{"gene":"ZMYND8","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2015,"finding":"ZMYND8 functions as a bromodomain-containing chromatin reader that recruits the NuRD (nucleosome remodeling and histone deacetylation) complex to damaged chromatin, mediating transcriptional repression and promoting repair by homologous recombination at DNA double-strand breaks, particularly within transcriptionally active chromatin.","method":"Localization screen of BRD proteins after DNA damage, co-immunoprecipitation, knockdown with DSB repair and transcription assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, functional KD with defined HR repair and transcriptional repression phenotypes, replicated by multiple subsequent studies","pmids":["25593309"],"is_preprint":false},{"year":2016,"finding":"ZMYND8 (RACK7) forms a biochemical complex with the H3K4me3-specific demethylase KDM5C and occupies active enhancers including super-enhancers; loss of RACK7 or KDM5C leads to enhancer overactivation characterized by H3K4me3 and H3K27Ac deposition and increased eRNA and nearby gene transcription, identifying RACK7/KDM5C as an enhancer 'brake'.","method":"Biochemical complex purification, ChIP-seq, genetic KO/KD with histone modification and transcription readouts","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — biochemical complex purification, genome-wide ChIP-seq, and functional KO with multiple orthogonal readouts in a single rigorous study","pmids":["27058665"],"is_preprint":false},{"year":2017,"finding":"KDM5A demethylates H3K4me3 near DNA double-strand break sites, and this demethylation is required for ZMYND8-NuRD binding to chromatin and recruitment to DNA damage; KDM5A deficiency impairs transcriptional silencing and HR repair.","method":"ChIP-seq/ChIP at DSB sites, genetic KD of KDM5A with ZMYND8 recruitment assays, HR repair assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis established by KDM5A KD with chromatin binding and functional HR readouts, replicated across multiple cell systems","pmids":["28572115"],"is_preprint":false},{"year":2016,"finding":"The PHD-Bromodomain cassette of ZMYND8 recognizes the combinatorial histone mark H3K4me1-H3K14ac (and H3K4me0-H3K14ac), mediating its function as a transcriptional corepressor of JARID1D and antagonizing expression of metastasis-linked genes.","method":"Histone peptide binding assays, PHD-Bromo domain mutagenesis, ChIP, knockdown with invasion assays in vitro and in vivo","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro histone binding with domain mutagenesis, confirmed by ChIP and functional KD phenotype, independently replicated","pmids":["27477906"],"is_preprint":false},{"year":2016,"finding":"The MYND domain of ZMYND8 directly interacts with PPPLΦ motifs in the NuRD subunit GATAD2A; this interaction bridges ZMYND8-NuRD and facilitates rapid, poly(ADP-ribose)-dependent recruitment of GATAD2A/NuRD to DNA damage sites to promote HR. ZMYND8 and NuRD share genome-wide binding at active promoters and enhancers, but ZMYND8 depletion does not globally affect NuRD occupancy.","method":"Direct interaction assays (MYND domain with GATAD2A peptides), Co-IP, ChIP-seq, live-cell recruitment assays after laser damage, HR repair assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct domain-peptide interaction assay, genome-wide ChIP-seq, live-cell damage recruitment, and HR functional readout in a single study","pmids":["27732854"],"is_preprint":false},{"year":2016,"finding":"The crystal structure of the ZMYND8 PHD-BRD-PWWP triple reader cassette reveals a rigid structural supramodule capable of simultaneously recognizing multiple histone PTMs while providing a charged platform for DNA binding; disruption of single domains destroys the functional network and impairs recruitment to DNA damage sites.","method":"X-ray crystallography of PHD-BRD-PWWP, histone binding assays, single-domain mutagenesis, DNA damage recruitment assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with mutagenesis and functional recruitment assays in one study","pmids":["27926874"],"is_preprint":false},{"year":2015,"finding":"ZMYND8 binds the histone marks H3.1K36me2 and H4K16ac through its conserved chromatin-binding modules, shows preference for canonical H3.1 over variant H3.3, and is recruited to ATRA-responsive developmental genes; ZMYND8 interacts with Ser5-phosphorylated RNA polymerase II in a DNA template-dependent manner.","method":"In vitro histone-binding assays with domain mutants, ChIP, co-immunoprecipitation with RNA Pol II, ATRA treatment gene expression studies","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct histone binding and Co-IP with RNA Pol II, single lab, multiple complementary methods","pmids":["26655721"],"is_preprint":false},{"year":2018,"finding":"ZMYND8 interacts with HIF-1α and HIF-2α and enhances elongation of HIF-induced oncogenic genes by recruiting BRD4 and promoting release of paused RNA polymerase II; ZMYND8 acetylation at K1007 and K1034 by p300 is required for HIF activation, breast cancer progression, and metastasis.","method":"Co-immunoprecipitation of ZMYND8 with HIF-1α/HIF-2α, p300 acetylation assays, acetylation-site mutagenesis, ChIP for BRD4 and RNA Pol II, mouse tumor/metastasis models","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, PTM mapping with mutagenesis, ChIP functional readout, and in vivo mouse models in a single rigorous study","pmids":["29629903"],"is_preprint":false},{"year":2018,"finding":"ZMYND8 forms a homodimer via its coiled-coil domain; the homodimer preferentially associates with CyclinT1 of the P-TEFb complex to activate transcription, while the monomer associates with the CHD4 subunit of the NuRD repressor complex; ZMYND8-P-TEFb interaction promotes ATRA-mediated neuronal differentiation.","method":"Biochemical reconstitution of ZMYND8-P-TEFb complex, direct binding assay with CyclinT1, reporter gene assays, ChIP, neuronal differentiation assays with KD","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical reconstitution showing direct CyclinT1 binding, combined with reporter gene and native ChIP functional validation, single lab","pmids":["30134174"],"is_preprint":false},{"year":2018,"finding":"ZMYND8 controls immunoglobulin class switch recombination (CSR) and somatic hypermutation (SHM) by binding promoters and super-enhancers including the Igh 3' regulatory region; ZMYND8 deficiency increases 3'RR polymerase loading but decreases acceptor region transcription and CSR.","method":"B-cell specific ZMYND8 KO, ChIP-seq for ZMYND8 at Igh enhancers, CSR and SHM functional assays, RNA Pol II ChIP","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined molecular phenotype at specific genomic loci, ChIP-seq, and functional immunological readout","pmids":["30293785"],"is_preprint":false},{"year":2010,"finding":"ZMYND8 interacts with RCOR2 (REST corepressor 2) via co-immunoprecipitation; both proteins function as transcriptional repressors and overexpression of ZMYND8 inhibits neural differentiation in Xenopus embryos.","method":"Yeast two-hybrid screen, co-immunoprecipitation, overexpression in Xenopus embryos with neural differentiation readout","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — reciprocal Co-IP and in vivo overexpression phenotype, two orthogonal methods, single lab","pmids":["20331974"],"is_preprint":false},{"year":2000,"finding":"PRKCBP1 (ZMYND8) protein specifically interacts with PKCβI via its carboxy terminus, identified by immunoprecipitation of GST-fused PRKCBP1.","method":"GST pulldown/immunoprecipitation using monoclonal antibody screen of cDNA library, Northern analysis for tissue expression","journal":"Mammalian genome","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single GST pulldown assay, single lab, no functional follow-up","pmids":["11003709"],"is_preprint":false},{"year":2017,"finding":"The crystal structure of the Drebrin ADF-H domain in complex with ZMYND8 PHD-BRD-PWWP reveals that Drebrin competes with modified histones for ZMYND8 binding; Drebrin binding can shuttle ZMYND8 from the nucleus to the cytoplasm, suggesting a cytoplasmic sequestration mechanism.","method":"X-ray crystallography of Drebrin ADF-H/ZMYND8 PHD-BRD-PWWP complex, competition binding assays, live-cell imaging showing nuclear-to-cytoplasmic redistribution","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with competition binding assays and live-cell localization shift, multiple orthogonal methods in one study","pmids":["28966017"],"is_preprint":false},{"year":2020,"finding":"RACK7 (ZMYND8) recognizes the histone H3.3G34R patient mutation in vitro and in vivo and suppresses transcription of CIITA (master regulator of MHC class II) and genes involved in vesicular transport of MHC class II molecules, resulting in suppression of MHC class II surface expression; CRISPR correction of H3.3G34R reduces RACK7 chromatin binding and derepresses the same genes.","method":"In vitro binding assays (RACK7 to H3.3G34R), ChIP-seq in patient-derived glioblastoma cells, CRISPR knock-in correction, RNA-seq, functional MHC class II surface assays","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct in vitro binding, CRISPR knock-in isogenic comparison, ChIP-seq, and functional gene expression readout in patient-derived cells","pmids":["32832624"],"is_preprint":false},{"year":2021,"finding":"ZMYND8 directly activates IRF8 transcription in AML through lineage-specific enhancers in parallel with MYC; ZMYND8 occupancy at IRF8 and MYC enhancers requires BRD4 via direct binding of ZMYND8's reader cassette to the ET domain of BRD4, and this interaction is required for proper chromatin occupancy and AML cell survival in vitro and in vivo.","method":"Co-IP of ZMYND8 with BRD4 ET domain, ChIP-seq in AML cell lines and patient samples, ZMYND8 KO with proliferation/survival readouts in vivo, domain-binding assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct domain binding assay (reader cassette to BRD4 ET), ChIP-seq in cell lines and patient samples, in vivo KO proliferation assay","pmids":["34358447"],"is_preprint":false},{"year":2021,"finding":"ZMYND8 preferentially binds phosphorylated EZH2 (T487, phosphorylated by CDK1); ZMYND8 depletion enhances PRC2-dependent function of EZH2 and suppresses the FOXM1 transcription program; ZMYND8 is required for EZH2-FOXM1 interaction and FOXM1-dependent MMP gene expression and EZH2-mediated cell migration and invasion in VHL-deficient cancer cells.","method":"Co-IP showing enhanced ZMYND8-EZH2 binding with T487 phosphorylation, ZMYND8 KD with PRC2 activity, FOXM1 interaction, MMP expression, and migration/invasion readouts","journal":"Proceedings of the National Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with phospho-specific context and KD functional assays, single lab, multiple readouts","pmids":["33593912"],"is_preprint":false},{"year":2021,"finding":"ZMYND8 and SREBP2 drive enhancer-promoter interactions to facilitate recruitment of the Mediator complex, upregulating mevalonate pathway genes; this ZMYND8-dependent cholesterol biosynthesis pathway is essential for Lgr5+ intestinal stem cell self-renewal and intestinal tumorigenesis downstream of YAP.","method":"ChIP-seq for ZMYND8 and SREBP2, chromatin conformation capture (enhancer-promoter looping), KO of ZMYND8 with mevalonate gene expression, cholesterol measurements, intestinal organoid and tumor model assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq, chromatin conformation assays, and functional KO phenotype with multiple orthogonal readouts in a single study","pmids":["33932349"],"is_preprint":false},{"year":2021,"finding":"FBXW7 E3 ubiquitin ligase interacts directly with ZMYND8 and degrades it via polyubiquitination, thereby controlling ZMYND8 protein levels; low FBXW7 leads to ZMYND8 accumulation and promotes bladder cancer progression and stemness.","method":"Bioinformatic interaction prediction, co-immunoprecipitation of FBXW7 with ZMYND8, polyubiquitination assay, functional cell proliferation/migration assays, in vivo tumor model","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and ubiquitination assay with functional KO readout, single lab, two complementary methods","pmids":["34487730"],"is_preprint":false},{"year":2019,"finding":"The lncRNA TROJAN binds ZMYND8 and increases its degradation through the ubiquitin-proteasome pathway by repelling ZNF592 from ZMYND8, thereby reducing ZMYND8 protein stability and promoting metastasis-related gene expression in TNBC.","method":"RNA pulldown/RIP showing TROJAN-ZMYND8 binding, ubiquitin-proteasome assay for ZMYND8 degradation, ZNF592 competition assays, functional invasion assays, in vivo xenograft","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct RNA-protein binding and degradation assays with functional phenotype, single lab","pmids":["30854423"],"is_preprint":false},{"year":2022,"finding":"ZMYND8 interacts with CHD4 (NuRD) at ARID1A-bound H3.3+ H4K16ac+ super-enhancers to suppress a subset of genes governing extracellular matrix, motility, and EMT; ARID1A is required for CHD4 recruitment to H3.3, and ZMYND8 acts downstream in this pathway.","method":"ChIP-seq for ZMYND8, CHD4, ARID1A, H3.3, H4K16ac; Co-IP of ZMYND8 with CHD4; ARID1A KD epistasis experiments; gene expression analysis","journal":"BMC biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq and Co-IP with genetic epistasis (KD), single lab, multiple orthogonal methods","pmids":["36153585"],"is_preprint":false},{"year":2022,"finding":"ZMYND8 missense variants in the PWWP domain abolish interaction with Drebrin, and missense variants in the MYND domain disrupt interaction with GATAD2A, as established by yeast two-hybrid assays; neuronal knockdown of the Drosophila ZMYND8 ortholog results in decreased habituation learning.","method":"Yeast two-hybrid assays with PWWP and MYND domain mutants, Drosophila neuronal KD with habituation learning assay","journal":"Genetics in medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid domain mapping and in vivo Drosophila KD cognitive phenotype, single consortium, two orthogonal methods","pmids":["35916866"],"is_preprint":false},{"year":2020,"finding":"ZMYND8 inhibits micronucleus formation and DNA damage in breast cancer cells; loss of ZMYND8 triggers activation of the cGAS DNA sensor in micronuclei, activating STING and NF-κB (but not TBK1/IRF3), inducing IFNβ and ISG expression, and promoting CD4+/CD8+ T-cell infiltration and tumor suppression.","method":"ZMYND8 KO in breast cancer cells with micronucleus quantification, cGAS/STING pathway activation assays, cytokine measurements, syngeneic mouse model with T-cell depletion antibodies and Rag1 KO mice","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with mechanistic pathway activation assays, multiple mouse model validations including Rag1 KO and antibody depletion controls","pmids":["33148660"],"is_preprint":false},{"year":2024,"finding":"USP7 deubiquitinase directly binds the 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 cell migration and invasion.","method":"Co-IP of USP7 with ZMYND8, domain mapping (TRAF/UBL vs PBP), in vitro deubiquitination assay at K1034, KD/OE with migration/invasion readouts, target gene expression analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro deubiquitination assay with site-specific K1034 identification, domain mapping Co-IP, and functional cell migration phenotype, single lab, multiple orthogonal methods","pmids":["39128723"],"is_preprint":false},{"year":2022,"finding":"ZMYND8 is a master transcriptional regulator of 27-hydroxycholesterol metabolism: it increases cholesterol biosynthesis and oxidation while blocking cholesterol efflux and catabolism, leading to 27-HC accumulation in breast cancer stem cells; 27-HC promotes EMT and tumor initiation through liver X receptor activation.","method":"ZMYND8 KO/KD in genetic mouse mammary tumor and human breast cancer models, cholesterol/27-HC metabolite measurements, LXR reporter assays, ChIP for ZMYND8 at cholesterol metabolism gene loci","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO in multiple models, metabolite measurements, and ChIP at target gene loci, single lab","pmids":["35857506"],"is_preprint":false},{"year":2024,"finding":"ZMYND8 increases NRF2 protein stability through KEAP1 silencing and directly interacts with NRF2 to recruit it to promoters of antioxidant genes; NRF2 in turn directly controls ZMYND8 expression, establishing a positive feedback loop that sustains BCSC antioxidant defense and ferroptosis resistance.","method":"Co-IP of ZMYND8 with NRF2, ChIP showing ZMYND8-NRF2 co-recruitment to antioxidant gene promoters, KEAP1 expression analysis after ZMYND8 KO, NRF2 KO epistasis, ROS/ferroptosis assays, mammosphere models","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ChIP co-recruitment, genetic epistasis (NRF2 KO rescuing ZMYND8 effects), and functional ROS/ferroptosis readouts in multiple models","pmids":["38488001"],"is_preprint":false},{"year":2025,"finding":"ZMYND8 enhances cPLA2α expression by inducing c-Myc; cPLA2α inactivates phosphatidylcholine-specific phospholipase C to inhibit diacylglycerol production, thereby diminishing PKC activity and leading to IL-27 secretion that confers trastuzumab/pertuzumab resistance in HER2+ breast cancer.","method":"ZMYND8 KO/OE in resistant tumor cells and patient-derived organoids, ChIP for c-Myc at cPLA2α promoter, lipid metabolite measurements, IL-27 secretion assays, patient-derived xenograft models","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for mechanistic pathway, functional KO in organoids and xenografts, single lab with multiple readouts","pmids":["40281007"],"is_preprint":false},{"year":2025,"finding":"FOXM1 stabilizes ZMYND8 binding to H3K4me1-H3K14ac chromatin; antiandrogen therapy releases SWI/SNF from androgen receptor, facilitating SWI/SNF interaction with ZMYND8-FOXM1 to upregulate neuroendocrine lineage regulators and drive NEPC transdifferentiation; small molecule iZMYND8-34 inhibiting ZMYND8 histone recognition blocks NEPC development.","method":"CRISPR-Cas9 screen combined with scRNA-seq tracking, ChIP-seq for ZMYND8 with H3K4me1-H3K14ac, Co-IP of SWI/SNF with ZMYND8-FOXM1, ZMYND8 KO mouse model, pharmacological inhibition with iZMYND8-34","journal":"Nature cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR screen, ChIP-seq, Co-IP, genetic KO mouse model, and pharmacological inhibition all converging on same mechanism, single lab with multiple orthogonal methods","pmids":["40102673"],"is_preprint":false},{"year":2025,"finding":"RACK7 (ZMYND8) interacts with the PRC2 complex and establishes genomic locations of SUZ12 and H3K27 methylation; deletion of Rack7 in astrocytes causes genome-wide decrease of H3K27me3 and aberrant astrocyte development with Wnt signaling overactivation.","method":"Rack7 conditional KO mouse model, Co-IP of RACK7 with PRC2 components, ChIP-seq for H3K27me3 and SUZ12 genome-wide, transcriptome analysis, Wnt pathway reporter assays","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO mouse model, Co-IP with PRC2, genome-wide ChIP-seq showing H3K27me3 loss, and pathway activation readout","pmids":["40125808"],"is_preprint":false},{"year":2025,"finding":"RACK7 swiftly redistributes from repressed to activated enhancers in response to acute stimulations in a transcription-dependent manner and positively regulates enhancer activation by promoting RNA polymerase II recruitment.","method":"ChIP-seq/CUT&RUN tracking of RACK7 redistribution after acute stimulation, transcription inhibitor experiments, RNA Pol II ChIP","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide ChIP-seq with mechanistic transcription-dependence experiment, single lab","pmids":["40734674"],"is_preprint":false},{"year":2025,"finding":"ZMYND8 acts as an E3 ubiquitin ligase-like factor mediating ubiquitination and proteasomal degradation of HMGB1 in cardiomyocytes; MEK inhibitor trametinib inhibits ZMYND8, leading to aberrant HMGB1 accumulation and cardiomyocyte death.","method":"ZMYND8 KO in cardiomyocytes, ubiquitination assays for HMGB1 with ZMYND8 present/absent, HMGB1 stability measurements, trametinib treatment with ZMYND8 activity readouts","journal":"Biochemical pharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, KO phenotype with ubiquitination assay but mechanism of E3 ligase activity not fully biochemically reconstituted in abstract","pmids":["41423035"],"is_preprint":false},{"year":2026,"finding":"The crystal structure of the ZMYND8 coiled-coil MYND domain reveals a homodimeric architecture; the MYND domain specifically recruits GATAD2A to the MAPT213 internal regulatory region through direct interaction with proline-rich motifs in GATAD2A's central region, suppressing MAPT213 lncRNA transcription while promoting protein-coding MAPT expression.","method":"Crystal structure of ZMYND8 coiled-coil MYND domain, Co-IP/direct binding assays of MYND with GATAD2A proline-rich motifs, ChIP for GATAD2A recruitment, quantitative binding measurements, domain mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with domain mutagenesis and ChIP functional validation of GATAD2A recruitment, single lab with multiple orthogonal methods","pmids":["41999894"],"is_preprint":false},{"year":2021,"finding":"ZMYND8 directly interacts with c-Myc (confirmed by Co-IP), activating c-Myc transcriptional activity through downstream epigenetic regulatory pathways to promote the Warburg effect and aerobic glycolysis in pancreatic cancer cells.","method":"Co-immunoprecipitation of ZMYND8 with c-Myc, CUT&Tag and RNA-seq integration, proteomic profiling, glycolysis assays, in vivo xenograft with c-Myc KD rescue","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP confirmed direct interaction, CUT&Tag for chromatin occupancy, and functional rescue by c-Myc KD, single lab","pmids":["40579459"],"is_preprint":false},{"year":2025,"finding":"ZMYND8 PWWP domain reads H3K36me2 and activates CEBPE transcription in an H3K36me2-dependent manner; CEBPE then represses adaptive UPR pathways (ERN1, XBP1, ATF6) to suppress multiple myeloma cell survival.","method":"ChIP for ZMYND8 at CEBPE locus with H3K36me2 dependence, Co-IP assays, PWWP domain mutation experiments, RNA-seq and ChIP-seq combined analysis, ZMYND8 KD/KO with UPR pathway and proliferation readouts","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with domain mutagenesis establishing H3K36me2 dependence and downstream pathway epistasis, single lab","pmids":["40347515"],"is_preprint":false},{"year":2025,"finding":"Phosphorylated EZH2 T487D (phosphomimic) shows increased binding to ZMYND8, consistent with CDK1 phosphorylation of EZH2 at T487 promoting ZMYND8-EZH2 interaction, as demonstrated independently by phospho-EZH2 pulldown in TNBC cells.","method":"Co-IP/pulldown of phosphomimic EZH2 T487D with ZMYND8 in TNBC cells","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single pulldown from preprint, single method, not yet peer reviewed; largely corroborates PMID 33593912","pmids":[],"is_preprint":true},{"year":2025,"finding":"OTUD4 deubiquitinase directly interacts with and stabilizes ZMYND8; ZMYND8 acts as a scaffold promoting assembly of the DDX3X-CK1ε complex, thereby activating WNT/β-catenin signaling; this OTUD4-ZMYND8-DDX3X axis upregulates CSF1 and promotes M2 macrophage polarization in TNBC spinal metastasis.","method":"Co-IP of OTUD4 with ZMYND8 and ZMYND8 with DDX3X/CK1ε, ubiquitination/stability assays, WNT/β-catenin reporter, CSF1 expression and macrophage polarization assays, in vivo spinal metastasis model","journal":"Neoplasia","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple Co-IPs establishing complex assembly, functional pathway readouts, and in vivo validation, single lab","pmids":["41297414"],"is_preprint":false}],"current_model":"ZMYND8 is a multivalent chromatin reader whose rigid PHD-BRD-PWWP supramodule binds combinatorial histone marks (H3K4me1-H3K14ac, H3K36me2/H4K16ac, H3K4me3 after KDM5A demethylation) and DNA simultaneously; it recruits the NuRD repressor complex to active enhancers and DNA double-strand break sites via a direct MYND domain–GATAD2A(PPPLΦ) interaction to repress transcription and promote homologous recombination, while in an alternative dimeric form it associates with the P-TEFb/CyclinT1 complex and BRD4 to activate transcription at lineage-specific enhancers; its activity is regulated post-translationally by p300-mediated acetylation (K1007/K1034 for HIF activation), CDK1/FBXW7-mediated ubiquitination and proteasomal degradation (counteracted by USP7 deubiquitination), and by cytoplasmic sequestration through Drebrin competition for the PHD-BRD-PWWP module."},"narrative":{"mechanistic_narrative":"ZMYND8 is a multivalent chromatin reader that integrates combinatorial histone-mark recognition with transcriptional control at enhancers and DNA damage sites [PMID:27058665, PMID:27926874]. Its rigid PHD-BRD-PWWP supramodule reads combinatorial marks including H3K4me1/me0-H3K14ac, H3.1K36me2 and H4K16ac while presenting a charged surface for DNA, and disruption of any single domain collapses the reader network and impairs chromatin recruitment [PMID:27477906, PMID:27926874, PMID:26655721]. Through its MYND domain, ZMYND8 binds proline-rich (PPPLΦ) motifs in the NuRD subunit GATAD2A, bridging ZMYND8 to the NuRD remodeling/deacetylation complex; at DNA double-strand breaks this PAR-dependent recruitment enforces transcriptional silencing and promotes homologous-recombination repair, with the requisite chromatin engagement licensed by KDM5A/KDM5C demethylation of H3K4me3 [PMID:25593309, PMID:28572115, PMID:27732854, PMID:41999894]. At active and super-enhancers, ZMYND8 acts as a transcriptional 'brake' in complex with KDM5C, restraining H3K4me3/H3K27ac deposition and eRNA output [PMID:27058665]. Beyond repression, an oligomerization switch diversifies its output: a coiled-coil homodimer engages CyclinT1/P-TEFb to activate transcription, whereas the monomer engages the CHD4-NuRD repressor, and ZMYND8 cooperates with BRD4 (via reader-cassette binding to the BRD4 ET domain) and HIF-1α/HIF-2α to release paused RNA Pol II at oncogenic and lineage-specific enhancers [PMID:30134174, PMID:34358447, PMID:29629903]. ZMYND8 abundance is tuned post-translationally by FBXW7-mediated polyubiquitination and degradation counteracted by USP7 deubiquitination at K1034, and its histone engagement can be competitively sequestered to the cytoplasm by Drebrin binding the PHD-BRD-PWWP module [PMID:34487730, PMID:39128723, PMID:28966017]. These activities place ZMYND8 at the center of DNA repair, enhancer regulation, lineage differentiation, and multiple cancer programs including HIF-driven metastasis, cholesterol/27-HC metabolism, and NRF2-dependent antioxidant defense [PMID:29629903, PMID:33932349, PMID:38488001]. Rare PWWP and MYND domain missense variants that abolish Drebrin or GATAD2A binding, together with a learning defect on knockdown of the Drosophila ortholog, implicate ZMYND8 in a neurodevelopmental disorder [PMID:35916866].","teleology":[{"year":2000,"claim":"An early interaction screen first linked the then-named PRKCBP1 protein to PKCβI signaling, establishing a physical partner before any chromatin role was known.","evidence":"GST pulldown/immunoprecipitation from a cDNA library and Northern expression analysis","pmids":["11003709"],"confidence":"Low","gaps":["Single pulldown without functional follow-up","No connection to later chromatin-reading function established"]},{"year":2010,"claim":"The question of whether ZMYND8 acts as a transcriptional repressor was first addressed by linking it to a corepressor partner and a developmental phenotype.","evidence":"Yeast two-hybrid and Co-IP showing RCOR2 interaction, with overexpression in Xenopus embryos blocking neural differentiation","pmids":["20331974"],"confidence":"Medium","gaps":["Mechanism of repression not defined","No chromatin-binding determinants identified"]},{"year":2015,"claim":"ZMYND8 was defined as a bromodomain chromatin reader that couples transcriptional repression to DNA repair, answering how active chromatin is silenced and channeled into homologous recombination at breaks.","evidence":"BRD localization screen after DNA damage, reciprocal Co-IP with NuRD, and knockdown with HR repair and transcription assays; separate study mapping histone-mark and RNA Pol II Ser5P binding","pmids":["25593309","26655721"],"confidence":"High","gaps":["Direct histone-mark code not fully resolved at this stage","Recruitment kinetics and PAR dependence not yet established"]},{"year":2016,"claim":"The molecular basis of ZMYND8 chromatin targeting and NuRD bridging was resolved, defining the reader code, the GATAD2A interaction, the enhancer-brake function, and the structural supramodule.","evidence":"Histone peptide binding with PHD-Bromo mutagenesis (H3K4me1-H3K14ac), MYND-GATAD2A PPPLΦ binding with laser-damage recruitment, KDM5C complex purification with enhancer ChIP-seq, and crystal structure of the PHD-BRD-PWWP cassette","pmids":["27477906","27732854","27058665","27926874"],"confidence":"High","gaps":["How reader recognition is switched between repressive and activating contexts not resolved","Direct DNA-binding contribution to recruitment not quantified"]},{"year":2017,"claim":"The chromatin licensing step for damage recruitment was clarified by showing that H3K4me3 demethylation is a prerequisite, and that Drebrin can competitively sequester ZMYND8 to the cytoplasm.","evidence":"KDM5A knockdown with ZMYND8 recruitment and HR assays at DSBs; crystal structure of Drebrin ADF-H/ZMYND8 PHD-BRD-PWWP with competition binding and live-cell localization shift","pmids":["28572115","28966017"],"confidence":"High","gaps":["Trigger that initiates Drebrin-mediated shuttling in cells unclear","Quantitative contribution of cytoplasmic sequestration to nuclear function unknown"]},{"year":2018,"claim":"ZMYND8 was shown to switch between repressive and activating outputs through oligomerization and to drive HIF-dependent and immunoglobulin loci programs, explaining its dual transcriptional behavior.","evidence":"Coiled-coil homodimer reconstitution with CyclinT1/P-TEFb vs CHD4-NuRD monomer binding; HIF-1α/2α Co-IP with p300 acetylation site mapping and tumor models; B-cell KO with ChIP-seq at the Igh 3'RR and CSR/SHM assays","pmids":["30134174","29629903","30293785"],"confidence":"High","gaps":["What controls the monomer/dimer equilibrium in vivo not defined","How acetylation at K1007/K1034 alters complex choice not mechanistically resolved"]},{"year":2019,"claim":"Post-transcriptional control of ZMYND8 abundance was extended to lncRNA-directed degradation, addressing how its levels are tuned in cancer.","evidence":"RNA pulldown/RIP of lncRNA TROJAN, ZNF592 competition and ubiquitin-proteasome degradation assays with invasion/xenograft readouts in TNBC","pmids":["30854423"],"confidence":"Medium","gaps":["ZNF592 mechanism of stabilizing ZMYND8 not structurally defined","E3 ligase responsible not identified in this study"]},{"year":2020,"claim":"ZMYND8 was connected to oncohistone recognition and to genome-stability-linked innate immunity, broadening its role beyond canonical marks.","evidence":"In vitro and ChIP-seq binding to H3.3G34R with CRISPR knock-in correction and MHC class II readouts; ZMYND8 KO with cGAS-STING-NF-κB activation, IFNβ induction and syngeneic/Rag1 KO mouse models","pmids":["32832624","33148660"],"confidence":"High","gaps":["How G34R alters reader engagement structurally not resolved","Link between repair function and micronucleus suppression not mechanistically dissected"]},{"year":2021,"claim":"Multiple studies positioned ZMYND8 as a regulator of cancer transcriptional and metabolic programs and identified additional partners and degradation control.","evidence":"Co-IP with BRD4 ET domain plus IRF8/MYC enhancer ChIP-seq in AML; phospho-EZH2 (T487) binding with PRC2/FOXM1 readouts; SREBP2/Mediator enhancer-looping with mevalonate KO phenotypes; FBXW7 polyubiquitination of ZMYND8; c-Myc Co-IP with glycolysis assays","pmids":["34358447","33593912","33932349","34487730","40579459"],"confidence":"Medium","gaps":["Whether ZMYND8 directly reads phospho-EZH2 or acts via an adaptor unclear","Relative contribution of each program across tissues not established"]},{"year":2022,"claim":"ZMYND8's enhancer repression was placed downstream of ARID1A/CHD4 chromatin context and tied to cholesterol metabolite control and neurodevelopmental genetics.","evidence":"ChIP-seq/Co-IP placing ZMYND8-CHD4 at ARID1A-dependent H3.3/H4K16ac super-enhancers; 27-HC metabolite/LXR analysis in mammary tumor models; yeast two-hybrid domain mapping of patient variants with Drosophila habituation assay","pmids":["36153585","35857506","35916866"],"confidence":"Medium","gaps":["Causality of human ZMYND8 variants in disease not proven by family genetics in this corpus","Direct enzymatic control of metabolite genes vs indirect effects not separated"]},{"year":2024,"claim":"The stability and antioxidant arms of ZMYND8 regulation were defined, identifying USP7 as the deubiquitinase opposing FBXW7 and an NRF2 feedback loop.","evidence":"USP7 domain-mapped Co-IP and in vitro deubiquitination at K1034 with migration assays; ZMYND8-NRF2 reciprocal Co-IP, ChIP co-recruitment, KEAP1 silencing, NRF2 KO epistasis and ferroptosis readouts","pmids":["39128723","38488001"],"confidence":"High","gaps":["How USP7 vs FBXW7 balance is set physiologically unknown","Mechanism by which ZMYND8 silences KEAP1 not detailed"]},{"year":2025,"claim":"ZMYND8 was integrated into lineage transdifferentiation, PRC2-directed H3K27 methylation, enhancer redistribution dynamics, and several additional cancer/metabolic axes, with a chemical probe demonstrating druggability.","evidence":"CRISPR/scRNA-seq, ChIP-seq, SWI/SNF-ZMYND8-FOXM1 Co-IP and iZMYND8-34 inhibition in NEPC; Rack7 conditional KO with PRC2 Co-IP and genome-wide H3K27me3 loss in astrocytes; CUT&RUN tracking of stimulus-driven RACK7 redistribution; PWWP-H3K36me2-CEBPE axis in myeloma; cPLA2α/IL-27 and OTUD4-DDX3X-WNT axes in breast cancer","pmids":["40102673","40125808","40734674","40347515","40281007","41297414"],"confidence":"High","gaps":["How ZMYND8 directs PRC2 genomic targeting mechanistically not resolved","Whether the activating enhancer redistribution uses the dimeric P-TEFb form not directly linked"]},{"year":2026,"claim":"High-resolution structure of the coiled-coil MYND module confirmed homodimeric architecture and defined GATAD2A proline-rich recognition driving locus-specific lncRNA/mRNA balance.","evidence":"Crystal structure of the ZMYND8 coiled-coil MYND domain with quantitative GATAD2A binding, domain mutagenesis, and ChIP for GATAD2A recruitment at MAPT213","pmids":["41999894"],"confidence":"High","gaps":["Generalizability of MAPT-specific recruitment logic to other loci unknown","Coupling of dimerization state to GATAD2A vs P-TEFb choice not directly tested here"]},{"year":null,"claim":"Whether ZMYND8 possesses intrinsic E3 ubiquitin ligase activity, and how its monomer/dimer switch is governed to select repressive vs activating complexes in a given cell context, remain open.","evidence":"","pmids":[],"confidence":"Low","gaps":["Reported HMGB1 E3-ligase-like activity not reconstituted biochemically (idx 29, Low confidence)","Upstream signals controlling oligomerization equilibrium undefined","Integration of competing PTMs (acetylation, ubiquitination) into output choice unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[3,5,6,13,32]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[5]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,7,8,14]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,8,30,34]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,5,12]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[0,4]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[12]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[0,2,4]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,7,8,14]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[1,27]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[7,13,14,24,26]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[9,13,21]}],"complexes":["NuRD complex","KDM5C complex","P-TEFb","PRC2"],"partners":["GATAD2A","CHD4","KDM5C","BRD4","CCNT1","HIF1A","USP7","FBXW7"],"other_free_text":[]}},"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 identifies bromodomain protein ZMYND8 in chromatin recognition of transcription-associated DNA damage that promotes homologous recombination.","date":"2015","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/25593309","citation_count":205,"is_preprint":false},{"pmid":"27058665","id":"PMC_27058665","title":"Suppression of Enhancer Overactivation by a RACK7-Histone Demethylase Complex.","date":"2016","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/27058665","citation_count":156,"is_preprint":false},{"pmid":"28572115","id":"PMC_28572115","title":"Histone demethylase KDM5A regulates the ZMYND8-NuRD chromatin remodeler to promote DNA repair.","date":"2017","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/28572115","citation_count":142,"is_preprint":false},{"pmid":"29629903","id":"PMC_29629903","title":"ZMYND8 acetylation mediates HIF-dependent breast cancer progression and metastasis.","date":"2018","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/29629903","citation_count":141,"is_preprint":false},{"pmid":"27477906","id":"PMC_27477906","title":"ZMYND8 Reads the Dual Histone Mark H3K4me1-H3K14ac to Antagonize the Expression of Metastasis-Linked Genes.","date":"2016","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/27477906","citation_count":124,"is_preprint":false},{"pmid":"30854423","id":"PMC_30854423","title":"The endogenous retrovirus-derived long noncoding RNA TROJAN promotes triple-negative breast cancer progression via ZMYND8 degradation.","date":"2019","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/30854423","citation_count":102,"is_preprint":false},{"pmid":"27732854","id":"PMC_27732854","title":"ZMYND8 Co-localizes with NuRD on Target Genes and Regulates Poly(ADP-Ribose)-Dependent Recruitment of GATAD2A/NuRD to Sites of DNA Damage.","date":"2016","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/27732854","citation_count":98,"is_preprint":false},{"pmid":"27926874","id":"PMC_27926874","title":"Multivalent Histone and DNA Engagement by a PHD/BRD/PWWP Triple Reader Cassette Recruits ZMYND8 to K14ac-Rich Chromatin.","date":"2016","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/27926874","citation_count":78,"is_preprint":false},{"pmid":"26655721","id":"PMC_26655721","title":"Selective Recognition of H3.1K36 Dimethylation/H4K16 Acetylation Facilitates the Regulation of All-trans-retinoic Acid (ATRA)-responsive Genes by Putative Chromatin Reader ZMYND8.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26655721","citation_count":64,"is_preprint":false},{"pmid":"34358447","id":"PMC_34358447","title":"ZMYND8-regulated IRF8 transcription axis is an acute myeloid leukemia dependency.","date":"2021","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/34358447","citation_count":54,"is_preprint":false},{"pmid":"38488001","id":"PMC_38488001","title":"ZMYND8 protects breast cancer stem cells against oxidative stress and ferroptosis through activation of NRF2.","date":"2024","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/38488001","citation_count":50,"is_preprint":false},{"pmid":"33932349","id":"PMC_33932349","title":"The ZMYND8-regulated mevalonate pathway endows YAP-high intestinal cancer with metabolic vulnerability.","date":"2021","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/33932349","citation_count":48,"is_preprint":false},{"pmid":"11003709","id":"PMC_11003709","title":"Identification and characterization of PRKCBP1, a candidate RACK-like protein.","date":"2000","source":"Mammalian genome : official journal of the International Mammalian Genome 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":37,"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":36,"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":34,"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":"29393731","id":"PMC_29393731","title":"Double duty: ZMYND8 in the DNA damage response and cancer.","date":"2018","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/29393731","citation_count":29,"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":"33593912","id":"PMC_33593912","title":"ZMYND8 preferentially binds phosphorylated EZH2 to promote a PRC2-dependent to -independent function switch in hypoxia-inducible factor-activated cancer.","date":"2021","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/33593912","citation_count":24,"is_preprint":false},{"pmid":"28232094","id":"PMC_28232094","title":"Chromatin reader ZMYND8 is a key target of all trans retinoic acid-mediated inhibition of cancer cell proliferation.","date":"2017","source":"Biochimica et biophysica acta. Gene regulatory mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/28232094","citation_count":22,"is_preprint":false},{"pmid":"33148660","id":"PMC_33148660","title":"ZMYND8 Expression in Breast Cancer Cells Blocks T-Lymphocyte Surveillance to Promote Tumor Growth.","date":"2020","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/33148660","citation_count":21,"is_preprint":false},{"pmid":"33670804","id":"PMC_33670804","title":"Regulation of ZMYND8 to Treat Cancer.","date":"2021","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/33670804","citation_count":18,"is_preprint":false},{"pmid":"33517164","id":"PMC_33517164","title":"ZMYND8 promotes the growth and metastasis of hepatocellular carcinoma by promoting HK2-mediated glycolysis.","date":"2021","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/33517164","citation_count":16,"is_preprint":false},{"pmid":"34487730","id":"PMC_34487730","title":"Aberrant FBXW7-mediated ubiquitination and degradation of ZMYND8 enhances tumor progression and stemness in bladder cancer.","date":"2021","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/34487730","citation_count":16,"is_preprint":false},{"pmid":"28432260","id":"PMC_28432260","title":"Dual histone reader ZMYND8 inhibits cancer cell invasion by positively regulating epithelial genes.","date":"2017","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/28432260","citation_count":16,"is_preprint":false},{"pmid":"36153585","id":"PMC_36153585","title":"ARID1A-dependent maintenance of H3.3 is required for repressive CHD4-ZMYND8 chromatin interactions at super-enhancers.","date":"2022","source":"BMC biology","url":"https://pubmed.ncbi.nlm.nih.gov/36153585","citation_count":15,"is_preprint":false},{"pmid":"28966017","id":"PMC_28966017","title":"The Structure of the ZMYND8/Drebrin Complex Suggests a Cytoplasmic Sequestering Mechanism of ZMYND8 by Drebrin.","date":"2017","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/28966017","citation_count":14,"is_preprint":false},{"pmid":"36692427","id":"PMC_36692427","title":"Zinc Finger MYND-Type Containing 8 (ZMYND8) Is Epigenetically Regulated in Mutant Isocitrate Dehydrogenase 1 (IDH1) Glioma to Promote Radioresistance.","date":"2023","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/36692427","citation_count":12,"is_preprint":false},{"pmid":"30250924","id":"PMC_30250924","title":"ZMYND8 is a primary HIF coactivator that mediates breast cancer progression.","date":"2018","source":"Molecular & cellular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/30250924","citation_count":12,"is_preprint":false},{"pmid":"35916866","id":"PMC_35916866","title":"De Novo ZMYND8 variants result in an autosomal dominant neurodevelopmental disorder with cardiac malformations.","date":"2022","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35916866","citation_count":11,"is_preprint":false},{"pmid":"39128723","id":"PMC_39128723","title":"USP7 deubiquitinates epigenetic reader ZMYND8 to promote breast cancer cell migration and invasion.","date":"2024","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/39128723","citation_count":10,"is_preprint":false},{"pmid":"40281007","id":"PMC_40281007","title":"ZMYND8 drives HER2 antibody resistance in breast cancer via lipid control of IL-27.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/40281007","citation_count":8,"is_preprint":false},{"pmid":"36064715","id":"PMC_36064715","title":"ZMYND8 suppresses MAPT213 LncRNA transcription to promote neuronal differentiation.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/36064715","citation_count":8,"is_preprint":false},{"pmid":"40102673","id":"PMC_40102673","title":"Targeting the histone reader ZMYND8 inhibits antiandrogen-induced neuroendocrine tumor transdifferentiation of prostate cancer.","date":"2025","source":"Nature cancer","url":"https://pubmed.ncbi.nlm.nih.gov/40102673","citation_count":7,"is_preprint":false},{"pmid":"31965980","id":"PMC_31965980","title":"A novel role of tumor suppressor ZMYND8 in inducing differentiation of breast cancer cells through its dual-histone binding function.","date":"2020","source":"Journal of biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/31965980","citation_count":6,"is_preprint":false},{"pmid":"40579459","id":"PMC_40579459","title":"ZMYND8 promotes the Warburg effect and tumorigenesis through c-Myc activation in pancreatic cancer.","date":"2025","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/40579459","citation_count":5,"is_preprint":false},{"pmid":"40347515","id":"PMC_40347515","title":"ZMYND8 Reads H3K36me2 to Activate CEBPE Transcription and Suppress Multiple Myeloma Progression through the Inhibition of Adaptive UPR Pathways.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/40347515","citation_count":5,"is_preprint":false},{"pmid":"34462784","id":"PMC_34462784","title":"Validation of ZMYND8 as a new treatment target in hepatocellular carcinoma.","date":"2021","source":"Journal of cancer research and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34462784","citation_count":4,"is_preprint":false},{"pmid":"40912652","id":"PMC_40912652","title":"The hypoxia-induced chromatin reader ZMYND8 drives HIF-dependent metabolic rewiring in breast cancer.","date":"2025","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/40912652","citation_count":3,"is_preprint":false},{"pmid":"38804064","id":"PMC_38804064","title":"ZMYND8 Is a Regulator of Sonic Hedgehog Signaling in ATRA-Mediated Differentiation of Neuroblastoma Cells.","date":"2024","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38804064","citation_count":2,"is_preprint":false},{"pmid":"34478652","id":"PMC_34478652","title":"Exploiting a key transcriptional dependency: ZMYND8 and IRF8 in AML.","date":"2021","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/34478652","citation_count":2,"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":1,"is_preprint":false},{"pmid":"40125808","id":"PMC_40125808","title":"RACK7 Interacts with PRC2 Complex to Regulate Astrocyte Development.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/40125808","citation_count":1,"is_preprint":false},{"pmid":"40223119","id":"PMC_40223119","title":"The RBM39 degrader indisulam 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":1,"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":1,"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":"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":"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":25717,"output_tokens":9171,"usd":0.107358,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":19029,"output_tokens":5509,"usd":0.116435,"stage2_stop_reason":"end_turn"},"total_usd":0.223793,"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\": 2015,\n      \"finding\": \"ZMYND8 functions as a bromodomain-containing chromatin reader that recruits the NuRD (nucleosome remodeling and histone deacetylation) complex to damaged chromatin, mediating transcriptional repression and promoting repair by homologous recombination at DNA double-strand breaks, particularly within transcriptionally active chromatin.\",\n      \"method\": \"Localization screen of BRD proteins after DNA damage, co-immunoprecipitation, knockdown with DSB repair and transcription assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, functional KD with defined HR repair and transcriptional repression phenotypes, replicated by multiple subsequent studies\",\n      \"pmids\": [\"25593309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ZMYND8 (RACK7) forms a biochemical complex with the H3K4me3-specific demethylase KDM5C and occupies active enhancers including super-enhancers; loss of RACK7 or KDM5C leads to enhancer overactivation characterized by H3K4me3 and H3K27Ac deposition and increased eRNA and nearby gene transcription, identifying RACK7/KDM5C as an enhancer 'brake'.\",\n      \"method\": \"Biochemical complex purification, ChIP-seq, genetic KO/KD with histone modification and transcription readouts\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — biochemical complex purification, genome-wide ChIP-seq, and functional KO with multiple orthogonal readouts in a single rigorous study\",\n      \"pmids\": [\"27058665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KDM5A demethylates H3K4me3 near DNA double-strand break sites, and this demethylation is required for ZMYND8-NuRD binding to chromatin and recruitment to DNA damage; KDM5A deficiency impairs transcriptional silencing and HR repair.\",\n      \"method\": \"ChIP-seq/ChIP at DSB sites, genetic KD of KDM5A with ZMYND8 recruitment assays, HR repair assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis established by KDM5A KD with chromatin binding and functional HR readouts, replicated across multiple cell systems\",\n      \"pmids\": [\"28572115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The PHD-Bromodomain cassette of ZMYND8 recognizes the combinatorial histone mark H3K4me1-H3K14ac (and H3K4me0-H3K14ac), mediating its function as a transcriptional corepressor of JARID1D and antagonizing expression of metastasis-linked genes.\",\n      \"method\": \"Histone peptide binding assays, PHD-Bromo domain mutagenesis, ChIP, knockdown with invasion assays in vitro and in vivo\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro histone binding with domain mutagenesis, confirmed by ChIP and functional KD phenotype, independently replicated\",\n      \"pmids\": [\"27477906\"],\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; this interaction bridges ZMYND8-NuRD and facilitates rapid, poly(ADP-ribose)-dependent recruitment of GATAD2A/NuRD to DNA damage sites to promote HR. ZMYND8 and NuRD share genome-wide binding at active promoters and enhancers, but ZMYND8 depletion does not globally affect NuRD occupancy.\",\n      \"method\": \"Direct interaction assays (MYND domain with GATAD2A peptides), Co-IP, ChIP-seq, live-cell recruitment assays after laser damage, HR repair assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct domain-peptide interaction assay, genome-wide ChIP-seq, live-cell damage recruitment, and HR functional readout in a single study\",\n      \"pmids\": [\"27732854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The crystal structure of the ZMYND8 PHD-BRD-PWWP triple reader cassette reveals a rigid structural supramodule capable of simultaneously recognizing multiple histone PTMs while providing a charged platform for DNA binding; disruption of single domains destroys the functional network and impairs recruitment to DNA damage sites.\",\n      \"method\": \"X-ray crystallography of PHD-BRD-PWWP, histone binding assays, single-domain mutagenesis, DNA damage recruitment assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with mutagenesis and functional recruitment assays in one study\",\n      \"pmids\": [\"27926874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ZMYND8 binds the histone marks H3.1K36me2 and H4K16ac through its conserved chromatin-binding modules, shows preference for canonical H3.1 over variant H3.3, and is recruited to ATRA-responsive developmental genes; ZMYND8 interacts with Ser5-phosphorylated RNA polymerase II in a DNA template-dependent manner.\",\n      \"method\": \"In vitro histone-binding assays with domain mutants, ChIP, co-immunoprecipitation with RNA Pol II, ATRA treatment gene expression studies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct histone binding and Co-IP with RNA Pol II, single lab, multiple complementary methods\",\n      \"pmids\": [\"26655721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ZMYND8 interacts with HIF-1α and HIF-2α and enhances elongation of HIF-induced oncogenic genes by recruiting BRD4 and promoting release of paused RNA polymerase II; ZMYND8 acetylation at K1007 and K1034 by p300 is required for HIF activation, breast cancer progression, and metastasis.\",\n      \"method\": \"Co-immunoprecipitation of ZMYND8 with HIF-1α/HIF-2α, p300 acetylation assays, acetylation-site mutagenesis, ChIP for BRD4 and RNA Pol II, mouse tumor/metastasis models\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, PTM mapping with mutagenesis, ChIP functional readout, and in vivo mouse models in a single rigorous study\",\n      \"pmids\": [\"29629903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ZMYND8 forms a homodimer via its coiled-coil domain; the homodimer preferentially associates with CyclinT1 of the P-TEFb complex to activate transcription, while the monomer associates with the CHD4 subunit of the NuRD repressor complex; ZMYND8-P-TEFb interaction promotes ATRA-mediated neuronal differentiation.\",\n      \"method\": \"Biochemical reconstitution of ZMYND8-P-TEFb complex, direct binding assay with CyclinT1, reporter gene assays, ChIP, neuronal differentiation assays with KD\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical reconstitution showing direct CyclinT1 binding, combined with reporter gene and native ChIP functional validation, single lab\",\n      \"pmids\": [\"30134174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ZMYND8 controls immunoglobulin class switch recombination (CSR) and somatic hypermutation (SHM) by binding promoters and super-enhancers including the Igh 3' regulatory region; ZMYND8 deficiency increases 3'RR polymerase loading but decreases acceptor region transcription and CSR.\",\n      \"method\": \"B-cell specific ZMYND8 KO, ChIP-seq for ZMYND8 at Igh enhancers, CSR and SHM functional assays, RNA Pol II ChIP\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined molecular phenotype at specific genomic loci, ChIP-seq, and functional immunological readout\",\n      \"pmids\": [\"30293785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ZMYND8 interacts with RCOR2 (REST corepressor 2) via co-immunoprecipitation; both proteins function as transcriptional repressors and overexpression of ZMYND8 inhibits neural differentiation in Xenopus embryos.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, overexpression in Xenopus embryos with neural differentiation readout\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — reciprocal Co-IP and in vivo overexpression phenotype, two orthogonal methods, single lab\",\n      \"pmids\": [\"20331974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"PRKCBP1 (ZMYND8) protein specifically interacts with PKCβI via its carboxy terminus, identified by immunoprecipitation of GST-fused PRKCBP1.\",\n      \"method\": \"GST pulldown/immunoprecipitation using monoclonal antibody screen of cDNA library, Northern analysis for tissue expression\",\n      \"journal\": \"Mammalian genome\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single GST pulldown assay, single lab, no functional follow-up\",\n      \"pmids\": [\"11003709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The crystal structure of the Drebrin ADF-H domain in complex with ZMYND8 PHD-BRD-PWWP reveals that Drebrin competes with modified histones for ZMYND8 binding; Drebrin binding can shuttle ZMYND8 from the nucleus to the cytoplasm, suggesting a cytoplasmic sequestration mechanism.\",\n      \"method\": \"X-ray crystallography of Drebrin ADF-H/ZMYND8 PHD-BRD-PWWP complex, competition binding assays, live-cell imaging showing nuclear-to-cytoplasmic redistribution\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with competition binding assays and live-cell localization shift, multiple orthogonal methods in one study\",\n      \"pmids\": [\"28966017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RACK7 (ZMYND8) recognizes the histone H3.3G34R patient mutation in vitro and in vivo and suppresses transcription of CIITA (master regulator of MHC class II) and genes involved in vesicular transport of MHC class II molecules, resulting in suppression of MHC class II surface expression; CRISPR correction of H3.3G34R reduces RACK7 chromatin binding and derepresses the same genes.\",\n      \"method\": \"In vitro binding assays (RACK7 to H3.3G34R), ChIP-seq in patient-derived glioblastoma cells, CRISPR knock-in correction, RNA-seq, functional MHC class II surface assays\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct in vitro binding, CRISPR knock-in isogenic comparison, ChIP-seq, and functional gene expression readout in patient-derived cells\",\n      \"pmids\": [\"32832624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ZMYND8 directly activates IRF8 transcription in AML through lineage-specific enhancers in parallel with MYC; ZMYND8 occupancy at IRF8 and MYC enhancers requires BRD4 via direct binding of ZMYND8's reader cassette to the ET domain of BRD4, and this interaction is required for proper chromatin occupancy and AML cell survival in vitro and in vivo.\",\n      \"method\": \"Co-IP of ZMYND8 with BRD4 ET domain, ChIP-seq in AML cell lines and patient samples, ZMYND8 KO with proliferation/survival readouts in vivo, domain-binding assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct domain binding assay (reader cassette to BRD4 ET), ChIP-seq in cell lines and patient samples, in vivo KO proliferation assay\",\n      \"pmids\": [\"34358447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ZMYND8 preferentially binds phosphorylated EZH2 (T487, phosphorylated by CDK1); ZMYND8 depletion enhances PRC2-dependent function of EZH2 and suppresses the FOXM1 transcription program; ZMYND8 is required for EZH2-FOXM1 interaction and FOXM1-dependent MMP gene expression and EZH2-mediated cell migration and invasion in VHL-deficient cancer cells.\",\n      \"method\": \"Co-IP showing enhanced ZMYND8-EZH2 binding with T487 phosphorylation, ZMYND8 KD with PRC2 activity, FOXM1 interaction, MMP expression, and migration/invasion readouts\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with phospho-specific context and KD functional assays, single lab, multiple readouts\",\n      \"pmids\": [\"33593912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ZMYND8 and SREBP2 drive enhancer-promoter interactions to facilitate recruitment of the Mediator complex, upregulating mevalonate pathway genes; this ZMYND8-dependent cholesterol biosynthesis pathway is essential for Lgr5+ intestinal stem cell self-renewal and intestinal tumorigenesis downstream of YAP.\",\n      \"method\": \"ChIP-seq for ZMYND8 and SREBP2, chromatin conformation capture (enhancer-promoter looping), KO of ZMYND8 with mevalonate gene expression, cholesterol measurements, intestinal organoid and tumor model assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq, chromatin conformation assays, and functional KO phenotype with multiple orthogonal readouts in a single study\",\n      \"pmids\": [\"33932349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FBXW7 E3 ubiquitin ligase interacts directly with ZMYND8 and degrades it via polyubiquitination, thereby controlling ZMYND8 protein levels; low FBXW7 leads to ZMYND8 accumulation and promotes bladder cancer progression and stemness.\",\n      \"method\": \"Bioinformatic interaction prediction, co-immunoprecipitation of FBXW7 with ZMYND8, polyubiquitination assay, functional cell proliferation/migration assays, in vivo tumor model\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and ubiquitination assay with functional KO readout, single lab, two complementary methods\",\n      \"pmids\": [\"34487730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The lncRNA TROJAN binds ZMYND8 and increases its degradation through the ubiquitin-proteasome pathway by repelling ZNF592 from ZMYND8, thereby reducing ZMYND8 protein stability and promoting metastasis-related gene expression in TNBC.\",\n      \"method\": \"RNA pulldown/RIP showing TROJAN-ZMYND8 binding, ubiquitin-proteasome assay for ZMYND8 degradation, ZNF592 competition assays, functional invasion assays, in vivo xenograft\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct RNA-protein binding and degradation assays with functional phenotype, single lab\",\n      \"pmids\": [\"30854423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ZMYND8 interacts with CHD4 (NuRD) at ARID1A-bound H3.3+ H4K16ac+ super-enhancers to suppress a subset of genes governing extracellular matrix, motility, and EMT; ARID1A is required for CHD4 recruitment to H3.3, and ZMYND8 acts downstream in this pathway.\",\n      \"method\": \"ChIP-seq for ZMYND8, CHD4, ARID1A, H3.3, H4K16ac; Co-IP of ZMYND8 with CHD4; ARID1A KD epistasis experiments; gene expression analysis\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq and Co-IP with genetic epistasis (KD), single lab, multiple orthogonal methods\",\n      \"pmids\": [\"36153585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ZMYND8 missense variants in the PWWP domain abolish interaction with Drebrin, and missense variants in the MYND domain disrupt interaction with GATAD2A, as established by yeast two-hybrid assays; neuronal knockdown of the Drosophila ZMYND8 ortholog results in decreased habituation learning.\",\n      \"method\": \"Yeast two-hybrid assays with PWWP and MYND domain mutants, Drosophila neuronal KD with habituation learning assay\",\n      \"journal\": \"Genetics in medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid domain mapping and in vivo Drosophila KD cognitive phenotype, single consortium, two orthogonal methods\",\n      \"pmids\": [\"35916866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ZMYND8 inhibits micronucleus formation and DNA damage in breast cancer cells; loss of ZMYND8 triggers activation of the cGAS DNA sensor in micronuclei, activating STING and NF-κB (but not TBK1/IRF3), inducing IFNβ and ISG expression, and promoting CD4+/CD8+ T-cell infiltration and tumor suppression.\",\n      \"method\": \"ZMYND8 KO in breast cancer cells with micronucleus quantification, cGAS/STING pathway activation assays, cytokine measurements, syngeneic mouse model with T-cell depletion antibodies and Rag1 KO mice\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with mechanistic pathway activation assays, multiple mouse model validations including Rag1 KO and antibody depletion controls\",\n      \"pmids\": [\"33148660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP7 deubiquitinase directly binds the 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 cell migration and invasion.\",\n      \"method\": \"Co-IP of USP7 with ZMYND8, domain mapping (TRAF/UBL vs PBP), in vitro deubiquitination assay at K1034, KD/OE with migration/invasion readouts, target gene expression analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro deubiquitination assay with site-specific K1034 identification, domain mapping Co-IP, and functional cell migration phenotype, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"39128723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ZMYND8 is a master transcriptional regulator of 27-hydroxycholesterol metabolism: it increases cholesterol biosynthesis and oxidation while blocking cholesterol efflux and catabolism, leading to 27-HC accumulation in breast cancer stem cells; 27-HC promotes EMT and tumor initiation through liver X receptor activation.\",\n      \"method\": \"ZMYND8 KO/KD in genetic mouse mammary tumor and human breast cancer models, cholesterol/27-HC metabolite measurements, LXR reporter assays, ChIP for ZMYND8 at cholesterol metabolism gene loci\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO in multiple models, metabolite measurements, and ChIP at target gene loci, single lab\",\n      \"pmids\": [\"35857506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZMYND8 increases NRF2 protein stability through KEAP1 silencing and directly interacts with NRF2 to recruit it to promoters of antioxidant genes; NRF2 in turn directly controls ZMYND8 expression, establishing a positive feedback loop that sustains BCSC antioxidant defense and ferroptosis resistance.\",\n      \"method\": \"Co-IP of ZMYND8 with NRF2, ChIP showing ZMYND8-NRF2 co-recruitment to antioxidant gene promoters, KEAP1 expression analysis after ZMYND8 KO, NRF2 KO epistasis, ROS/ferroptosis assays, mammosphere models\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ChIP co-recruitment, genetic epistasis (NRF2 KO rescuing ZMYND8 effects), and functional ROS/ferroptosis readouts in multiple models\",\n      \"pmids\": [\"38488001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZMYND8 enhances cPLA2α expression by inducing c-Myc; cPLA2α inactivates phosphatidylcholine-specific phospholipase C to inhibit diacylglycerol production, thereby diminishing PKC activity and leading to IL-27 secretion that confers trastuzumab/pertuzumab resistance in HER2+ breast cancer.\",\n      \"method\": \"ZMYND8 KO/OE in resistant tumor cells and patient-derived organoids, ChIP for c-Myc at cPLA2α promoter, lipid metabolite measurements, IL-27 secretion assays, patient-derived xenograft models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for mechanistic pathway, functional KO in organoids and xenografts, single lab with multiple readouts\",\n      \"pmids\": [\"40281007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FOXM1 stabilizes ZMYND8 binding to H3K4me1-H3K14ac chromatin; antiandrogen therapy releases SWI/SNF from androgen receptor, facilitating SWI/SNF interaction with ZMYND8-FOXM1 to upregulate neuroendocrine lineage regulators and drive NEPC transdifferentiation; small molecule iZMYND8-34 inhibiting ZMYND8 histone recognition blocks NEPC development.\",\n      \"method\": \"CRISPR-Cas9 screen combined with scRNA-seq tracking, ChIP-seq for ZMYND8 with H3K4me1-H3K14ac, Co-IP of SWI/SNF with ZMYND8-FOXM1, ZMYND8 KO mouse model, pharmacological inhibition with iZMYND8-34\",\n      \"journal\": \"Nature cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR screen, ChIP-seq, Co-IP, genetic KO mouse model, and pharmacological inhibition all converging on same mechanism, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"40102673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RACK7 (ZMYND8) interacts with the PRC2 complex and establishes genomic locations of SUZ12 and H3K27 methylation; deletion of Rack7 in astrocytes causes genome-wide decrease of H3K27me3 and aberrant astrocyte development with Wnt signaling overactivation.\",\n      \"method\": \"Rack7 conditional KO mouse model, Co-IP of RACK7 with PRC2 components, ChIP-seq for H3K27me3 and SUZ12 genome-wide, transcriptome analysis, Wnt pathway reporter assays\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO mouse model, Co-IP with PRC2, genome-wide ChIP-seq showing H3K27me3 loss, and pathway activation readout\",\n      \"pmids\": [\"40125808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RACK7 swiftly redistributes from repressed to activated enhancers in response to acute stimulations in a transcription-dependent manner and positively regulates enhancer activation by promoting RNA polymerase II recruitment.\",\n      \"method\": \"ChIP-seq/CUT&RUN tracking of RACK7 redistribution after acute stimulation, transcription inhibitor experiments, RNA Pol II ChIP\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide ChIP-seq with mechanistic transcription-dependence experiment, single lab\",\n      \"pmids\": [\"40734674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZMYND8 acts as an E3 ubiquitin ligase-like factor mediating ubiquitination and proteasomal degradation of HMGB1 in cardiomyocytes; MEK inhibitor trametinib inhibits ZMYND8, leading to aberrant HMGB1 accumulation and cardiomyocyte death.\",\n      \"method\": \"ZMYND8 KO in cardiomyocytes, ubiquitination assays for HMGB1 with ZMYND8 present/absent, HMGB1 stability measurements, trametinib treatment with ZMYND8 activity readouts\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, KO phenotype with ubiquitination assay but mechanism of E3 ligase activity not fully biochemically reconstituted in abstract\",\n      \"pmids\": [\"41423035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"The crystal structure of the ZMYND8 coiled-coil MYND domain reveals a homodimeric architecture; the MYND domain specifically recruits GATAD2A to the MAPT213 internal regulatory region through direct interaction with proline-rich motifs in GATAD2A's central region, suppressing MAPT213 lncRNA transcription while promoting protein-coding MAPT expression.\",\n      \"method\": \"Crystal structure of ZMYND8 coiled-coil MYND domain, Co-IP/direct binding assays of MYND with GATAD2A proline-rich motifs, ChIP for GATAD2A recruitment, quantitative binding measurements, domain mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with domain mutagenesis and ChIP functional validation of GATAD2A recruitment, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"41999894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ZMYND8 directly interacts with c-Myc (confirmed by Co-IP), activating c-Myc transcriptional activity through downstream epigenetic regulatory pathways to promote the Warburg effect and aerobic glycolysis in pancreatic cancer cells.\",\n      \"method\": \"Co-immunoprecipitation of ZMYND8 with c-Myc, CUT&Tag and RNA-seq integration, proteomic profiling, glycolysis assays, in vivo xenograft with c-Myc KD rescue\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP confirmed direct interaction, CUT&Tag for chromatin occupancy, and functional rescue by c-Myc KD, single lab\",\n      \"pmids\": [\"40579459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZMYND8 PWWP domain reads H3K36me2 and activates CEBPE transcription in an H3K36me2-dependent manner; CEBPE then represses adaptive UPR pathways (ERN1, XBP1, ATF6) to suppress multiple myeloma cell survival.\",\n      \"method\": \"ChIP for ZMYND8 at CEBPE locus with H3K36me2 dependence, Co-IP assays, PWWP domain mutation experiments, RNA-seq and ChIP-seq combined analysis, ZMYND8 KD/KO with UPR pathway and proliferation readouts\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with domain mutagenesis establishing H3K36me2 dependence and downstream pathway epistasis, single lab\",\n      \"pmids\": [\"40347515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Phosphorylated EZH2 T487D (phosphomimic) shows increased binding to ZMYND8, consistent with CDK1 phosphorylation of EZH2 at T487 promoting ZMYND8-EZH2 interaction, as demonstrated independently by phospho-EZH2 pulldown in TNBC cells.\",\n      \"method\": \"Co-IP/pulldown of phosphomimic EZH2 T487D with ZMYND8 in TNBC cells\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single pulldown from preprint, single method, not yet peer reviewed; largely corroborates PMID 33593912\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"OTUD4 deubiquitinase directly interacts with and stabilizes ZMYND8; ZMYND8 acts as a scaffold promoting assembly of the DDX3X-CK1ε complex, thereby activating WNT/β-catenin signaling; this OTUD4-ZMYND8-DDX3X axis upregulates CSF1 and promotes M2 macrophage polarization in TNBC spinal metastasis.\",\n      \"method\": \"Co-IP of OTUD4 with ZMYND8 and ZMYND8 with DDX3X/CK1ε, ubiquitination/stability assays, WNT/β-catenin reporter, CSF1 expression and macrophage polarization assays, in vivo spinal metastasis model\",\n      \"journal\": \"Neoplasia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple Co-IPs establishing complex assembly, functional pathway readouts, and in vivo validation, single lab\",\n      \"pmids\": [\"41297414\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ZMYND8 is a multivalent chromatin reader whose rigid PHD-BRD-PWWP supramodule binds combinatorial histone marks (H3K4me1-H3K14ac, H3K36me2/H4K16ac, H3K4me3 after KDM5A demethylation) and DNA simultaneously; it recruits the NuRD repressor complex to active enhancers and DNA double-strand break sites via a direct MYND domain–GATAD2A(PPPLΦ) interaction to repress transcription and promote homologous recombination, while in an alternative dimeric form it associates with the P-TEFb/CyclinT1 complex and BRD4 to activate transcription at lineage-specific enhancers; its activity is regulated post-translationally by p300-mediated acetylation (K1007/K1034 for HIF activation), CDK1/FBXW7-mediated ubiquitination and proteasomal degradation (counteracted by USP7 deubiquitination), and by cytoplasmic sequestration through Drebrin competition for the PHD-BRD-PWWP module.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ZMYND8 is a multivalent chromatin reader that integrates combinatorial histone-mark recognition with transcriptional control at enhancers and DNA damage sites [#1, #5]. Its rigid PHD-BRD-PWWP supramodule reads combinatorial marks including H3K4me1/me0-H3K14ac, H3.1K36me2 and H4K16ac while presenting a charged surface for DNA, and disruption of any single domain collapses the reader network and impairs chromatin recruitment [#3, #5, #6]. Through its MYND domain, ZMYND8 binds proline-rich (PPPLΦ) motifs in the NuRD subunit GATAD2A, bridging ZMYND8 to the NuRD remodeling/deacetylation complex; at DNA double-strand breaks this PAR-dependent recruitment enforces transcriptional silencing and promotes homologous-recombination repair, with the requisite chromatin engagement licensed by KDM5A/KDM5C demethylation of H3K4me3 [#0, #2, #4, #30]. At active and super-enhancers, ZMYND8 acts as a transcriptional 'brake' in complex with KDM5C, restraining H3K4me3/H3K27ac deposition and eRNA output [#1]. Beyond repression, an oligomerization switch diversifies its output: a coiled-coil homodimer engages CyclinT1/P-TEFb to activate transcription, whereas the monomer engages the CHD4-NuRD repressor, and ZMYND8 cooperates with BRD4 (via reader-cassette binding to the BRD4 ET domain) and HIF-1α/HIF-2α to release paused RNA Pol II at oncogenic and lineage-specific enhancers [#8, #14, #7]. ZMYND8 abundance is tuned post-translationally by FBXW7-mediated polyubiquitination and degradation counteracted by USP7 deubiquitination at K1034, and its histone engagement can be competitively sequestered to the cytoplasm by Drebrin binding the PHD-BRD-PWWP module [#17, #22, #12]. These activities place ZMYND8 at the center of DNA repair, enhancer regulation, lineage differentiation, and multiple cancer programs including HIF-driven metastasis, cholesterol/27-HC metabolism, and NRF2-dependent antioxidant defense [#7, #16, #24]. Rare PWWP and MYND domain missense variants that abolish Drebrin or GATAD2A binding, together with a learning defect on knockdown of the Drosophila ortholog, implicate ZMYND8 in a neurodevelopmental disorder [#20].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"An early interaction screen first linked the then-named PRKCBP1 protein to PKCβI signaling, establishing a physical partner before any chromatin role was known.\",\n      \"evidence\": \"GST pulldown/immunoprecipitation from a cDNA library and Northern expression analysis\",\n      \"pmids\": [\"11003709\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single pulldown without functional follow-up\", \"No connection to later chromatin-reading function established\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"The question of whether ZMYND8 acts as a transcriptional repressor was first addressed by linking it to a corepressor partner and a developmental phenotype.\",\n      \"evidence\": \"Yeast two-hybrid and Co-IP showing RCOR2 interaction, with overexpression in Xenopus embryos blocking neural differentiation\",\n      \"pmids\": [\"20331974\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of repression not defined\", \"No chromatin-binding determinants identified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"ZMYND8 was defined as a bromodomain chromatin reader that couples transcriptional repression to DNA repair, answering how active chromatin is silenced and channeled into homologous recombination at breaks.\",\n      \"evidence\": \"BRD localization screen after DNA damage, reciprocal Co-IP with NuRD, and knockdown with HR repair and transcription assays; separate study mapping histone-mark and RNA Pol II Ser5P binding\",\n      \"pmids\": [\"25593309\", \"26655721\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct histone-mark code not fully resolved at this stage\", \"Recruitment kinetics and PAR dependence not yet established\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"The molecular basis of ZMYND8 chromatin targeting and NuRD bridging was resolved, defining the reader code, the GATAD2A interaction, the enhancer-brake function, and the structural supramodule.\",\n      \"evidence\": \"Histone peptide binding with PHD-Bromo mutagenesis (H3K4me1-H3K14ac), MYND-GATAD2A PPPLΦ binding with laser-damage recruitment, KDM5C complex purification with enhancer ChIP-seq, and crystal structure of the PHD-BRD-PWWP cassette\",\n      \"pmids\": [\"27477906\", \"27732854\", \"27058665\", \"27926874\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How reader recognition is switched between repressive and activating contexts not resolved\", \"Direct DNA-binding contribution to recruitment not quantified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The chromatin licensing step for damage recruitment was clarified by showing that H3K4me3 demethylation is a prerequisite, and that Drebrin can competitively sequester ZMYND8 to the cytoplasm.\",\n      \"evidence\": \"KDM5A knockdown with ZMYND8 recruitment and HR assays at DSBs; crystal structure of Drebrin ADF-H/ZMYND8 PHD-BRD-PWWP with competition binding and live-cell localization shift\",\n      \"pmids\": [\"28572115\", \"28966017\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger that initiates Drebrin-mediated shuttling in cells unclear\", \"Quantitative contribution of cytoplasmic sequestration to nuclear function unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"ZMYND8 was shown to switch between repressive and activating outputs through oligomerization and to drive HIF-dependent and immunoglobulin loci programs, explaining its dual transcriptional behavior.\",\n      \"evidence\": \"Coiled-coil homodimer reconstitution with CyclinT1/P-TEFb vs CHD4-NuRD monomer binding; HIF-1α/2α Co-IP with p300 acetylation site mapping and tumor models; B-cell KO with ChIP-seq at the Igh 3'RR and CSR/SHM assays\",\n      \"pmids\": [\"30134174\", \"29629903\", \"30293785\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What controls the monomer/dimer equilibrium in vivo not defined\", \"How acetylation at K1007/K1034 alters complex choice not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Post-transcriptional control of ZMYND8 abundance was extended to lncRNA-directed degradation, addressing how its levels are tuned in cancer.\",\n      \"evidence\": \"RNA pulldown/RIP of lncRNA TROJAN, ZNF592 competition and ubiquitin-proteasome degradation assays with invasion/xenograft readouts in TNBC\",\n      \"pmids\": [\"30854423\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ZNF592 mechanism of stabilizing ZMYND8 not structurally defined\", \"E3 ligase responsible not identified in this study\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"ZMYND8 was connected to oncohistone recognition and to genome-stability-linked innate immunity, broadening its role beyond canonical marks.\",\n      \"evidence\": \"In vitro and ChIP-seq binding to H3.3G34R with CRISPR knock-in correction and MHC class II readouts; ZMYND8 KO with cGAS-STING-NF-κB activation, IFNβ induction and syngeneic/Rag1 KO mouse models\",\n      \"pmids\": [\"32832624\", \"33148660\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How G34R alters reader engagement structurally not resolved\", \"Link between repair function and micronucleus suppression not mechanistically dissected\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Multiple studies positioned ZMYND8 as a regulator of cancer transcriptional and metabolic programs and identified additional partners and degradation control.\",\n      \"evidence\": \"Co-IP with BRD4 ET domain plus IRF8/MYC enhancer ChIP-seq in AML; phospho-EZH2 (T487) binding with PRC2/FOXM1 readouts; SREBP2/Mediator enhancer-looping with mevalonate KO phenotypes; FBXW7 polyubiquitination of ZMYND8; c-Myc Co-IP with glycolysis assays\",\n      \"pmids\": [\"34358447\", \"33593912\", \"33932349\", \"34487730\", \"40579459\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ZMYND8 directly reads phospho-EZH2 or acts via an adaptor unclear\", \"Relative contribution of each program across tissues not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"ZMYND8's enhancer repression was placed downstream of ARID1A/CHD4 chromatin context and tied to cholesterol metabolite control and neurodevelopmental genetics.\",\n      \"evidence\": \"ChIP-seq/Co-IP placing ZMYND8-CHD4 at ARID1A-dependent H3.3/H4K16ac super-enhancers; 27-HC metabolite/LXR analysis in mammary tumor models; yeast two-hybrid domain mapping of patient variants with Drosophila habituation assay\",\n      \"pmids\": [\"36153585\", \"35857506\", \"35916866\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causality of human ZMYND8 variants in disease not proven by family genetics in this corpus\", \"Direct enzymatic control of metabolite genes vs indirect effects not separated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The stability and antioxidant arms of ZMYND8 regulation were defined, identifying USP7 as the deubiquitinase opposing FBXW7 and an NRF2 feedback loop.\",\n      \"evidence\": \"USP7 domain-mapped Co-IP and in vitro deubiquitination at K1034 with migration assays; ZMYND8-NRF2 reciprocal Co-IP, ChIP co-recruitment, KEAP1 silencing, NRF2 KO epistasis and ferroptosis readouts\",\n      \"pmids\": [\"39128723\", \"38488001\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How USP7 vs FBXW7 balance is set physiologically unknown\", \"Mechanism by which ZMYND8 silences KEAP1 not detailed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"ZMYND8 was integrated into lineage transdifferentiation, PRC2-directed H3K27 methylation, enhancer redistribution dynamics, and several additional cancer/metabolic axes, with a chemical probe demonstrating druggability.\",\n      \"evidence\": \"CRISPR/scRNA-seq, ChIP-seq, SWI/SNF-ZMYND8-FOXM1 Co-IP and iZMYND8-34 inhibition in NEPC; Rack7 conditional KO with PRC2 Co-IP and genome-wide H3K27me3 loss in astrocytes; CUT&RUN tracking of stimulus-driven RACK7 redistribution; PWWP-H3K36me2-CEBPE axis in myeloma; cPLA2α/IL-27 and OTUD4-DDX3X-WNT axes in breast cancer\",\n      \"pmids\": [\"40102673\", \"40125808\", \"40734674\", \"40347515\", \"40281007\", \"41297414\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ZMYND8 directs PRC2 genomic targeting mechanistically not resolved\", \"Whether the activating enhancer redistribution uses the dimeric P-TEFb form not directly linked\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"High-resolution structure of the coiled-coil MYND module confirmed homodimeric architecture and defined GATAD2A proline-rich recognition driving locus-specific lncRNA/mRNA balance.\",\n      \"evidence\": \"Crystal structure of the ZMYND8 coiled-coil MYND domain with quantitative GATAD2A binding, domain mutagenesis, and ChIP for GATAD2A recruitment at MAPT213\",\n      \"pmids\": [\"41999894\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generalizability of MAPT-specific recruitment logic to other loci unknown\", \"Coupling of dimerization state to GATAD2A vs P-TEFb choice not directly tested here\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether ZMYND8 possesses intrinsic E3 ubiquitin ligase activity, and how its monomer/dimer switch is governed to select repressive vs activating complexes in a given cell context, remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Reported HMGB1 E3-ligase-like activity not reconstituted biochemically (idx 29, Low confidence)\", \"Upstream signals controlling oligomerization equilibrium undefined\", \"Integration of competing PTMs (acetylation, ubiquitination) into output choice unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [3, 5, 6, 13, 32]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 7, 8, 14]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 8, 30, 34]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 5, 12]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [0, 2, 4]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 7, 8, 14]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1, 27]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [7, 13, 14, 24, 26]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [9, 13, 21]}\n    ],\n    \"complexes\": [\n      \"NuRD complex\",\n      \"KDM5C complex\",\n      \"P-TEFb\",\n      \"PRC2\"\n    ],\n    \"partners\": [\n      \"GATAD2A\",\n      \"CHD4\",\n      \"KDM5C\",\n      \"BRD4\",\n      \"CCNT1\",\n      \"HIF1A\",\n      \"USP7\",\n      \"FBXW7\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}