallel studies extended ZMYND8 transcriptional programs to WNT/β-catenin signaling, phospholipid metabolism, and unfolded protein response suppression.","evidence":"X-ray crystallography of CC-MYND with quantitative binding; Co-IP with DDX3X-CK1ε for WNT; ChIP and metabolomics for cPLA2α/IL-27 axis; PWWP mutagenesis linking H3K36me2 to CEBPE and UPR","pmids":["41999894","41297414","40281007","40347515"],"confidence":"High","gaps":["Full-length ZMYND8 structure including disordered regions remains undetermined","Relative contribution of each target gene program to overall ZMYND8 biology in normal physiology unclear"]},{"year":null,"claim":"Unresolved: how ZMYND8 selects among its many chromatin-remodeling partners (NuRD, PRC2, SWI/SNF, P-TEFb, BRD4, Mediator) at individual genomic loci, and whether the dimer–monomer switch fully explains this selectivity, remain central open questions.","evidence":"","pmids":[],"confidence":"High","gaps":["Full-length structural model needed to understand allosteric regulation across domains","In vivo stoichiometry and dynamics of partner switching uncharacterized","Normal physiological role of ZMYND8 in non-cancer tissues (brain, immune, cardiac) remains poorly defined genetically in mammals"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[2,5,6,14,29]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,7,8,12,16,17,21,27,32]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,8,16,17,33]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,5,9,14]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[0,3,5,6]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[0,3,4]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,7,8,12,16,17,27,32]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[1,5,14,23,27]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[19]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[15,21,33]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[17,20]}],"complexes":["NuRD complex (via GATAD2A/CHD4)","P-TEFb complex (via CyclinT1)","PRC2 complex"],"partners":["GATAD2A","CHD4","BRD4","KDM5C","KDM5A","DBN1","USP7","FBXW7"],"other_free_text":[]},"mechanistic_narrative":"ZMYND8 is a multivalent chromatin reader and transcriptional regulator that integrates histone mark recognition with recruitment of chromatin-modifying complexes to control enhancer activity, DNA damage repair, and gene expression programs across diverse cell types. Its PHD-BRD-PWWP supramodule forms a rigid structural unit that simultaneously engages combinatorial histone modifications (H3K4me1-H3K14ac, H3K36me2, H4K16ac) and DNA, while its MYND domain directly binds PPPLΦ motifs in the NuRD subunit GATAD2A; homodimerization via the coiled-coil domain switches ZMYND8 between an activating P-TEFb-associated state and a repressive NuRD/CHD4-associated state [PMID:27926874, PMID:27732854, PMID:30134174, PMID:41999894]. At DNA double-strand breaks, KDM5A-mediated H3K4me3 demethylation and poly(ADP-ribose) signaling recruit ZMYND8-NuRD to silence transcription at damaged active chromatin and promote homologous recombination, while at enhancers ZMYND8 cooperates with KDM5C, BRD4, PRC2, and Mediator to modulate super-enhancer output, cholesterol biosynthesis, and immune gene regulation [PMID:25593309, PMID:28572115, PMID:27058665, PMID:34358447, PMID:33932349, PMID:40125808]. ZMYND8 protein stability is controlled by FBXW7-mediated polyubiquitination counteracted by USP7- and OTUD4-dependent deubiquitination, and its chromatin engagement is regulated by p300-mediated acetylation at K1007/K1034 and cytoplasmic sequestration by Drebrin [PMID:34487730, PMID:39128723, PMID:29629903, PMID:28966017]."},"prefetch_data":{"uniprot":{"accession":"Q9ULU4","full_name":"MYND-type zinc finger-containing chromatin reader ZMYND8","aliases":["Cutaneous T-cell lymphoma-associated antigen se14-3","CTCL-associated antigen se14-3","Protein kinase C-binding protein 1","Rack7","Transcription coregulator ZMYND8","Zinc finger MYND domain-containing protein 8"],"length_aa":1186,"mass_kda":131.7,"function":"Chromatin reader that recognizes dual histone modifications such as histone H3.1 dimethylated at 'Lys-36' and histone H4 acetylated at 'Lys-16' (H3.1K36me2-H4K16ac) and histone H3 methylated at 'Lys-4' and histone H4 acetylated at 'Lys-14' (H3K4me1-H3K14ac) (PubMed:26655721, PubMed:27477906, PubMed:31965980, PubMed:36064715). May act as a transcriptional corepressor for KDM5D by recognizing the dual histone signature H3K4me1-H3K14ac (PubMed:27477906). May also act as a transcriptional corepressor for KDM5C and EZH2 (PubMed:33323928). Recognizes acetylated histone H4 and recruits the NuRD chromatin remodeling complex to damaged chromatin for transcriptional repression and double-strand break repair by homologous recombination (PubMed:25593309, PubMed:27732854, PubMed:30134174). Also activates transcription elongation by RNA polymerase II through recruiting the P-TEFb complex to target promoters (PubMed:26655721, PubMed:30134174). Localizes to H3.1K36me2-H4K16ac marks at all-trans-retinoic acid (ATRA)-responsive genes and positively regulates their expression (PubMed:26655721). Promotes neuronal differentiation by associating with regulatory regions within the MAPT gene, to enhance transcription of a protein-coding MAPT isoform and suppress the non-coding MAPT213 isoform (PubMed:30134174, PubMed:35916866, PubMed:36064715). Suppresses breast cancer, and prostate cancer cell invasion and metastasis (PubMed:27477906, PubMed:31965980, PubMed:33323928)","subcellular_location":"Nucleus; Chromosome; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9ULU4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ZMYND8","classification":"Not Classified","n_dependent_lines":410,"n_total_lines":1208,"dependency_fraction":0.3394039735099338},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"HDAC2","stoichiometry":4.0},{"gene":"HDAC1","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"SSRP1","stoichiometry":0.2},{"gene":"TOP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ZMYND8","total_profiled":1310},"omim":[{"mim_id":"615713","title":"ZINC FINGER MYND DOMAIN-CONTAINING PROTEIN 8; ZMYND8","url":"https://www.omim.org/entry/615713"},{"mim_id":"610568","title":"ZINC FINGER PROTEIN 687; ZNF687","url":"https://www.omim.org/entry/610568"},{"mim_id":"606881","title":"FORMIN HOMOLOGY-2 DOMAIN-CONTAINING PROTEIN 1; FHOD1","url":"https://www.omim.org/entry/606881"},{"mim_id":"606671","title":"NCK-INTERACTING PROTEIN WITH SH3 DOMAIN; NCKIPSD","url":"https://www.omim.org/entry/606671"},{"mim_id":"314690","title":"LYSINE DEMETHYLASE 5C; KDM5C","url":"https://www.omim.org/entry/314690"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoli","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ZMYND8"},"hgnc":{"alias_symbol":["RACK7","KIAA1125"],"prev_symbol":["PRKCBP1"]},"alphafold":{"accession":"Q9ULU4","domains":[{"cath_id":"1.20.920.10","chopping":"85-266","consensus_level":"medium","plddt":95.0174,"start":85,"end":266},{"cath_id":"2.30.30.140","chopping":"268-390","consensus_level":"medium","plddt":92.3613,"start":268,"end":390},{"cath_id":"-","chopping":"1027-1060","consensus_level":"medium","plddt":92.8391,"start":1027,"end":1060},{"cath_id":"1.20.5","chopping":"960-1025","consensus_level":"medium","plddt":89.0076,"start":960,"end":1025}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULU4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULU4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULU4-F1-predicted_aligned_error_v6.png","plddt_mean":58.34},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ZMYND8","jax_strain_url":"https://www.jax.org/strain/search?query=ZMYND8"},"sequence":{"accession":"Q9ULU4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9ULU4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9ULU4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULU4"}},"corpus_meta":[{"pmid":"25593309","id":"PMC_25593309","title":"Screen 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Society","url":"https://pubmed.ncbi.nlm.nih.gov/11003709","citation_count":42,"is_preprint":false},{"pmid":"30134174","id":"PMC_30134174","title":"Positive Regulation of Transcription by Human ZMYND8 through Its Association with P-TEFb Complex.","date":"2018","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/30134174","citation_count":38,"is_preprint":false},{"pmid":"23667654","id":"PMC_23667654","title":"Fusion of ZMYND8 and RELA genes in acute erythroid leukemia.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23667654","citation_count":35,"is_preprint":false},{"pmid":"35857506","id":"PMC_35857506","title":"ZMYND8 is a master regulator of 27-hydroxycholesterol that promotes tumorigenicity of breast cancer stem cells.","date":"2022","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/35857506","citation_count":34,"is_preprint":false},{"pmid":"20331974","id":"PMC_20331974","title":"Xenopus RCOR2 (REST corepressor 2) interacts with ZMYND8, which is involved in neural differentiation.","date":"2010","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/20331974","citation_count":33,"is_preprint":false},{"pmid":"30293785","id":"PMC_30293785","title":"The Chromatin Reader ZMYND8 Regulates Igh Enhancers to Promote Immunoglobulin Class Switch Recombination.","date":"2018","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/30293785","citation_count":32,"is_preprint":false},{"pmid":"32832624","id":"PMC_32832624","title":"RACK7 recognizes H3.3G34R mutation to suppress expression of MHC class II complex components and their delivery pathway in pediatric glioblastoma.","date":"2020","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/32832624","citation_count":29,"is_preprint":false},{"pmid":"29393731","id":"PMC_29393731","title":"Double duty: ZMYND8 in the DNA damage response and cancer.","date":"2018","source":"Cell cycle (Georgetown, 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inhibits acute megakaryoblastic leukemia by altering the alternative splicing of ZMYND8.","date":"2025","source":"Cell & bioscience","url":"https://pubmed.ncbi.nlm.nih.gov/40223119","citation_count":0,"is_preprint":false},{"pmid":"36826993","id":"PMC_36826993","title":"Radiosensitization of IDH-Mutated Gliomas through ZMYND8 - a Pathway to Improved Outcomes.","date":"2023","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/36826993","citation_count":0,"is_preprint":false},{"pmid":"40734674","id":"PMC_40734674","title":"RACK7 senses and fine-tunes enhancer activity.","date":"2025","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/40734674","citation_count":0,"is_preprint":false},{"pmid":"41423035","id":"PMC_41423035","title":"MEK inhibitor induces cardiac complications by preventing ZMYND8-mediated ubiquitination and proteasomal degradation of HMGB1.","date":"2025","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41423035","citation_count":0,"is_preprint":false},{"pmid":"41297414","id":"PMC_41297414","title":"OTUD4-ZMYND8-DDX3X Axis Drives Immunosuppressive Microenvironment in Spinal Metastases of Triple-Negative Breast Cancer.","date":"2025","source":"Neoplasia (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/41297414","citation_count":0,"is_preprint":false},{"pmid":"41913198","id":"PMC_41913198","title":"The novel retinoid WYC-209 sensitizes multiple myeloma to carfilzomib via epigenetically upregulating ZMYND8.","date":"2026","source":"Experimental hematology & oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41913198","citation_count":0,"is_preprint":false},{"pmid":"41999894","id":"PMC_41999894","title":"The chromatin reader ZMYND8 recruits the NuRD component GATAD2A through its MYND domain to regulate MAPT213 long noncoding RNA transcription.","date":"2026","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41999894","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.02.18.638898","title":"ABL Kinases Modulate EZH2 Phosphorylation and Signaling in Metastatic Triple Negative Breast Cancer","date":"2025-02-23","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.18.638898","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":24952,"output_tokens":7805,"usd":0.095965},"stage2":{"model":"claude-opus-4-6","input_tokens":11600,"output_tokens":4286,"usd":0.247725},"total_usd":0.34369,"stage1_batch_id":"msgbatch_01BparvgRZ9S2LMidvaoo86K","stage2_batch_id":"msgbatch_01NkBfv9SVZWthhS7j6mU6G3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"ZMYND8 bromodomain changes localization in response to DNA damage and recruits the NuRD (nucleosome remodeling and histone deacetylation) complex to damaged chromatin to repress transcription and promote repair by homologous recombination at transcriptionally active regions.\",\n      \"method\": \"Fluorescence microscopy (localization screen), Co-IP, ChIP, HR repair assays, knockdown with defined phenotypic readout\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, ChIP, functional HR assay, replicated across multiple studies\",\n      \"pmids\": [\"25593309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ZMYND8 (RACK7) forms a biochemical complex with the histone H3K4me3-specific demethylase KDM5C and occupies active enhancers including super-enhancers; loss of RACK7 or KDM5C causes enhancer overactivation characterized by H3K4me3 and H3K27Ac deposition and increased eRNA transcription.\",\n      \"method\": \"Biochemical co-purification, ChIP-seq, RNA-seq, KO/KD with defined chromatin and transcriptional phenotype\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, independent functional validation\",\n      \"pmids\": [\"27058665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ZMYND8 PHD-Bromodomain cassette recognizes the dual histone mark H3K4me1-H3K14ac (and H3K4me0-H3K14ac) and acts as a transcriptional co-repressor by recruiting histone demethylase JARID1D, antagonizing expression of metastasis-linked genes.\",\n      \"method\": \"Histone peptide pulldown, Co-IP, domain mutagenesis, ChIP-seq, invasion assays in vitro and in vivo\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — combinatorial histone mark binding defined by mutagenesis and peptide pulldown, functional validation in multiple contexts\",\n      \"pmids\": [\"27477906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Histone demethylase KDM5A demethylates H3K4me3 near DNA double-strand breaks, and this demethylation is required for ZMYND8-NuRD binding to chromatin and recruitment to damage sites; KDM5A deficiency impairs ZMYND8-NuRD-dependent transcriptional silencing and HR repair.\",\n      \"method\": \"ChIP, Co-IP, KDM5A KD with HR repair assay, epistasis between KDM5A and ZMYND8-NuRD\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistatic placement with orthogonal ChIP and functional assays, replicated\",\n      \"pmids\": [\"28572115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The MYND domain of ZMYND8 directly interacts with PPPLΦ motifs in the NuRD subunit GATAD2A, bridging ZMYND8 to specific NuRD subcomplexes; GATAD2A and GATAD2B form mutually exclusive NuRD subcomplexes, and the MYND domain facilitates poly(ADP-ribose)-dependent rapid recruitment of GATAD2A/NuRD to DNA damage sites to promote HR.\",\n      \"method\": \"Mass spectrometry interactome, Co-IP, domain mutagenesis, live-cell imaging at laser-induced DSBs, PARP inhibition\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct domain-motif interaction mapped, reconstitution-level evidence, functional HR readout\",\n      \"pmids\": [\"27732854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Crystal structure of the ZMYND8 PHD-BRD-PWWP triple reader cassette reveals a rigid structural supramodule that simultaneously engages multiple histone PTMs and DNA; disruption of any single domain impairs multivalent chromatin engagement and recruitment to DNA damage sites.\",\n      \"method\": \"X-ray crystallography, histone peptide binding assays, domain mutagenesis, live-cell DNA damage recruitment assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with mutagenesis and functional validation\",\n      \"pmids\": [\"27926874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ZMYND8 selectively reads H3.1K36me2/H4K16ac marks through its conserved chromatin-binding modules and is recruited to ATRA-responsive developmental gene promoters; ZMYND8 interacts with Ser5-phosphorylated (initiation-competent) RNA Pol II in a DNA template-dependent manner to modulate transcription.\",\n      \"method\": \"Histone peptide pulldown, Co-IP with RNA Pol II CTD, ChIP, ATRA treatment, domain mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in a single study, not independently replicated\",\n      \"pmids\": [\"26655721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ZMYND8 interacts with HIF-1α and HIF-2α and promotes elongation of HIF-induced oncogenic genes by increasing BRD4 recruitment and release of paused RNA Pol II; ZMYND8 acetylation at K1007 and K1034 by p300 is required for HIF activation and breast cancer progression.\",\n      \"method\": \"Co-IP, ChIP, RNA Pol II pausing analysis, acetylation site mutagenesis (K→R), in vitro acetylation assay, mouse metastasis model\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — site-specific mutagenesis, in vitro acetylation, multiple chromatin assays, in vivo validation\",\n      \"pmids\": [\"29629903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ZMYND8, through direct association with CyclinT1, forms a ZMYND8-P-TEFb complex that activates transcription; ZMYND8 homodimerizes via its coiled-coil domain to preferentially associate with P-TEFb (activator), while the monomer associates with CHD4/NuRD (repressor), providing a dual activator/repressor switch.\",\n      \"method\": \"Biochemical reconstitution, Co-IP, reporter gene assay, domain mutagenesis (coiled-coil), ATRA-induced differentiation assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical reconstitution of minimal complex, domain mutagenesis, functional reporter assay\",\n      \"pmids\": [\"30134174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Crystal structure of Drebrin ADF-H domain in complex with ZMYND8 PHD-BRD-PWWP supramodule shows that Drebrin ADF-H competes with modified histones for ZMYND8 binding and can shuttle ZMYND8 from nucleus to cytoplasm, suggesting cytoplasmic sequestration as a regulatory mechanism.\",\n      \"method\": \"X-ray crystallography, competitive binding assay, live-cell fluorescence imaging (nuclear-cytoplasmic fractionation)\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus competition assay and live-cell localization consequence\",\n      \"pmids\": [\"28966017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In Xenopus, ZMYND8 was identified as a binding partner of RCOR2 via yeast two-hybrid and confirmed by Co-IP; both proteins function as transcriptional repressors and co-localize in the nervous system; overexpression of XZMYND8 inhibits neural differentiation in Xenopus embryos.\",\n      \"method\": \"Yeast two-hybrid screen, Co-IP, overexpression in Xenopus embryos with neural differentiation readout\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP plus in vivo overexpression, single lab\",\n      \"pmids\": [\"20331974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"PRKCBP1 (ZMYND8) was identified as a RACK family protein whose carboxy terminus interacts specifically with PKCβI by GST pulldown/immunoprecipitation assay.\",\n      \"method\": \"GST pulldown, immunoprecipitation with GST-fused PRKCBP1\",\n      \"journal\": \"Mammalian genome\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single pulldown, single lab, not replicated\",\n      \"pmids\": [\"11003709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ZMYND8 binds to and regulates the 3' Igh super-enhancer (3'RR) in B cells, controlling its transcriptional status; ZMYND8 deficiency increases polymerase loading at the 3'RR but decreases acceptor region transcription, impairing both class switch recombination and somatic hypermutation.\",\n      \"method\": \"ChIP-seq, B cell-specific KO mice, CSR and SHM assays, RNA Pol II ChIP\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO with defined mechanistic phenotype at super-enhancer, multiple assays\",\n      \"pmids\": [\"30293785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The lncRNA TROJAN binds to ZMYND8 and increases its degradation through the ubiquitin-proteasome pathway by repelling the stabilizing factor ZNF592, thereby upregulating ZMYND8 target metastasis-related genes in TNBC.\",\n      \"method\": \"RNA pulldown, Co-IP, ubiquitination assay, ZNF592 interaction studies, gene expression analysis\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single-lab RNA-protein interaction with functional proteasome and ZNF592 validation\",\n      \"pmids\": [\"30854423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RACK7 (ZMYND8) recognizes histone H3.3G34R patient mutation in vitro and in vivo, and binding of RACK7 to H3.3G34R suppresses transcription of CIITA and downstream MHC class II genes; CRISPR knock-in correction of H3.3G34R reduces RACK7 chromatin binding and derepresses these genes.\",\n      \"method\": \"In vitro binding assay, ChIP-seq, CRISPR knock-in correction, RACK7 KO in patient-derived cells\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct in vitro binding plus orthogonal CRISPR genetics and ChIP validation\",\n      \"pmids\": [\"32832624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ZMYND8 binds to EZH2, and this interaction is enhanced by CDK1-mediated phosphorylation of EZH2 at T487; ZMYND8 is required for EZH2-FOXM1 interaction and FOXM1-dependent MMP gene expression and cancer cell migration, constituting a polycomb-independent oncogenic switch.\",\n      \"method\": \"Co-IP, CDK1 phosphorylation assay, ZMYND8 KD with FOXM1/MMP expression and migration readout, domain mapping\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple Co-IPs, phosphorylation-dependent interaction tested, functional migration assay, single lab\",\n      \"pmids\": [\"33593912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ZMYND8 directly activates IRF8 and MYC through their lineage-specific enhancers in AML; ZMYND8 binds the ET domain of BRD4 via its chromatin reader cassette, and this interaction is required for proper chromatin occupancy and maintenance of AML proliferation.\",\n      \"method\": \"ChIP-seq in cell lines and patient samples, BRD4 Co-IP/domain mapping, ZMYND8 KO with in vitro and in vivo AML proliferation assay\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with domain mapping, ChIP-seq, in vivo mouse model validation\",\n      \"pmids\": [\"34358447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ZMYND8 and SREBP2 drive enhancer-promoter interaction to recruit the Mediator complex and upregulate mevalonate pathway genes; loss of ZMYND8 restricts cholesterol biosynthesis and intestinal tumorigenesis in a YAP-dependent context.\",\n      \"method\": \"ChIP-seq, HiChIP (enhancer-promoter interaction), Co-IP with Mediator, ZMYND8 KO with metabolic and tumorigenesis readout\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — chromatin looping assay, Mediator Co-IP, in vivo genetic model\",\n      \"pmids\": [\"33932349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"E3 ubiquitin ligase FBXW7 directly interacts with ZMYND8 and degrades it via polyubiquitination, controlling ZMYND8 protein stability; low FBXW7 leads to ZMYND8 accumulation promoting bladder cancer progression.\",\n      \"method\": \"Co-IP, ubiquitination assay, FBXW7/ZMYND8 interaction mapping, KD/KO with tumor growth readout\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single-lab Co-IP and ubiquitination assay with in vivo validation\",\n      \"pmids\": [\"34487730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ZMYND8 maintains genome stability in breast cancer cells; ZMYND8 loss triggers micronucleus formation, activation of cGAS in micronuclei, and downstream STING/NF-κB signaling (but not TBK1/IRF3), inducing IFNβ and ISG expression and promoting CD4+/CD8+ T cell infiltration and tumor inhibition.\",\n      \"method\": \"ZMYND8 KO with micronucleus assay, cGAS/STING pathway analysis, in vivo syngeneic tumor model with T cell depletion\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with mechanistic pathway dissection, in vivo validation, single lab\",\n      \"pmids\": [\"33148660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ZMYND8 is a master transcriptional regulator of 27-hydroxycholesterol metabolism, increasing cholesterol biosynthesis/oxidation and blocking efflux/catabolism; 27-HC accumulation activates liver X receptor to promote EMT and tumor initiation.\",\n      \"method\": \"ZMYND8 KO in mouse mammary tumor models, metabolomics, ChIP, gene expression with LXR pathway assays\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — metabolomics plus ChIP, genetic mouse model, functional EMT assay, single lab\",\n      \"pmids\": [\"35857506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZMYND8 increases NRF2 protein stability by silencing KEAP1 (indirect), and also directly interacts with NRF2 and recruits it to promoters of antioxidant genes; NRF2 in turn directly controls ZMYND8 expression, forming a positive feedback loop that sustains BCSC survival by inhibiting ROS and ferroptosis.\",\n      \"method\": \"Co-IP (ZMYND8-NRF2), ChIP, ZMYND8/NRF2 KO/KD with ROS and ferroptosis assays, mammosphere formation\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, ChIP, epistasis via NRF2 KO rescue, multiple functional readouts\",\n      \"pmids\": [\"38488001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP7 directly binds the PBP (PHD-BRD-PWWP) domain of ZMYND8 via its TRAF and UBL domains and removes FBXW7-catalyzed poly-ubiquitin chains at K1034 of ZMYND8, stabilizing ZMYND8 and stimulating transcription of target genes ZEB1 and VEGFA to enhance breast cancer migration and invasion.\",\n      \"method\": \"Co-IP with domain mapping, in vitro deubiquitination assay, site-specific mutagenesis (K1034), target gene expression and migration assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro deubiquitination assay, domain-level binding mapped, site mutagenesis, functional rescue\",\n      \"pmids\": [\"39128723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ARID1A-containing BAF complexes maintain histone H3.3 at super-enhancers; ARID1A is required for CHD4 (NuRD) recruitment to H3.3-marked regions; ZMYND8 interacts with CHD4 to suppress a subset of H3.3+/H4K16ac+ super-enhancers regulating EMT-related genes.\",\n      \"method\": \"ChIP-seq, ATAC-seq, H3.3 native ChIP, ARID1A KD epistasis with CHD4 and ZMYND8 Co-IP\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — genome-wide epistasis analysis with Co-IP, single lab\",\n      \"pmids\": [\"36153585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Missense variants in the PWWP domain of ZMYND8 abolish its interaction with Drebrin, and missense variants in the MYND domain disrupt the interaction with GATAD2A; neuronal knockdown of the Drosophila ZMYND8 ortholog causes decreased habituation learning.\",\n      \"method\": \"Yeast two-hybrid assay, molecular modeling, Drosophila neuronal knockdown with behavioral phenotype\",\n      \"journal\": \"Genetics in medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — yeast two-hybrid and modeling, in vivo fly behavioral phenotype, clinically defined variants\",\n      \"pmids\": [\"35916866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FOXM1 stabilizes ZMYND8 binding to H3K4me1-H3K14ac-marked chromatin; antiandrogen therapy releases SWI/SNF from the androgen receptor, enabling SWI/SNF interaction with ZMYND8-FOXM1 to upregulate neuroendocrine lineage regulators, driving NEPC transdifferentiation.\",\n      \"method\": \"CRISPR-Cas9 screen combined with scRNA-seq, ChIP-seq, Co-IP (ZMYND8-FOXM1-SWI/SNF), small molecule inhibitor iZMYND8-34 in NEPC models\",\n      \"journal\": \"Nature cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multi-orthogonal approach (CRISPR screen, scRNA-seq, ChIP-seq, Co-IP, small molecule validation)\",\n      \"pmids\": [\"40102673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZMYND8 enhances cPLA2α expression through c-Myc induction; cPLA2α inactivates phosphatidylcholine-specific phospholipase C, reducing phosphatidylcholine breakdown to diacylglycerol, which diminishes PKC activity and leads to IL-27 secretion conferring trastuzumab/pertuzumab resistance.\",\n      \"method\": \"ChIP, Co-IP, cPLA2α KD/KO with phospholipid metabolite measurements, IL-27 rescue experiments, patient-derived organoids, PDX models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway dissected with metabolomics, multiple orthogonal assays, patient-derived and in vivo validation\",\n      \"pmids\": [\"40281007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RACK7 (ZMYND8) interacts with PRC2 complex and establishes genomic localization of SUZ12 and H3K27 methylation in astrocytes; Rack7 deletion in astrocytes causes genome-wide decrease in H3K27me3 and derepression of Wnt signaling pathway genes, impairing astrocyte development.\",\n      \"method\": \"Conditional KO mouse model, Co-IP (RACK7-PRC2), ChIP-seq (H3K27me3, SUZ12), RNA-seq\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean conditional KO, reciprocal Co-IP, genome-wide ChIP-seq with mechanistic consequence\",\n      \"pmids\": [\"40125808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZMYND8 interacts with c-Myc directly and activates c-Myc transcriptional activity to promote the Warburg effect in pancreatic cancer; ZMYND8 physically associates with c-Myc as shown by Co-IP and proteomic profiling.\",\n      \"method\": \"Co-IP, proteomics, CUT&Tag, RNA-seq, in vivo xenograft with c-Myc KD rescue\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP plus multi-omic analysis, single lab\",\n      \"pmids\": [\"40579459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZMYND8's PWWP domain reads H3K36me2 and activates CEBPE transcription in an H3K36me2-dependent manner; ZMYND8-driven CEBPE expression suppresses adaptive UPR pathways (ERN1, XBP1, ATF6) to inhibit multiple myeloma cell survival.\",\n      \"method\": \"Co-IP, ChIP, domain mutagenesis (PWWP), CUT&RUN, RNA-seq, KD/KO with UPR and proliferation assays\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain mutagenesis and ChIP linking H3K36me2 to target gene activation, functional UPR epistasis, single lab\",\n      \"pmids\": [\"40347515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZMYND8 mediates ubiquitination and proteasomal degradation of HMGB1 in cardiomyocytes; trametinib (MEK inhibitor) inhibits ZMYND8-mediated ubiquitination of HMGB1, causing its accumulation and cardiomyocyte death.\",\n      \"method\": \"Co-IP, ubiquitination assay, ZMYND8 KD/KO in cardiomyocytes, HMGB1 stability assay, cardiac function readout in mice\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — ubiquitination assay, Co-IP, in vivo mouse cardiac phenotype, single lab\",\n      \"pmids\": [\"41423035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Crystal structure of the ZMYND8 coiled-coil MYND domain reveals a homodimeric architecture; the MYND domain recognizes proline-rich motifs in GATAD2A's central region with moderate affinity enhanced by multivalency; ZMYND8 recruits GATAD2A specifically to the MAPT213 internal regulatory region to suppress MAPT213 lncRNA transcription while promoting MAPT protein-coding transcript expression.\",\n      \"method\": \"X-ray crystallography, ChIP, Co-IP, domain mutagenesis, quantitative binding measurements\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus mutagenesis plus ChIP functional validation\",\n      \"pmids\": [\"41999894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RACK7 rapidly redistributes from repressed to activated enhancers in response to acute stimulations in a transcription-dependent manner and positively regulates enhancer activation by promoting RNA Pol II recruitment.\",\n      \"method\": \"ChIP-seq under acute stimulation conditions, RNA Pol II ChIP, transcription inhibitor experiments\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide ChIP-seq with pharmacological perturbation, single lab\",\n      \"pmids\": [\"40734674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"OTUD4 deubiquitinase directly interacts with and stabilizes ZMYND8; ZMYND8 acts as a scaffold promoting DDX3X-CK1ε complex assembly and WNT/β-catenin activation, which upregulates CSF1 to promote M2 macrophage polarization and immunosuppressive niche formation in TNBC spinal metastasis.\",\n      \"method\": \"Co-IP, deubiquitination assay, ZMYND8 KD with WNT signaling and macrophage polarization readout, in vivo spinal metastasis model\",\n      \"journal\": \"Neoplasia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP with functional pathway validation, single lab\",\n      \"pmids\": [\"41297414\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ZMYND8 is a multivalent chromatin reader that uses its PHD-BRD-PWWP supramodule to recognize combinatorial histone marks (H3K4me1-H3K14ac, H3K36me2, H4K16ac) and DNA simultaneously; its MYND domain directly engages PPPLΦ motifs in NuRD subunit GATAD2A to recruit the NuRD complex, while its coiled-coil domain mediates homodimerization that determines whether it associates with the activating P-TEFb complex or the repressive NuRD/CHD4 complex; at DNA double-strand breaks it is recruited to damaged active chromatin in a KDM5A-dependent (H3K4me3 demethylation) and poly(ADP-ribose)-dependent manner to silence transcription and promote homologous recombination, and its activity is regulated post-translationally by p300-mediated acetylation (K1007/K1034), FBXW7-mediated polyubiquitination/degradation, and USP7-mediated deubiquitination, while Drebrin can sequester the entire PHD-BRD-PWWP supramodule to the cytoplasm.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ZMYND8 is a multivalent chromatin reader and transcriptional regulator that integrates histone mark recognition with recruitment of chromatin-modifying complexes to control enhancer activity, DNA damage repair, and gene expression programs across diverse cell types. Its PHD-BRD-PWWP supramodule forms a rigid structural unit that simultaneously engages combinatorial histone modifications (H3K4me1-H3K14ac, H3K36me2, H4K16ac) and DNA, while its MYND domain directly binds PPPLΦ motifs in the NuRD subunit GATAD2A; homodimerization via the coiled-coil domain switches ZMYND8 between an activating P-TEFb-associated state and a repressive NuRD/CHD4-associated state [PMID:27926874, PMID:27732854, PMID:30134174, PMID:41999894]. At DNA double-strand breaks, KDM5A-mediated H3K4me3 demethylation and poly(ADP-ribose) signaling recruit ZMYND8-NuRD to silence transcription at damaged active chromatin and promote homologous recombination, while at enhancers ZMYND8 cooperates with KDM5C, BRD4, PRC2, and Mediator to modulate super-enhancer output, cholesterol biosynthesis, and immune gene regulation [PMID:25593309, PMID:28572115, PMID:27058665, PMID:34358447, PMID:33932349, PMID:40125808]. ZMYND8 protein stability is controlled by FBXW7-mediated polyubiquitination counteracted by USP7- and OTUD4-dependent deubiquitination, and its chromatin engagement is regulated by p300-mediated acetylation at K1007/K1034 and cytoplasmic sequestration by Drebrin [PMID:34487730, PMID:39128723, PMID:29629903, PMID:28966017].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Establishing ZMYND8 as a transcriptional repressor with neuronal relevance: before this, ZMYND8 lacked functional characterization beyond PKCβI binding; interaction with RCOR2 and neural differentiation inhibition upon overexpression placed it in a repressive transcriptional context.\",\n      \"evidence\": \"Yeast two-hybrid and Co-IP in Xenopus, embryo overexpression with neural differentiation readout\",\n      \"pmids\": [\"20331974\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Not replicated independently\", \"Mammalian relevance of RCOR2 interaction not confirmed\", \"Mechanism of repression undefined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defining ZMYND8 as a DNA damage-responsive factor that recruits NuRD to silence transcription at breaks and promote HR resolved a key question about how transcriptionally active chromatin is silenced during repair.\",\n      \"evidence\": \"Fluorescence microscopy localization screen, Co-IP with NuRD, ChIP, HR repair assays in human cells\",\n      \"pmids\": [\"25593309\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signal triggering ZMYND8 recruitment not yet defined\", \"Histone mark specificity at damage sites unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Structural and biochemical dissection of the PHD-BRD-PWWP supramodule as a rigid multivalent reader that simultaneously engages histone PTMs and DNA explained how ZMYND8 achieves chromatin targeting specificity; parallel work defined H3K4me1-H3K14ac as a preferred dual mark and mapped the MYND-GATAD2A interface.\",\n      \"evidence\": \"X-ray crystallography of the triple reader cassette, histone peptide pulldowns and mutagenesis, mass spectrometry interactome with GATAD2A domain mapping, live-cell DNA damage recruitment\",\n      \"pmids\": [\"27926874\", \"27477906\", \"27732854\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length ZMYND8 structure unresolved\", \"Contribution of DNA binding versus histone binding in vivo not quantitated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Discovering that ZMYND8 partners with KDM5C at active enhancers and super-enhancers, where their loss causes H3K4me3 gain and enhancer overactivation, established ZMYND8 as a guardian of enhancer homeostasis beyond DNA damage.\",\n      \"evidence\": \"Co-purification, ChIP-seq, RNA-seq with KO/KD in breast cancer cells\",\n      \"pmids\": [\"27058665\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether KDM5C and KDM5A act redundantly at enhancers unknown\", \"Mechanism of ZMYND8-KDM5C cooperation not structurally resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"KDM5A-mediated H3K4me3 demethylation was shown to be prerequisite for ZMYND8-NuRD binding at DSBs, placing ZMYND8 downstream of a histone demethylation step and explaining mark-dependent recruitment; the Drebrin crystal structure revealed a cytoplasmic sequestration mechanism that competes with chromatin binding.\",\n      \"evidence\": \"KDM5A KD with epistasis to ZMYND8/HR, ChIP; X-ray crystallography of Drebrin ADF-H–ZMYND8 complex with competitive binding and localization assays\",\n      \"pmids\": [\"28572115\", \"28966017\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological conditions triggering Drebrin-mediated sequestration unknown\", \"Whether KDM5A acts catalytically or as a scaffold not fully distinguished\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"A dimerization-dependent functional switch was uncovered: homodimeric ZMYND8 associates with P-TEFb via CyclinT1 to activate transcription, while monomeric ZMYND8 binds CHD4/NuRD to repress, resolving the paradox of ZMYND8 acting as both activator and repressor.\",\n      \"evidence\": \"Biochemical reconstitution of ZMYND8-P-TEFb, coiled-coil domain mutagenesis, reporter assays, ATRA differentiation\",\n      \"pmids\": [\"30134174\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What controls the dimer–monomer equilibrium in vivo is unknown\", \"Structural basis of CyclinT1 interaction not determined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"p300-mediated acetylation of ZMYND8 at K1007/K1034 was shown to be required for HIF transcriptional activation and BRD4 recruitment, establishing post-translational regulation of ZMYND8 coactivator function and linking it to hypoxic oncogenesis; separately, ZMYND8 was found to regulate Igh super-enhancer activity controlling class switch recombination and somatic hypermutation in B cells.\",\n      \"evidence\": \"K-to-R site mutagenesis with in vitro acetylation, ChIP, Pol II pausing analysis, mouse metastasis model; B cell-specific KO with CSR/SHM assays\",\n      \"pmids\": [\"29629903\", \"30293785\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether acetylation-dependent and dimerization-dependent activation are the same pathway is unclear\", \"Acetylation dynamics and opposing deacetylase not identified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"ZMYND8 was found to recognize the oncohistone H3.3G34R mutation, suppressing CIITA and MHC-II expression; loss of ZMYND8 triggered cGAS-STING innate immune signaling via micronucleus formation, revealing ZMYND8 as a genome stability factor with immune-evasion consequences.\",\n      \"evidence\": \"In vitro binding and ChIP-seq for H3.3G34R recognition, CRISPR knock-in correction; ZMYND8 KO with micronucleus assay and cGAS-STING pathway analysis in syngeneic tumor models\",\n      \"pmids\": [\"32832624\", \"33148660\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of H3.3G34R recognition not resolved\", \"Whether genome instability is direct or via transcriptional deregulation unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"ZMYND8 was shown to directly interact with BRD4's ET domain in AML and to cooperate with SREBP2 and Mediator at enhancer-promoter loops for cholesterol biosynthesis, broadening its role to lineage-specific transcriptional activation and metabolic gene regulation.\",\n      \"evidence\": \"Reciprocal Co-IP with BRD4 domain mapping, ChIP-seq in AML patient samples, in vivo AML model; HiChIP, Mediator Co-IP, ZMYND8 KO with metabolic and tumorigenesis readout\",\n      \"pmids\": [\"34358447\", \"33932349\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether BRD4-ET and P-TEFb interactions are concurrent or mutually exclusive unknown\", \"Mediator subunit specificity not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"FBXW7 was identified as the E3 ligase that polyubiquitinates and degrades ZMYND8, and clinically observed ZMYND8 missense variants were shown to disrupt specific domain interactions (PWWP–Drebrin, MYND–GATAD2A), with a Drosophila ortholog knockdown linking ZMYND8 to habituation learning.\",\n      \"evidence\": \"Co-IP and ubiquitination assays for FBXW7; yeast two-hybrid with patient variants and Drosophila neuronal KD with behavioral phenotype\",\n      \"pmids\": [\"34487730\", \"35916866\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"FBXW7 degron motif on ZMYND8 not mapped\", \"Mammalian neurological phenotype of ZMYND8 loss not established\", \"ZMYND8 variant pathogenicity not confirmed in mammalian neurons\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"USP7 was identified as the deubiquitinase that directly reverses FBXW7-catalyzed polyubiquitination at K1034, stabilizing ZMYND8; a ZMYND8-NRF2 positive feedback loop was shown to suppress ferroptosis in breast cancer stem cells, connecting ZMYND8 to redox homeostasis.\",\n      \"evidence\": \"In vitro deubiquitination assay with domain mapping and K1034 mutagenesis; reciprocal Co-IP of ZMYND8-NRF2, ChIP, ROS and ferroptosis assays\",\n      \"pmids\": [\"39128723\", \"38488001\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether USP7-ZMYND8 interaction is regulated by signaling is unknown\", \"Structural basis of K1034 ubiquitination/deubiquitination not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"ZMYND8 was shown to interact with PRC2 to establish H3K27me3 domains in astrocytes, to dynamically redistribute to activated enhancers upon stimulation, and to cooperate with FOXM1 and SWI/SNF in driving neuroendocrine prostate cancer transdifferentiation, revealing context-dependent partnerships with multiple chromatin-modifying complexes.\",\n      \"evidence\": \"Conditional KO with ChIP-seq for PRC2/H3K27me3 in astrocytes; acute stimulation ChIP-seq; CRISPR screen with scRNA-seq and small molecule ZMYND8 inhibitor in NEPC models\",\n      \"pmids\": [\"40125808\", \"40734674\", \"40102673\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ZMYND8 selects between NuRD, PRC2, P-TEFb, BRD4, and SWI/SNF at individual loci is unclear\", \"Therapeutic window and selectivity of iZMYND8-34 not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The coiled-coil MYND domain crystal structure confirmed homodimeric architecture and provided quantitative binding parameters for GATAD2A recognition; parallel studies extended ZMYND8 transcriptional programs to WNT/β-catenin signaling, phospholipid metabolism, and unfolded protein response suppression.\",\n      \"evidence\": \"X-ray crystallography of CC-MYND with quantitative binding; Co-IP with DDX3X-CK1ε for WNT; ChIP and metabolomics for cPLA2α/IL-27 axis; PWWP mutagenesis linking H3K36me2 to CEBPE and UPR\",\n      \"pmids\": [\"41999894\", \"41297414\", \"40281007\", \"40347515\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length ZMYND8 structure including disordered regions remains undetermined\", \"Relative contribution of each target gene program to overall ZMYND8 biology in normal physiology unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Unresolved: how ZMYND8 selects among its many chromatin-remodeling partners (NuRD, PRC2, SWI/SNF, P-TEFb, BRD4, Mediator) at individual genomic loci, and whether the dimer–monomer switch fully explains this selectivity, remain central open questions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length structural model needed to understand allosteric regulation across domains\", \"In vivo stoichiometry and dynamics of partner switching uncharacterized\", \"Normal physiological role of ZMYND8 in non-cancer tissues (brain, immune, cardiac) remains poorly defined genetically in mammals\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [2, 5, 6, 14, 29]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 7, 8, 12, 16, 17, 21, 27, 32]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 8, 16, 17, 33]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 5, 9, 14]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0, 3, 5, 6]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [0, 3, 4]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 7, 8, 12, 16, 17, 27, 32]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1, 5, 14, 23, 27]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [19]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [15, 21, 33]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [17, 20]}\n    ],\n    \"complexes\": [\n      \"NuRD complex (via GATAD2A/CHD4)\",\n      \"P-TEFb complex (via CyclinT1)\",\n      \"PRC2 complex\"\n    ],\n    \"partners\": [\n      \"GATAD2A\",\n      \"CHD4\",\n      \"BRD4\",\n      \"KDM5C\",\n      \"KDM5A\",\n      \"DBN1\",\n      \"USP7\",\n      \"FBXW7\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}