{"gene":"CHD3","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2011,"finding":"ATM-dependent phosphorylation of KAP-1 at Ser824 generates a motif that directly perturbs the interaction between CHD3's SUMO-interacting motif (SIM) and SUMO1 on KAP-1, causing dispersal of CHD3 from heterochromatic DNA double-strand breaks (DSBs) and enabling chromatin relaxation and DSB repair. Depletion or inactivation of CHD3, or ablation of its interaction with KAP-1(SUMO1), bypassed the requirement for pKAP-1 in heterochromatic DSB repair.","method":"Co-immunoprecipitation, siRNA depletion, site-directed mutagenesis (CHD3 SIM mutant, KAP-1 Ser824 mutant), chromatin relaxation assays, epistasis (KAP-1 phospho-mutant rescue by CHD3 depletion)","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (Co-IP, mutagenesis of both CHD3 SIM and KAP-1 Ser824, functional rescue/epistasis), rigorous mechanistic dissection in single study","pmids":["21642969"],"is_preprint":false},{"year":2017,"finding":"CHD3 and CHD4 form mutually exclusive, isoform-specific NuRD complexes (each complex contains either CHD3 or CHD4 as a monomeric ATPase subunit, not both). CHD3- and CHD4-NuRD complexes differ in nucleosome remodeling and positioning behavior in vitro, exhibit distinct nuclear localization patterns, and regulate overlapping but also distinct target genes. Both complexes interact with HP1 and accumulate at UV-induced DNA repair sites.","method":"Mass spectrometry-based proteomic mapping of NuRD subunit composition, FRAP (intranuclear mobility), Co-immunoprecipitation with HP1, live-cell imaging at UV damage sites, in vitro nucleosome remodeling assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (MS, Co-IP, in vitro remodeling, live imaging) in single rigorous study","pmids":["28977666"],"is_preprint":false},{"year":2017,"finding":"The tandem PHD fingers of CHD3 bind histone H3 tails, and post-translational modifications that increase hydrophobicity at H3K9 (H3K9me3 or H3K9ac) enhance this interaction. Binding of CHD3 PHDs promotes H3K9Cme3-nucleosome unwrapping in vitro and perturbs pericentric heterochromatin structure in vivo. H3K9 methylation or acetylation alleviates intra-nucleosomal interaction of H3 tails, increasing H3K9 accessibility for CHD3 binding.","method":"Peptide binding assays, in vitro nucleosome unwrapping assays, immunofluorescence/chromatin fractionation in cells (PHD mutants), ChIP co-localization with NuRD subunits","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reconstitution (in vitro binding and unwrapping), structural/biochemical analysis of PHD-histone interaction, cellular validation with mutants","pmids":["29020631"],"is_preprint":false},{"year":2018,"finding":"De novo missense mutations clustering in the ATPase/helicase domain of CHD3 cause Snijders Blok-Campeau syndrome. Structural modeling shows these mutations disturb critical binding and interaction motifs. Experimental assays with six identified mutations showed a subset directly reduces ATPase activity, and all but one alter chromatin remodeling activity.","method":"Whole genome sequencing (patient cohort), 3D protein structural modeling, ATPase activity assays, chromatin remodeling assays (in vitro, six mutant variants tested)","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct in vitro ATPase and remodeling assays on multiple patient-derived mutations, structural modeling, large patient cohort","pmids":["30397230"],"is_preprint":false},{"year":2018,"finding":"CHD3 is recruited to DNA double-strand breaks in a poly(ADP-ribosyl)ation-dependent manner (dependent on PARP1 activity), similar to CHD4, but not through direct PAR binding. Both CHD3 and CHD4 actively participate in chromatin remodeling at DNA breaks. An initial chromatin relaxation phase driven by PARP1 and Alc1/CHD1L promotes subsequent CHD3 and CHD4 recruitment via DNA binding for further remodeling.","method":"Live-cell fluorescence three-hybrid assay, laser micro-irradiation with live imaging, siRNA knockdown, PARP inhibitor treatment","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live-cell imaging with functional assays, single lab, two orthogonal methods","pmids":["29733391"],"is_preprint":false},{"year":2014,"finding":"CHD3 localizes to early herpes simplex virus (HSV) foci in infected cells, suppresses viral immediate early gene expression, and reduces the number of transcriptionally active viral genomes. CHD3 can recognize repressive histone marks associated with HSV chromatin. Depletion of CHD3 results in enhanced viral immediate early gene expression and increased numbers of transcriptionally active viral genomes.","method":"Immunofluorescence localization, siRNA depletion, reporter gene assays for viral immediate early gene expression, chromatin accessibility assays","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — localization with functional consequence (KD phenotype), single lab, multiple readouts","pmids":["24425734"],"is_preprint":false},{"year":2003,"finding":"Two human proteins, CGI-55 and Ki-1/57, interact with the C-terminal region of CHD3 (residues after aa 1676). The CGI-55–CHD3 interaction was confirmed by yeast two-hybrid, in vitro pulldown, and co-immunoprecipitation from Sf9 insect cells. CGI-55 interacts with CHD3 via two regions at its N- and C-termini.","method":"Yeast two-hybrid, in vitro pulldown, co-immunoprecipitation from Sf9 cells, GFP-fusion localization","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — reciprocal validation across multiple assays (Y2H + in vitro + Co-IP), single lab","pmids":["12505151"],"is_preprint":false},{"year":2007,"finding":"The C-terminal region of CHD3/ZFH (amino acids 1676–2000) interacts with the CIDD region (aa 96–349, critical residues 200–299) of the Ets transcription factor ERM, and this interaction represses transcription of the presenilin 1 (PS1) gene. CHD3 C-terminal fragment (aa 1676–2000) occupies the PS1 promoter in vivo. Sequences critical for repression and ERM binding are between aa 1862 and 1877 of CHD3.","method":"Yeast two-hybrid (interaction mapping), transfection reporter assays (transcription repression), chromatin immunoprecipitation (ChIP at PS1 promoter), deletion mutagenesis of both CHD3 and ERM","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Y2H + ChIP + reporter assays + deletion mutagenesis, single lab","pmids":["17489097"],"is_preprint":false},{"year":2014,"finding":"CHD3 interacts with nuclear export signal 1 (NES1) of influenza A virus NS2 protein and co-localizes NS2 and Crm1 on dense chromatin to facilitate Crm1-dependent vRNP nuclear export. Disruption of the NS2–CHD3 interaction (by NES1 mutation) significantly delays vRNP export and viral propagation. CHD3 knockdown impairs propagation of wild-type virus but not a mutant with weakened NS2–CHD3 interaction.","method":"Co-immunoprecipitation, site-directed mutagenesis of NES1, siRNA knockdown of CHD3, viral propagation assays, nuclear export kinetics","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, mutagenesis, KD with functional viral readout, single lab","pmids":["25213355"],"is_preprint":false},{"year":2021,"finding":"The ATPase domain of CHD3 exhibits differential regulatory properties compared to SNF2H: IP6 inhibits CHD3 nucleosome translocation competitively (but not SNF2H), and CHD3 can translocate nucleosomes even at very low ATP concentrations. Mutations in conserved Q- and K-residues of the ATPase domain motifs show that basal ATP hydrolysis activity of CHD3 is sufficient for nucleosome remodeling (unlike SNF2H mutants), suggesting more efficient coupling of ATP hydrolysis and remodeling in CHD3.","method":"In vitro ATPase assays, nucleosome remodeling/translocation assays, site-directed mutagenesis of conserved ATPase motif residues, inhibitor dose-response (ADP, IP6)","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted in vitro enzymatic assays with mutagenesis, single lab but multiple orthogonal biochemical methods","pmids":["33403747"],"is_preprint":false},{"year":2010,"finding":"Drosophila CHD3 proteins act as monomers (not found in protein complexes) that remodel chromatin in vitro. Drosophila CHD3 co-localizes with elongating RNA polymerase II on salivary gland polytene chromosomes. Deletion of Chd3 has no effect on viability or fertility in Drosophila.","method":"Protein complex fractionation (monomeric vs. complex), in vitro chromatin remodeling assay, polytene chromosome immunofluorescence, targeted gene replacement (deletion mutant viability/fertility assay)","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro remodeling assay, chromosome localization, genetic null mutant analysis, single lab","pmids":["20439780"],"is_preprint":false},{"year":2025,"finding":"CHD3 (as a NuRD component) promotes BMP signalling during cranial neural crest cell (CNCC) specification by opening chromatin at BMP-responsive cis-regulatory elements and increasing expression of BMP-responsive transcription factors (including DLX paralogs). CHD3 loss leads to repression of BMP target genes, reduced chromatin accessibility at BMP-responsive enhancers, imbalance between BMP and Wnt signalling, and failure of CNCC specification replaced by aberrant mesodermal identity. This phenotype can be partially rescued by titrating Wnt levels.","method":"CHD3-KO human iPSC differentiation to CNCCs, ATAC-seq (chromatin accessibility), RNA-seq, ChIP-seq, Wnt-level rescue experiments","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal genomics methods (ATAC-seq, RNA-seq, ChIP-seq), functional KO with defined phenotype and pathway rescue, peer-reviewed","pmids":["40835974"],"is_preprint":false},{"year":2026,"finding":"The recurrent CHD3 variant p.R1025W (modeled in humanized mice as Chd3hR1025W/+) reduces CHD3 protein levels and causes behavioural abnormalities including deficits in social communication, cognition and motor coordination recapitulating Snijders Blok-Campeau syndrome. In vivo adenine base editing (A•T-to-G•C correction) in the brain restored CHD3 protein levels and ameliorated these behavioural abnormalities.","method":"Humanized mouse knock-in model, in vivo dual-AAV delivery of adenine base editor (TeABE), behavioral phenotyping, western blot for CHD3 protein levels, on-target editing efficiency analysis across brain regions","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vivo genetic correction with protein-level and behavioral rescue, multiple brain regions, also tested in nonhuman primates; rigorous single study","pmids":["41708849"],"is_preprint":false},{"year":2020,"finding":"Conditional deletion of Chd3 throughout the epiblast results in partial lethality of homozygous Chd3Δ/Δ mice prior to weaning, establishing that CHD3 is required for embryonic viability. Endothelial-cell-specific deletion of Chd3 causes no vascular anomalies, and double-deletion of Chd3 and Chd4 in endothelial cells does not worsen CHD4-loss vascular phenotypes, indicating CHD3 does not cooperate with CHD4 in early vascular development.","method":"Conditional knockout mouse (floxed Chd3 allele, Sox2-Cre and endothelial Cre drivers), embryonic viability scoring, western blot for CHD3 protein, vascular phenotyping","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean in vivo KO with defined viability phenotype and negative vascular epistasis, single lab","pmids":["32658897"],"is_preprint":false},{"year":2024,"finding":"FBW7 targets CHD3 for ubiquitination and proteasomal degradation. FBW7 overexpression suppresses HCC cell migration, invasion, stemness and oxaliplatin resistance; these effects are mediated through CHD3 ubiquitination, as overexpression of CHD3 rescues the FBW7-mediated suppression.","method":"Co-immunoprecipitation, ubiquitination assay, western blot, shRNA knockdown and overexpression rescue experiments, CCK-8/wound healing/transwell/sphere formation assays","journal":"Frontiers in bioscience (Landmark edition)","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, ubiquitination assay, rescue epistasis; single lab, functional cellular readouts","pmids":["39473409"],"is_preprint":false},{"year":2026,"finding":"In SMARCA4/SMARCA2 dual-deficient cancers, CHD3 (within the NuRD complex) acts as an essential epigenetic repressor at the PARD3B enhancer. Loss of CHD3 causes aberrant chromatin hyper-accessibility at the PARD3B enhancer, toxic derepression of PARD3B, attenuation of MYC signaling, and cell death. CHD3 depletion causes tumor regression in dual SMARCA4/SMARCA2-deficient xenografts.","method":"CRISPR/siRNA depletion of CHD3, ATAC-seq (chromatin accessibility at PARD3B enhancer), RNA-seq, ChIP-seq, in vivo xenograft experiments, integrated genomic analyses","journal":"NPJ precision oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genomic methods (ATAC-seq, ChIP-seq, RNA-seq) with in vivo validation, single lab","pmids":["42174139"],"is_preprint":false},{"year":2018,"finding":"In C. elegans, the Mi2 homologs CHD-3 and its paralog LET-418 (components of the NuRD complex) facilitate meiotic progression by ensuring faithful DSB repair through homologous recombination. Loss of either CHD-3 or LET-418 results in elevated p53-dependent germ line apoptosis, activation of CHK-1, reduced offspring, persisting recombination intermediates in late pachytene nuclei, and chromosomal fusions due to inappropriate non-homologous end joining.","method":"C. elegans genetics (loss-of-function mutants), immunofluorescence for recombination intermediates, apoptosis quantification, double mutant analysis (Mi2 × cku-80 epistasis)","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with defined molecular phenotype (recombination intermediates, NHEJ fusions, CHK-1 activation), epistasis; C. elegans ortholog","pmids":["29339410"],"is_preprint":false}],"current_model":"CHD3 is an ATP-dependent chromatin remodeler that functions as the catalytic ATPase subunit of distinct, isoform-specific NuRD (nucleosome remodeling and deacetylase) complexes; its tandem PHD fingers bind H3K9me3/ac to target the complex to chromatin, its ATPase/helicase domain couples ATP hydrolysis efficiently to nucleosome remodeling and translocation, it is dispersed from heterochromatic DNA double-strand breaks via ATM-KAP-1 phosphorylation disrupting a CHD3 SIM–SUMO1 interaction to enable repair, it opens chromatin at BMP-responsive enhancers to promote BMP signalling during cranial neural crest specification, and pathogenic de novo variants in its ATPase/helicase domain reduce both ATPase activity and chromatin remodeling to cause the neurodevelopmental Snijders Blok-Campeau syndrome."},"narrative":{"mechanistic_narrative":"CHD3 is an ATP-dependent chromatin remodeler that serves as the monomeric catalytic ATPase subunit of isoform-specific NuRD (nucleosome remodeling and deacetylase) complexes, which it forms mutually exclusively with its paralog CHD4 and which differ in nucleosome remodeling behavior, nuclear localization, and target-gene regulation [PMID:28977666]. Targeting is mediated by its tandem PHD fingers, which bind histone H3 tails with affinity enhanced by hydrophobicity-increasing modifications at H3K9 (H3K9me3 or H3K9ac), promoting nucleosome unwrapping and remodeling of pericentric heterochromatin [PMID:29020631]. Its ATPase/helicase module couples ATP hydrolysis tightly to nucleosome translocation, such that basal hydrolysis suffices for remodeling, with translocation competitively inhibited by IP6 [PMID:33403747]. In DNA double-strand break repair, CHD3 is recruited to breaks in a PARP1/poly(ADP-ribosyl)ation-dependent manner [PMID:29733391], and at heterochromatic breaks its dispersal is driven by ATM-dependent KAP-1 Ser824 phosphorylation, which disrupts the CHD3 SUMO-interacting motif–SUMO1 contact to permit chromatin relaxation and repair [PMID:21642969]. Through NuRD, CHD3 controls developmental gene programs: it opens chromatin at BMP-responsive enhancers to drive BMP signalling and cranial neural crest specification, and its loss shifts cells toward aberrant mesodermal identity rescuable by Wnt titration [PMID:40835974]. De novo missense mutations clustering in the ATPase/helicase domain reduce ATPase and chromatin remodeling activity and cause the neurodevelopmental disorder Snijders Blok-Campeau syndrome [PMID:30397230, PMID:41708849].","teleology":[{"year":2003,"claim":"Established the first physical interaction partners of CHD3, mapping CGI-55 and Ki-1/57 to its C-terminal region and pointing to functions beyond the catalytic core.","evidence":"Yeast two-hybrid, in vitro pulldown, and Co-IP from Sf9 cells with GFP-fusion localization","pmids":["12505151"],"confidence":"Medium","gaps":["Functional consequence of the CGI-55/Ki-1/57 interactions unresolved","No structural detail on the C-terminal binding interface"]},{"year":2007,"claim":"Showed that CHD3's C-terminus acts as a sequence-specific transcriptional repressor by partnering with the Ets factor ERM to silence the presenilin 1 promoter, demonstrating directed gene repression.","evidence":"Yeast two-hybrid interaction mapping, reporter assays, ChIP at the PS1 promoter, and deletion mutagenesis of CHD3 and ERM","pmids":["17489097"],"confidence":"Medium","gaps":["Did not establish whether NuRD complex was required for repression","Generality beyond PS1 not addressed"]},{"year":2010,"claim":"Demonstrated in Drosophila that CHD3 acts as a monomeric remodeler associated with elongating RNA Pol II, raising the question of whether mammalian CHD3 is similarly complex-independent.","evidence":"Complex fractionation, in vitro chromatin remodeling, polytene chromosome immunofluorescence, and a viable/fertile deletion mutant","pmids":["20439780"],"confidence":"Medium","gaps":["Dispensability in fly does not predict mammalian requirement","Mechanism linking CHD3 to Pol II elongation unexplored"]},{"year":2011,"claim":"Answered how heterochromatic DSB repair is licensed, showing ATM-driven KAP-1 Ser824 phosphorylation disrupts a CHD3 SIM–SUMO1 contact to disperse CHD3 and relax chromatin.","evidence":"Co-IP, mutagenesis of CHD3 SIM and KAP-1 Ser824, chromatin relaxation assays, and epistatic rescue of pKAP-1 requirement by CHD3 depletion","pmids":["21642969"],"confidence":"High","gaps":["Does not address CHD3's catalytic role at euchromatic breaks","Whether SUMO1 contact is via the broader NuRD complex unresolved"]},{"year":2014,"claim":"Extended CHD3 function to host defense and viral hijacking, showing it represses HSV immediate-early genes via repressive histone marks yet is co-opted by influenza NS2 to promote vRNP nuclear export.","evidence":"Immunofluorescence, siRNA depletion, reporter assays, and NES1-mutagenesis Co-IP with viral propagation and export kinetics","pmids":["24425734","25213355"],"confidence":"Medium","gaps":["Mechanism of CHD3 recognition of viral chromatin not detailed","Whether NuRD or CHD3 alone mediates these activities unclear"]},{"year":2017,"claim":"Defined CHD3 as the ATPase of a distinct NuRD complex (mutually exclusive with CHD4) and identified its PHD fingers as the H3K9me3/ac reader that directs remodeling to heterochromatin.","evidence":"MS proteomics, FRAP, HP1 Co-IP, UV-damage live imaging, peptide-binding and in vitro nucleosome unwrapping/remodeling assays with PHD mutants","pmids":["28977666","29020631"],"confidence":"High","gaps":["Genome-wide division of labor between CHD3- and CHD4-NuRD incompletely mapped","Structural basis of PHD–H3K9 selectivity not solved"]},{"year":2018,"claim":"Connected CHD3 catalytic activity to human disease, showing ATPase/helicase-domain de novo mutations reduce ATPase and remodeling activity and cause Snijders Blok-Campeau syndrome, and clarified PARP-dependent recruitment to DSBs.","evidence":"Patient WGS cohort, structural modeling, in vitro ATPase and remodeling assays on six mutants; plus live-cell imaging with PARP inhibition for DSB recruitment","pmids":["30397230","29733391"],"confidence":"High","gaps":["How specific mutations map to distinct neurodevelopmental features unresolved","PAR recruitment is not via direct PAR binding—intermediary unknown"]},{"year":2018,"claim":"Showed via the C. elegans orthologs CHD-3/LET-418 that NuRD-class Mi2 remodelers ensure faithful homologous-recombination DSB repair during meiosis, preventing toxic NHEJ-driven chromosomal fusions.","evidence":"Loss-of-function genetics, recombination-intermediate immunofluorescence, apoptosis quantification, and Mi2 × cku-80 epistasis","pmids":["29339410"],"confidence":"Medium","gaps":["Worm ortholog—conservation of meiotic role in mammals not shown","Direct catalytic contribution versus complex role not separated"]},{"year":2020,"claim":"Established CHD3 as required for mammalian embryonic viability while demonstrating it does not cooperate with CHD4 in vascular development, reinforcing functional divergence between the paralogs.","evidence":"Conditional Chd3 knockout mice (Sox2-Cre and endothelial Cre), viability scoring, and double-deletion vascular epistasis","pmids":["32658897"],"confidence":"Medium","gaps":["Tissue/cell type driving lethality not identified","Molecular basis of the requirement undefined"]},{"year":2021,"claim":"Resolved the enzymatic regulation of CHD3, showing tight ATP-hydrolysis-to-remodeling coupling (basal hydrolysis suffices) and competitive IP6 inhibition distinguishing it from SNF2H.","evidence":"Reconstituted in vitro ATPase and nucleosome translocation assays with conserved-motif mutagenesis and inhibitor dose-response","pmids":["33403747"],"confidence":"High","gaps":["Physiological role of IP6 regulation in cells unknown","Structural basis of efficient coupling not determined"]},{"year":2025,"claim":"Demonstrated a developmental program in which CHD3-NuRD opens BMP-responsive enhancers to drive cranial neural crest specification, balancing BMP and Wnt signalling.","evidence":"CHD3-KO human iPSC differentiation with ATAC-seq, RNA-seq, ChIP-seq, and Wnt-level rescue","pmids":["40835974"],"confidence":"High","gaps":["Direct enhancer targets versus indirect effects not fully separated","Relationship to Snijders Blok-Campeau craniofacial features not tested"]},{"year":2024,"claim":"Identified post-translational control of CHD3 abundance, showing FBW7-mediated ubiquitination and degradation restrains hepatocellular carcinoma aggressiveness and oxaliplatin resistance.","evidence":"Co-IP, ubiquitination assay, knockdown/overexpression rescue, and migration/invasion/stemness assays","pmids":["39473409"],"confidence":"Medium","gaps":["Degron within CHD3 not mapped","Chromatin targets driving the oncogenic phenotype unidentified"]},{"year":2026,"claim":"Provided in vivo causal and therapeutic proof for CHD3 disease, with a humanized p.R1025W mouse recapitulating Snijders Blok-Campeau behavioural deficits that were reversed by in-brain adenine base editing, and revealed a context-specific cancer dependency via PARD3B enhancer repression.","evidence":"Humanized knock-in mice with dual-AAV base-editor delivery and behavioural rescue; plus CRISPR/siRNA depletion with ATAC/ChIP/RNA-seq and xenografts in SMARCA4/SMARCA2-deficient cancers","pmids":["41708849","42174139"],"confidence":"High","gaps":["Durability and off-target profile of in vivo editing not fully resolved","Determinants of the synthetic-lethal CHD3 dependency in SWI/SNF-deficient tumors incompletely defined"]},{"year":null,"claim":"How CHD3- versus CHD4-NuRD complexes are differentially assembled, targeted, and deployed across distinct cell types and developmental contexts remains the central open question.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of full-length CHD3 within an intact NuRD complex","Rules governing isoform-specific genomic targeting unresolved","Mechanistic link between specific patient mutations and tissue phenotypes unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[3,9]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[2]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[4]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[7,11,15]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[9]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,2]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[1,2,11]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[0,4]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[7,11,15]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[11]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,12,14,15]}],"complexes":["NuRD complex"],"partners":["CHD4","KAP-1/TRIM28","HP1","ERM/ETV5","CGI-55","FBW7"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q12873","full_name":"ATP-dependent chromatin remodeler CHD3","aliases":["Chromo domain-containing protein 3","CHD-3","Mi-2 autoantigen 240 kDa protein","Mi2-alpha","Zinc finger helicase-like","hZFH"],"length_aa":2000,"mass_kda":226.6,"function":"ATP-dependent chromatin-remodeling factor that binds and distorts nucleosomal DNA (PubMed:28977666). Acts as a component of the histone deacetylase NuRD complex which participates in the remodeling of chromatin (PubMed:16428440, PubMed:28977666, PubMed:30397230, PubMed:9804427). Involved in transcriptional repression as part of the NuRD complex (PubMed:27068747). Required for anchoring centrosomal pericentrin in both interphase and mitosis, for spindle organization and centrosome integrity (PubMed:17626165)","subcellular_location":"Nucleus, PML body; Nucleus; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome","url":"https://www.uniprot.org/uniprotkb/Q12873/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CHD3","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"TAF1","stoichiometry":10.0},{"gene":"HDAC1","stoichiometry":0.2},{"gene":"HDAC2","stoichiometry":0.2},{"gene":"RBBP4","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CHD3","total_profiled":1310},"omim":[{"mim_id":"618205","title":"SNIJDERS BLOK-CAMPEAU SYNDROME; SNIBCPS","url":"https://www.omim.org/entry/618205"},{"mim_id":"615074","title":"GAND SYNDROME; GAND","url":"https://www.omim.org/entry/615074"},{"mim_id":"614998","title":"GATA ZINC FINGER DOMAIN-CONTAINING PROTEIN 2B; GATAD2B","url":"https://www.omim.org/entry/614998"},{"mim_id":"614997","title":"GATA ZINC FINGER DOMAIN-CONTAINING PROTEIN 2A; GATAD2A","url":"https://www.omim.org/entry/614997"},{"mim_id":"610771","title":"CHROMODOMAIN HELICASE DNA-BINDING PROTEIN 5; CHD5","url":"https://www.omim.org/entry/610771"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nucleoli","reliability":"Supported"},{"location":"Centriolar satellite","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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Depletion or inactivation of CHD3, or ablation of its interaction with KAP-1(SUMO1), bypassed the requirement for pKAP-1 in heterochromatic DSB repair.\",\n      \"method\": \"Co-immunoprecipitation, siRNA depletion, site-directed mutagenesis (CHD3 SIM mutant, KAP-1 Ser824 mutant), chromatin relaxation assays, epistasis (KAP-1 phospho-mutant rescue by CHD3 depletion)\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (Co-IP, mutagenesis of both CHD3 SIM and KAP-1 Ser824, functional rescue/epistasis), rigorous mechanistic dissection in single study\",\n      \"pmids\": [\"21642969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CHD3 and CHD4 form mutually exclusive, isoform-specific NuRD complexes (each complex contains either CHD3 or CHD4 as a monomeric ATPase subunit, not both). CHD3- and CHD4-NuRD complexes differ in nucleosome remodeling and positioning behavior in vitro, exhibit distinct nuclear localization patterns, and regulate overlapping but also distinct target genes. Both complexes interact with HP1 and accumulate at UV-induced DNA repair sites.\",\n      \"method\": \"Mass spectrometry-based proteomic mapping of NuRD subunit composition, FRAP (intranuclear mobility), Co-immunoprecipitation with HP1, live-cell imaging at UV damage sites, in vitro nucleosome remodeling assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (MS, Co-IP, in vitro remodeling, live imaging) in single rigorous study\",\n      \"pmids\": [\"28977666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The tandem PHD fingers of CHD3 bind histone H3 tails, and post-translational modifications that increase hydrophobicity at H3K9 (H3K9me3 or H3K9ac) enhance this interaction. Binding of CHD3 PHDs promotes H3K9Cme3-nucleosome unwrapping in vitro and perturbs pericentric heterochromatin structure in vivo. H3K9 methylation or acetylation alleviates intra-nucleosomal interaction of H3 tails, increasing H3K9 accessibility for CHD3 binding.\",\n      \"method\": \"Peptide binding assays, in vitro nucleosome unwrapping assays, immunofluorescence/chromatin fractionation in cells (PHD mutants), ChIP co-localization with NuRD subunits\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reconstitution (in vitro binding and unwrapping), structural/biochemical analysis of PHD-histone interaction, cellular validation with mutants\",\n      \"pmids\": [\"29020631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"De novo missense mutations clustering in the ATPase/helicase domain of CHD3 cause Snijders Blok-Campeau syndrome. Structural modeling shows these mutations disturb critical binding and interaction motifs. Experimental assays with six identified mutations showed a subset directly reduces ATPase activity, and all but one alter chromatin remodeling activity.\",\n      \"method\": \"Whole genome sequencing (patient cohort), 3D protein structural modeling, ATPase activity assays, chromatin remodeling assays (in vitro, six mutant variants tested)\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct in vitro ATPase and remodeling assays on multiple patient-derived mutations, structural modeling, large patient cohort\",\n      \"pmids\": [\"30397230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CHD3 is recruited to DNA double-strand breaks in a poly(ADP-ribosyl)ation-dependent manner (dependent on PARP1 activity), similar to CHD4, but not through direct PAR binding. Both CHD3 and CHD4 actively participate in chromatin remodeling at DNA breaks. An initial chromatin relaxation phase driven by PARP1 and Alc1/CHD1L promotes subsequent CHD3 and CHD4 recruitment via DNA binding for further remodeling.\",\n      \"method\": \"Live-cell fluorescence three-hybrid assay, laser micro-irradiation with live imaging, siRNA knockdown, PARP inhibitor treatment\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live-cell imaging with functional assays, single lab, two orthogonal methods\",\n      \"pmids\": [\"29733391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CHD3 localizes to early herpes simplex virus (HSV) foci in infected cells, suppresses viral immediate early gene expression, and reduces the number of transcriptionally active viral genomes. CHD3 can recognize repressive histone marks associated with HSV chromatin. Depletion of CHD3 results in enhanced viral immediate early gene expression and increased numbers of transcriptionally active viral genomes.\",\n      \"method\": \"Immunofluorescence localization, siRNA depletion, reporter gene assays for viral immediate early gene expression, chromatin accessibility assays\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — localization with functional consequence (KD phenotype), single lab, multiple readouts\",\n      \"pmids\": [\"24425734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Two human proteins, CGI-55 and Ki-1/57, interact with the C-terminal region of CHD3 (residues after aa 1676). The CGI-55–CHD3 interaction was confirmed by yeast two-hybrid, in vitro pulldown, and co-immunoprecipitation from Sf9 insect cells. CGI-55 interacts with CHD3 via two regions at its N- and C-termini.\",\n      \"method\": \"Yeast two-hybrid, in vitro pulldown, co-immunoprecipitation from Sf9 cells, GFP-fusion localization\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — reciprocal validation across multiple assays (Y2H + in vitro + Co-IP), single lab\",\n      \"pmids\": [\"12505151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The C-terminal region of CHD3/ZFH (amino acids 1676–2000) interacts with the CIDD region (aa 96–349, critical residues 200–299) of the Ets transcription factor ERM, and this interaction represses transcription of the presenilin 1 (PS1) gene. CHD3 C-terminal fragment (aa 1676–2000) occupies the PS1 promoter in vivo. Sequences critical for repression and ERM binding are between aa 1862 and 1877 of CHD3.\",\n      \"method\": \"Yeast two-hybrid (interaction mapping), transfection reporter assays (transcription repression), chromatin immunoprecipitation (ChIP at PS1 promoter), deletion mutagenesis of both CHD3 and ERM\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Y2H + ChIP + reporter assays + deletion mutagenesis, single lab\",\n      \"pmids\": [\"17489097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CHD3 interacts with nuclear export signal 1 (NES1) of influenza A virus NS2 protein and co-localizes NS2 and Crm1 on dense chromatin to facilitate Crm1-dependent vRNP nuclear export. Disruption of the NS2–CHD3 interaction (by NES1 mutation) significantly delays vRNP export and viral propagation. CHD3 knockdown impairs propagation of wild-type virus but not a mutant with weakened NS2–CHD3 interaction.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis of NES1, siRNA knockdown of CHD3, viral propagation assays, nuclear export kinetics\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, mutagenesis, KD with functional viral readout, single lab\",\n      \"pmids\": [\"25213355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The ATPase domain of CHD3 exhibits differential regulatory properties compared to SNF2H: IP6 inhibits CHD3 nucleosome translocation competitively (but not SNF2H), and CHD3 can translocate nucleosomes even at very low ATP concentrations. Mutations in conserved Q- and K-residues of the ATPase domain motifs show that basal ATP hydrolysis activity of CHD3 is sufficient for nucleosome remodeling (unlike SNF2H mutants), suggesting more efficient coupling of ATP hydrolysis and remodeling in CHD3.\",\n      \"method\": \"In vitro ATPase assays, nucleosome remodeling/translocation assays, site-directed mutagenesis of conserved ATPase motif residues, inhibitor dose-response (ADP, IP6)\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted in vitro enzymatic assays with mutagenesis, single lab but multiple orthogonal biochemical methods\",\n      \"pmids\": [\"33403747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Drosophila CHD3 proteins act as monomers (not found in protein complexes) that remodel chromatin in vitro. Drosophila CHD3 co-localizes with elongating RNA polymerase II on salivary gland polytene chromosomes. Deletion of Chd3 has no effect on viability or fertility in Drosophila.\",\n      \"method\": \"Protein complex fractionation (monomeric vs. complex), in vitro chromatin remodeling assay, polytene chromosome immunofluorescence, targeted gene replacement (deletion mutant viability/fertility assay)\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro remodeling assay, chromosome localization, genetic null mutant analysis, single lab\",\n      \"pmids\": [\"20439780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CHD3 (as a NuRD component) promotes BMP signalling during cranial neural crest cell (CNCC) specification by opening chromatin at BMP-responsive cis-regulatory elements and increasing expression of BMP-responsive transcription factors (including DLX paralogs). CHD3 loss leads to repression of BMP target genes, reduced chromatin accessibility at BMP-responsive enhancers, imbalance between BMP and Wnt signalling, and failure of CNCC specification replaced by aberrant mesodermal identity. This phenotype can be partially rescued by titrating Wnt levels.\",\n      \"method\": \"CHD3-KO human iPSC differentiation to CNCCs, ATAC-seq (chromatin accessibility), RNA-seq, ChIP-seq, Wnt-level rescue experiments\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal genomics methods (ATAC-seq, RNA-seq, ChIP-seq), functional KO with defined phenotype and pathway rescue, peer-reviewed\",\n      \"pmids\": [\"40835974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"The recurrent CHD3 variant p.R1025W (modeled in humanized mice as Chd3hR1025W/+) reduces CHD3 protein levels and causes behavioural abnormalities including deficits in social communication, cognition and motor coordination recapitulating Snijders Blok-Campeau syndrome. In vivo adenine base editing (A•T-to-G•C correction) in the brain restored CHD3 protein levels and ameliorated these behavioural abnormalities.\",\n      \"method\": \"Humanized mouse knock-in model, in vivo dual-AAV delivery of adenine base editor (TeABE), behavioral phenotyping, western blot for CHD3 protein levels, on-target editing efficiency analysis across brain regions\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vivo genetic correction with protein-level and behavioral rescue, multiple brain regions, also tested in nonhuman primates; rigorous single study\",\n      \"pmids\": [\"41708849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Conditional deletion of Chd3 throughout the epiblast results in partial lethality of homozygous Chd3Δ/Δ mice prior to weaning, establishing that CHD3 is required for embryonic viability. Endothelial-cell-specific deletion of Chd3 causes no vascular anomalies, and double-deletion of Chd3 and Chd4 in endothelial cells does not worsen CHD4-loss vascular phenotypes, indicating CHD3 does not cooperate with CHD4 in early vascular development.\",\n      \"method\": \"Conditional knockout mouse (floxed Chd3 allele, Sox2-Cre and endothelial Cre drivers), embryonic viability scoring, western blot for CHD3 protein, vascular phenotyping\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean in vivo KO with defined viability phenotype and negative vascular epistasis, single lab\",\n      \"pmids\": [\"32658897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FBW7 targets CHD3 for ubiquitination and proteasomal degradation. FBW7 overexpression suppresses HCC cell migration, invasion, stemness and oxaliplatin resistance; these effects are mediated through CHD3 ubiquitination, as overexpression of CHD3 rescues the FBW7-mediated suppression.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, western blot, shRNA knockdown and overexpression rescue experiments, CCK-8/wound healing/transwell/sphere formation assays\",\n      \"journal\": \"Frontiers in bioscience (Landmark edition)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, ubiquitination assay, rescue epistasis; single lab, functional cellular readouts\",\n      \"pmids\": [\"39473409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In SMARCA4/SMARCA2 dual-deficient cancers, CHD3 (within the NuRD complex) acts as an essential epigenetic repressor at the PARD3B enhancer. Loss of CHD3 causes aberrant chromatin hyper-accessibility at the PARD3B enhancer, toxic derepression of PARD3B, attenuation of MYC signaling, and cell death. CHD3 depletion causes tumor regression in dual SMARCA4/SMARCA2-deficient xenografts.\",\n      \"method\": \"CRISPR/siRNA depletion of CHD3, ATAC-seq (chromatin accessibility at PARD3B enhancer), RNA-seq, ChIP-seq, in vivo xenograft experiments, integrated genomic analyses\",\n      \"journal\": \"NPJ precision oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genomic methods (ATAC-seq, ChIP-seq, RNA-seq) with in vivo validation, single lab\",\n      \"pmids\": [\"42174139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In C. elegans, the Mi2 homologs CHD-3 and its paralog LET-418 (components of the NuRD complex) facilitate meiotic progression by ensuring faithful DSB repair through homologous recombination. Loss of either CHD-3 or LET-418 results in elevated p53-dependent germ line apoptosis, activation of CHK-1, reduced offspring, persisting recombination intermediates in late pachytene nuclei, and chromosomal fusions due to inappropriate non-homologous end joining.\",\n      \"method\": \"C. elegans genetics (loss-of-function mutants), immunofluorescence for recombination intermediates, apoptosis quantification, double mutant analysis (Mi2 × cku-80 epistasis)\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with defined molecular phenotype (recombination intermediates, NHEJ fusions, CHK-1 activation), epistasis; C. elegans ortholog\",\n      \"pmids\": [\"29339410\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CHD3 is an ATP-dependent chromatin remodeler that functions as the catalytic ATPase subunit of distinct, isoform-specific NuRD (nucleosome remodeling and deacetylase) complexes; its tandem PHD fingers bind H3K9me3/ac to target the complex to chromatin, its ATPase/helicase domain couples ATP hydrolysis efficiently to nucleosome remodeling and translocation, it is dispersed from heterochromatic DNA double-strand breaks via ATM-KAP-1 phosphorylation disrupting a CHD3 SIM–SUMO1 interaction to enable repair, it opens chromatin at BMP-responsive enhancers to promote BMP signalling during cranial neural crest specification, and pathogenic de novo variants in its ATPase/helicase domain reduce both ATPase activity and chromatin remodeling to cause the neurodevelopmental Snijders Blok-Campeau syndrome.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CHD3 is an ATP-dependent chromatin remodeler that serves as the monomeric catalytic ATPase subunit of isoform-specific NuRD (nucleosome remodeling and deacetylase) complexes, which it forms mutually exclusively with its paralog CHD4 and which differ in nucleosome remodeling behavior, nuclear localization, and target-gene regulation [#1]. Targeting is mediated by its tandem PHD fingers, which bind histone H3 tails with affinity enhanced by hydrophobicity-increasing modifications at H3K9 (H3K9me3 or H3K9ac), promoting nucleosome unwrapping and remodeling of pericentric heterochromatin [#2]. Its ATPase/helicase module couples ATP hydrolysis tightly to nucleosome translocation, such that basal hydrolysis suffices for remodeling, with translocation competitively inhibited by IP6 [#9]. In DNA double-strand break repair, CHD3 is recruited to breaks in a PARP1/poly(ADP-ribosyl)ation-dependent manner [#4], and at heterochromatic breaks its dispersal is driven by ATM-dependent KAP-1 Ser824 phosphorylation, which disrupts the CHD3 SUMO-interacting motif\\u2013SUMO1 contact to permit chromatin relaxation and repair [#0]. Through NuRD, CHD3 controls developmental gene programs: it opens chromatin at BMP-responsive enhancers to drive BMP signalling and cranial neural crest specification, and its loss shifts cells toward aberrant mesodermal identity rescuable by Wnt titration [#11]. De novo missense mutations clustering in the ATPase/helicase domain reduce ATPase and chromatin remodeling activity and cause the neurodevelopmental disorder Snijders Blok-Campeau syndrome [#3, #12].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established the first physical interaction partners of CHD3, mapping CGI-55 and Ki-1/57 to its C-terminal region and pointing to functions beyond the catalytic core.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro pulldown, and Co-IP from Sf9 cells with GFP-fusion localization\",\n      \"pmids\": [\"12505151\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the CGI-55/Ki-1/57 interactions unresolved\", \"No structural detail on the C-terminal binding interface\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed that CHD3's C-terminus acts as a sequence-specific transcriptional repressor by partnering with the Ets factor ERM to silence the presenilin 1 promoter, demonstrating directed gene repression.\",\n      \"evidence\": \"Yeast two-hybrid interaction mapping, reporter assays, ChIP at the PS1 promoter, and deletion mutagenesis of CHD3 and ERM\",\n      \"pmids\": [\"17489097\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish whether NuRD complex was required for repression\", \"Generality beyond PS1 not addressed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated in Drosophila that CHD3 acts as a monomeric remodeler associated with elongating RNA Pol II, raising the question of whether mammalian CHD3 is similarly complex-independent.\",\n      \"evidence\": \"Complex fractionation, in vitro chromatin remodeling, polytene chromosome immunofluorescence, and a viable/fertile deletion mutant\",\n      \"pmids\": [\"20439780\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Dispensability in fly does not predict mammalian requirement\", \"Mechanism linking CHD3 to Pol II elongation unexplored\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Answered how heterochromatic DSB repair is licensed, showing ATM-driven KAP-1 Ser824 phosphorylation disrupts a CHD3 SIM\\u2013SUMO1 contact to disperse CHD3 and relax chromatin.\",\n      \"evidence\": \"Co-IP, mutagenesis of CHD3 SIM and KAP-1 Ser824, chromatin relaxation assays, and epistatic rescue of pKAP-1 requirement by CHD3 depletion\",\n      \"pmids\": [\"21642969\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address CHD3's catalytic role at euchromatic breaks\", \"Whether SUMO1 contact is via the broader NuRD complex unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended CHD3 function to host defense and viral hijacking, showing it represses HSV immediate-early genes via repressive histone marks yet is co-opted by influenza NS2 to promote vRNP nuclear export.\",\n      \"evidence\": \"Immunofluorescence, siRNA depletion, reporter assays, and NES1-mutagenesis Co-IP with viral propagation and export kinetics\",\n      \"pmids\": [\"24425734\", \"25213355\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of CHD3 recognition of viral chromatin not detailed\", \"Whether NuRD or CHD3 alone mediates these activities unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined CHD3 as the ATPase of a distinct NuRD complex (mutually exclusive with CHD4) and identified its PHD fingers as the H3K9me3/ac reader that directs remodeling to heterochromatin.\",\n      \"evidence\": \"MS proteomics, FRAP, HP1 Co-IP, UV-damage live imaging, peptide-binding and in vitro nucleosome unwrapping/remodeling assays with PHD mutants\",\n      \"pmids\": [\"28977666\", \"29020631\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide division of labor between CHD3- and CHD4-NuRD incompletely mapped\", \"Structural basis of PHD\\u2013H3K9 selectivity not solved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected CHD3 catalytic activity to human disease, showing ATPase/helicase-domain de novo mutations reduce ATPase and remodeling activity and cause Snijders Blok-Campeau syndrome, and clarified PARP-dependent recruitment to DSBs.\",\n      \"evidence\": \"Patient WGS cohort, structural modeling, in vitro ATPase and remodeling assays on six mutants; plus live-cell imaging with PARP inhibition for DSB recruitment\",\n      \"pmids\": [\"30397230\", \"29733391\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How specific mutations map to distinct neurodevelopmental features unresolved\", \"PAR recruitment is not via direct PAR binding\\u2014intermediary unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed via the C. elegans orthologs CHD-3/LET-418 that NuRD-class Mi2 remodelers ensure faithful homologous-recombination DSB repair during meiosis, preventing toxic NHEJ-driven chromosomal fusions.\",\n      \"evidence\": \"Loss-of-function genetics, recombination-intermediate immunofluorescence, apoptosis quantification, and Mi2 \\u00d7 cku-80 epistasis\",\n      \"pmids\": [\"29339410\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Worm ortholog\\u2014conservation of meiotic role in mammals not shown\", \"Direct catalytic contribution versus complex role not separated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established CHD3 as required for mammalian embryonic viability while demonstrating it does not cooperate with CHD4 in vascular development, reinforcing functional divergence between the paralogs.\",\n      \"evidence\": \"Conditional Chd3 knockout mice (Sox2-Cre and endothelial Cre), viability scoring, and double-deletion vascular epistasis\",\n      \"pmids\": [\"32658897\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tissue/cell type driving lethality not identified\", \"Molecular basis of the requirement undefined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved the enzymatic regulation of CHD3, showing tight ATP-hydrolysis-to-remodeling coupling (basal hydrolysis suffices) and competitive IP6 inhibition distinguishing it from SNF2H.\",\n      \"evidence\": \"Reconstituted in vitro ATPase and nucleosome translocation assays with conserved-motif mutagenesis and inhibitor dose-response\",\n      \"pmids\": [\"33403747\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological role of IP6 regulation in cells unknown\", \"Structural basis of efficient coupling not determined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated a developmental program in which CHD3-NuRD opens BMP-responsive enhancers to drive cranial neural crest specification, balancing BMP and Wnt signalling.\",\n      \"evidence\": \"CHD3-KO human iPSC differentiation with ATAC-seq, RNA-seq, ChIP-seq, and Wnt-level rescue\",\n      \"pmids\": [\"40835974\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct enhancer targets versus indirect effects not fully separated\", \"Relationship to Snijders Blok-Campeau craniofacial features not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified post-translational control of CHD3 abundance, showing FBW7-mediated ubiquitination and degradation restrains hepatocellular carcinoma aggressiveness and oxaliplatin resistance.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, knockdown/overexpression rescue, and migration/invasion/stemness assays\",\n      \"pmids\": [\"39473409\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Degron within CHD3 not mapped\", \"Chromatin targets driving the oncogenic phenotype unidentified\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Provided in vivo causal and therapeutic proof for CHD3 disease, with a humanized p.R1025W mouse recapitulating Snijders Blok-Campeau behavioural deficits that were reversed by in-brain adenine base editing, and revealed a context-specific cancer dependency via PARD3B enhancer repression.\",\n      \"evidence\": \"Humanized knock-in mice with dual-AAV base-editor delivery and behavioural rescue; plus CRISPR/siRNA depletion with ATAC/ChIP/RNA-seq and xenografts in SMARCA4/SMARCA2-deficient cancers\",\n      \"pmids\": [\"41708849\", \"42174139\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Durability and off-target profile of in vivo editing not fully resolved\", \"Determinants of the synthetic-lethal CHD3 dependency in SWI/SNF-deficient tumors incompletely defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CHD3- versus CHD4-NuRD complexes are differentially assembled, targeted, and deployed across distinct cell types and developmental contexts remains the central open question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of full-length CHD3 within an intact NuRD complex\", \"Rules governing isoform-specific genomic targeting unresolved\", \"Mechanistic link between specific patient mutations and tissue phenotypes unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [3, 9]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [7, 11, 15]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1, 2, 11]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [7, 11, 15]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 12, 14, 15]}\n    ],\n    \"complexes\": [\"NuRD complex\"],\n    \"partners\": [\"CHD4\", \"KAP-1/TRIM28\", \"HP1\", \"ERM/ETV5\", \"CGI-55\", \"FBW7\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}