{"gene":"CHD3","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2011,"finding":"ATM-dependent phosphorylation of KAP-1 at Ser824 disperses CHD3 from heterochromatic DNA double-strand breaks by directly perturbing the interaction between CHD3's SUMO-interacting motif and SUMO1 on KAP-1, thereby enabling chromatin relaxation and DSB repair. CHD3 depletion or inactivation, or ablation of its interaction with KAP-1(SUMO1), bypassed the requirement for pKAP-1 in heterochromatic repair.","method":"siRNA depletion, mutagenesis of CHD3 SUMO-interacting motif, irradiation-induced foci imaging, chromatin relaxation assays, co-immunoprecipitation","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (mutagenesis, co-IP, live-cell imaging, functional repair assays) in a single rigorous study","pmids":["21642969"],"is_preprint":false},{"year":2017,"finding":"CHD3 and CHD4 form distinct, isoform-specific NuRD complexes (each containing either CHD3 or CHD4 as a monomeric ATPase, not both simultaneously). CHD3-NuRD and CHD4-NuRD exhibit different nuclear localization patterns, different nucleosome remodeling and positioning behavior in vitro, and regulate overlapping but distinct sets of target genes. Both complexes interact with HP1 and rapidly accumulate at UV-induced DNA repair sites.","method":"Mass spectrometry-based interactome mapping, reciprocal co-immunoprecipitation, in vitro nucleosome remodeling assays, live-cell fluorescence imaging, UV laser micro-irradiation","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 — reciprocal Co-IP + MS interactome + in vitro remodeling assays + live-cell imaging, multiple orthogonal methods","pmids":["28977666"],"is_preprint":false},{"year":2018,"finding":"CHD3 is recruited to DNA double-strand breaks in a PAR-dependent manner (dependent on prior PARP1 activity and initial chromatin relaxation by Alc1/CHD1L) and actively contributes to chromatin remodeling at break sites. Recruitment is not mediated by direct PAR binding but by DNA binding after initial relaxation.","method":"Live-cell fluorescence three-hybrid assay, laser micro-irradiation, siRNA knockdown, real-time recruitment kinetics imaging","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 — clean live-cell assay with mechanistic dissection, single study","pmids":["29733391"],"is_preprint":false},{"year":2018,"finding":"De novo missense mutations clustering in the ATPase/helicase domain of CHD3 cause a neurodevelopmental syndrome (Snijders Blok-Campeau syndrome). Experimental assays of six identified mutations showed that a subset directly reduces ATPase activity and all but one alter chromatin remodeling activity in vitro.","method":"ATPase activity assays, chromatin remodeling assays, structural modeling of mutation impact on ATPase/helicase domain, whole genome sequencing","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro enzymatic assays + chromatin remodeling assays + structural modeling across multiple variants, replicated in large cohort","pmids":["30397230"],"is_preprint":false},{"year":2017,"finding":"The tandem PHD fingers of CHD3 bind histone H3 tails, and posttranslational 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. CHD3 co-localizes with HDAC1 and other NuRD subunits near H3K9ac-enriched promoters of NuRD target genes.","method":"In vitro nucleosome unwrapping assay, histone peptide binding assays, co-immunoprecipitation, chromatin immunoprecipitation, in vivo heterochromatin imaging","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro biochemical reconstitution + in vivo functional consequence, multiple orthogonal methods","pmids":["29020631"],"is_preprint":false},{"year":2014,"finding":"CHD3 localizes to early viral foci upon herpes simplex virus infection and suppresses viral gene expression. CHD3 can recognize repressive histone marks associated with the viral genome chromatin. Depletion of CHD3 results in enhanced viral immediate early gene expression and increased number of transcriptionally active viral genomes, establishing CHD3 as an antiviral chromatin repressor opposing the HCF-1 coactivator complex.","method":"siRNA depletion, viral gene expression assays, co-localization imaging, histone mark binding assays","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2-3 — functional KD with defined phenotypic readout plus binding data, single study","pmids":["24425734"],"is_preprint":false},{"year":2003,"finding":"Two human proteins, Ki-1/57 and CGI-55, interact with the C-terminal region of CHD3 (human chromatin-remodeling factor). The CHD3–CGI-55 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 insect cells","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 — multiple methods (Y2H + Co-IP) in single study for a binding partner identification","pmids":["12505151"],"is_preprint":false},{"year":2007,"finding":"The C-terminal region of CHD3 (amino acids 1676–2000, with critical sequences between residues 1877–1955) interacts with the CIDD region (residues 96–349, critical at 200–343 and 279–299) of the Ets transcription factor ERM, as defined by yeast two-hybrid mapping and deletion analysis. This CHD3 C-terminal fragment represses transcription of the presenilin 1 (PS1) gene in transfection assays and reduces PS1 protein expression. Chromatin immunoprecipitation confirmed CHD3 occupancy at the PS1 promoter in vivo.","method":"Yeast two-hybrid, deletion mapping, transfection/reporter assays, western blot, chromatin immunoprecipitation","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2-3 — Y2H + ChIP + functional reporter assays, single lab study","pmids":["17489097"],"is_preprint":false},{"year":2014,"finding":"CHD3 interacts with the nuclear export signal 1 (NES1) of influenza A virus NS2 protein. This interaction localizes NS2 and Crm1 to dense chromatin and is required for efficient vRNP nuclear export. CHD3 knockdown impairs wild-type influenza propagation but not a NES1 mutant virus with weakened NS2-CHD3 interaction, establishing CHD3 as a host factor hijacked for viral vRNP export.","method":"Co-immunoprecipitation, siRNA knockdown, viral propagation assays, site-directed mutagenesis of NES1, confocal localization","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP + mutagenesis + functional viral assay, single study","pmids":["25213355"],"is_preprint":false},{"year":2021,"finding":"The ATPase domain of CHD3 is sufficient for basal nucleosome remodeling activity at lower ATP concentrations than SNF2H. Mutagenesis of conserved Q- and K-residues in the ATPase domain motifs abolished nucleosome translocation while preserving basal ATP hydrolysis, demonstrating that basal ATPase activity of CHD3 is sufficient for remodeling. CHD3 and SNF2H show differential sensitivity to inhibition by ADP and IP6 (competitive inhibition mode at CHD3 but not SNF2H).","method":"In vitro ATPase assays, in vitro nucleosome remodeling/translocation assays, site-directed mutagenesis, competitive inhibition assays with ADP and IP6","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with mutagenesis, multiple biochemical assays","pmids":["33403747"],"is_preprint":false},{"year":2010,"finding":"Drosophila CHD3 proteins are found as monomers (not in multi-subunit complexes) and remodel chromatin in vitro as monomers. CHD3 co-localizes with elongating RNA polymerase II on salivary gland polytene chromosomes. Targeted gene replacement deletion of Drosophila Chd3 had no effect on viability or fertility.","method":"Protein complex analysis, in vitro chromatin remodeling assays, polytene chromosome immunostaining, targeted gene replacement","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 1-2 — in vitro remodeling assay + in vivo localization + genetic KO, single study in Drosophila ortholog","pmids":["20439780"],"is_preprint":false},{"year":2020,"finding":"Global homozygous deletion of Chd3 in mice results in partial lethality prior to weaning. Endothelial cell-specific deletion of Chd3 alone causes no vascular anomalies, and double deletion with Chd4 in endothelial cells does not worsen CHD4-KO phenotypes, indicating CHD3 is dispensable for early vascular development. CHD3 is highly expressed in adult gonads and brain.","method":"Conditional gene targeting (floxed allele), Cre-lox endothelial and epiblast deletion, embryonic viability analysis, tissue expression analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — clean in vivo KO with specific tissue-restricted deletions, single study","pmids":["32658897"],"is_preprint":false},{"year":2018,"finding":"In C. elegans, the CHD3 ortholog CHD-3 (Mi2 homolog) and its paralog LET-418 are components of the NuRD complex and are required for faithful meiotic DSB repair through homologous recombination. Loss of CHD-3 results in elevated CHK-1-dependent germ-line apoptosis, persisting recombination intermediates in late pachytene, and chromosomal fusions indicative of non-homologous end joining, demonstrating a role in maintaining genome integrity during meiosis.","method":"Genetic analysis of chd-3 mutants, cytological assays for recombination intermediates, apoptosis assays, double mutant epistasis (chd-3; cku-80)","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis + cytological readouts in C. elegans ortholog, single study","pmids":["29339410"],"is_preprint":false},{"year":2025,"finding":"CHD3 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 causes repression of BMP target genes, loss of chromatin accessibility at BMP-responsive enhancers, and an imbalance between BMP and Wnt signalling, resulting in aberrant early-mesoderm identity instead of CNCC fate. This failure could be partially rescued by titrating Wnt levels.","method":"CHD3 knockdown in human iPSC-derived CNCC differentiation, ATAC-seq (chromatin accessibility), RNA-seq, genetic rescue with Wnt titration","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 — KD with ATAC-seq + RNA-seq + functional rescue, single study","pmids":["40835974"],"is_preprint":false},{"year":2026,"finding":"Modeling the recurrent CHD3 variant p.R1025W in a humanized mouse (Chd3hR1025W/+) reduces CHD3 protein levels and recapitulates SNIBCPS behavioral features. In vivo adenine base editing (TadA-embedded ABE via dual AAV) correcting p.R1025W across cortical and hippocampal regions restored CHD3 protein levels and ameliorated behavioral abnormalities, establishing that CHD3 protein dosage is causally linked to the neurobehavioral phenotype.","method":"Humanized knock-in mouse model, in vivo dual AAV base editing, behavioral assays, immunostaining, protein quantification","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 — humanized mouse model with in vivo gene correction restoring protein and rescuing phenotype, multiple orthogonal readouts","pmids":["41708849"],"is_preprint":false},{"year":2024,"finding":"FBW7 targets CHD3 for ubiquitination and proteasomal degradation in hepatocellular carcinoma cells. FBW7 overexpression suppresses CHD3 protein levels, and the tumor-promoting effects of CHD3 overexpression (migration, invasion, stemness, oxaliplatin resistance) are attenuated by co-expression of FBW7, establishing FBW7 as an E3 ubiquitin ligase that writes ubiquitin on CHD3.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, FBW7 overexpression, cell functional assays (migration, invasion, sphere formation, drug sensitivity)","journal":"Frontiers in bioscience","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP + ubiquitination assay + functional rescue, single study","pmids":["39473409"],"is_preprint":false}],"current_model":"CHD3 is an ATP-dependent chromatin remodeler that functions as the catalytic ATPase subunit of isoform-specific NuRD complexes; its PHD fingers bind H3K9me3/ac to target nucleosomes, its ATPase/helicase domain remodels chromatin (basal ATPase activity is sufficient for translocation), it is dispersed from heterochromatic DNA breaks by ATM-mediated KAP-1 phosphorylation (disrupting CHD3's SUMO-interacting motif–SUMO1 interaction) to permit repair, it is recruited to breaks via PARP1-dependent chromatin relaxation, it promotes BMP signalling and chromatin opening during cranial neural crest specification, and its protein dosage is causally linked to the Snijders Blok-Campeau neurodevelopmental syndrome, with FBW7 serving as an E3 ubiquitin ligase that targets CHD3 for degradation."},"narrative":{"teleology":[{"year":2003,"claim":"Identification of physical interactors (Ki-1/57, CGI-55) for CHD3's C-terminal region established that this domain serves as a protein–protein interaction platform beyond the catalytic core.","evidence":"Yeast two-hybrid, in vitro pulldown, and co-immunoprecipitation from insect cells","pmids":["12505151"],"confidence":"Medium","gaps":["Functional consequence of Ki-1/57 and CGI-55 binding on CHD3 remodeling activity unknown","No in vivo validation in mammalian cells"]},{"year":2007,"claim":"Mapping the CHD3–ERM interaction and showing CHD3 occupancy at the PS1 promoter established CHD3 as a transcription-factor-recruited transcriptional repressor at specific gene loci.","evidence":"Yeast two-hybrid deletion mapping, reporter assays, and chromatin immunoprecipitation","pmids":["17489097"],"confidence":"Medium","gaps":["Dependence on NuRD complex versus CHD3 alone not tested","Endogenous PS1 expression change not measured by orthogonal methods"]},{"year":2010,"claim":"Demonstration that Drosophila CHD3 remodels chromatin as a monomer and co-localizes with elongating RNA Pol II revealed that CHD3 can function independently of NuRD and participates in active transcription zones.","evidence":"Protein complex analysis, in vitro remodeling, polytene chromosome staining, and targeted gene replacement in Drosophila","pmids":["20439780"],"confidence":"Medium","gaps":["Drosophila ortholog dispensability may not translate to mammals","Mechanism of CHD3 recruitment to active genes unresolved"]},{"year":2011,"claim":"Demonstrating that ATM-dependent KAP-1 phosphorylation disperses CHD3 from heterochromatic DSBs by disrupting its SUMO-interacting motif–SUMO1 interaction resolved how heterochromatic DNA breaks become accessible for repair.","evidence":"siRNA depletion, SIM mutagenesis, irradiation-induced foci imaging, chromatin relaxation assays, and co-immunoprecipitation in human cells","pmids":["21642969"],"confidence":"High","gaps":["Whether CHD3 dispersal is the sole mechanism enabling heterochromatic repair","Role of other SIM-containing remodelers not excluded"]},{"year":2014,"claim":"Two studies revealed CHD3 as a factor exploited by viruses: CHD3 silences incoming herpes simplex virus genomes via repressive chromatin, and influenza A NS2 hijacks CHD3 to facilitate vRNP nuclear export, broadening CHD3's roles to host–pathogen interactions.","evidence":"siRNA knockdown with viral gene expression and propagation assays, co-immunoprecipitation, NES1 mutagenesis, confocal imaging","pmids":["24425734","25213355"],"confidence":"Medium","gaps":["Structural basis of NS2–CHD3 interaction unresolved","Whether CHD3's antiviral role against HSV extends to other DNA viruses not tested"]},{"year":2017,"claim":"Biochemical separation of CHD3-NuRD from CHD4-NuRD as distinct complexes with different remodeling activities, combined with the finding that CHD3's PHD fingers preferentially bind H3K9me3/ac and promote nucleosome unwrapping, defined CHD3-NuRD as a functionally autonomous remodeling complex targeted by histone marks.","evidence":"Mass spectrometry interactome, reciprocal co-IP, in vitro nucleosome unwrapping and remodeling assays, ChIP, heterochromatin imaging","pmids":["28977666","29020631"],"confidence":"High","gaps":["Genome-wide target specificity differences between CHD3-NuRD and CHD4-NuRD not comprehensively mapped","Whether PHD-mark recognition is essential for all CHD3 functions in vivo"]},{"year":2018,"claim":"Demonstration that CHD3 is recruited to DSBs in a PARP1-dependent but PAR-binding-independent manner, and that CHD3 ortholog loss in C. elegans meiosis causes HR failure with chromosomal fusions, established CHD3 as an active participant in DNA repair at multiple levels.","evidence":"Live-cell fluorescence three-hybrid assay, laser micro-irradiation, siRNA knockdown (human); genetic epistasis, cytological assays (C. elegans)","pmids":["29733391","29339410"],"confidence":"Medium","gaps":["Precise substrate specificity of CHD3 at DSBs (which nucleosomes it repositions) unresolved","Whether meiotic role is conserved in mammals untested"]},{"year":2018,"claim":"Identification of de novo ATPase-domain mutations causing Snijders Blok–Campeau syndrome, with in vitro evidence that these mutations impair ATPase and remodeling activities, established CHD3 as a disease gene and linked its enzymatic activity to neurodevelopment.","evidence":"ATPase activity assays, chromatin remodeling assays, structural modeling, whole-genome sequencing of patient cohort","pmids":["30397230"],"confidence":"High","gaps":["Cell-type-specific downstream gene targets disrupted by SNIBCPS mutations not identified","Gain-of-function versus loss-of-function spectrum across all variants not fully resolved"]},{"year":2021,"claim":"Reconstitution showing that CHD3's ATPase domain alone suffices for nucleosome translocation and that conserved motif mutations uncouple hydrolysis from translocation clarified the minimal catalytic mechanism and revealed differential regulation by IP6 and ADP compared to SNF2H.","evidence":"In vitro ATPase and nucleosome translocation assays with purified wild-type and mutant ATPase domains, competitive inhibition studies","pmids":["33403747"],"confidence":"High","gaps":["How flanking domains (PHD, chromodomains) allosterically regulate ATPase activity not reconstituted","No structural data for CHD3-nucleosome complex"]},{"year":2024,"claim":"Identification of FBW7 as the E3 ubiquitin ligase that targets CHD3 for proteasomal degradation revealed a post-translational mechanism controlling CHD3 protein levels, with functional consequences for tumor cell migration and drug resistance.","evidence":"Co-immunoprecipitation, ubiquitination assay, FBW7 overexpression and knockdown in hepatocellular carcinoma cells","pmids":["39473409"],"confidence":"Medium","gaps":["Degron motif on CHD3 recognized by FBW7 not mapped","Whether FBW7-mediated CHD3 turnover operates in non-cancer contexts unknown"]},{"year":2025,"claim":"Showing that CHD3 opens chromatin at BMP-responsive enhancers during cranial neural crest specification linked its remodeling activity to a specific developmental signaling pathway and explained how SNIBCPS mutations may derail craniofacial development.","evidence":"CHD3 knockdown in human iPSC-derived CNCC differentiation, ATAC-seq, RNA-seq, Wnt titration rescue","pmids":["40835974"],"confidence":"Medium","gaps":["Whether CHD3 acts at BMP enhancers as part of NuRD or independently not determined","Direct CHD3 occupancy at BMP enhancers not shown by ChIP"]},{"year":2026,"claim":"In vivo base-editing correction of the recurrent SNIBCPS variant in a humanized mouse restored CHD3 protein and rescued behavioral deficits, causally linking CHD3 protein dosage to neurodevelopmental outcome and providing therapeutic proof-of-concept.","evidence":"Humanized Chd3hR1025W/+ knock-in mouse, dual-AAV adenine base editing, behavioral assays, protein quantification","pmids":["41708849"],"confidence":"High","gaps":["Long-term safety and off-target profile of in vivo base editing not characterized","Whether correction in other brain regions or at other developmental stages would improve rescue"]},{"year":null,"claim":"A high-resolution structure of CHD3 (or CHD3-NuRD) bound to a nucleosome is lacking, the allosteric regulation of CHD3 ATPase activity by its PHD and chromodomains remains unresolved, and the full spectrum of gain- versus loss-of-function consequences across all SNIBCPS variants has not been systematically defined.","evidence":"","pmids":[],"confidence":"High","gaps":["No cryo-EM or crystal structure of CHD3–nucleosome complex","Allosteric coupling between reader domains and ATPase motor not reconstituted","Cell-type-specific target gene programs of CHD3 versus CHD4 NuRD largely uncharacterized"]}],"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":[4]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,9]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,5]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[0,4]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,1,4,9,13]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[0,2,12]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[7,13]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[13,14]}],"complexes":["NuRD (CHD3-specific isoform)"],"partners":["KAP1","HDAC1","FBW7","GATAD2A","HP1","PARP1"],"other_free_text":[]},"mechanistic_narrative":"CHD3 is an ATP-dependent chromatin remodeling enzyme that serves as the catalytic ATPase subunit of a distinct, isoform-specific NuRD complex and functions in transcriptional regulation, DNA damage repair, and developmental cell-fate specification. Its tandem PHD fingers recognize H3K9me3 and H3K9ac marks to target nucleosomes, and its ATPase/helicase domain is sufficient for basal nucleosome translocation, with activity differentially regulated by ADP and IP6 compared to other remodelers [PMID:29020631, PMID:33403747, PMID:28977666]. At heterochromatic DNA double-strand breaks, ATM-mediated phosphorylation of KAP-1 disrupts the CHD3 SUMO-interacting motif–SUMO1 interaction, dispersing CHD3 to permit chromatin relaxation and repair; CHD3 is subsequently recruited back to break sites through PARP1-dependent chromatin opening [PMID:21642969, PMID:29733391]. De novo missense mutations in the ATPase/helicase domain cause Snijders Blok–Campeau neurodevelopmental syndrome, and in vivo base-editing correction of a recurrent variant in a humanized mouse model restores CHD3 protein levels and rescues behavioral deficits, establishing that CHD3 protein dosage is causally linked to disease [PMID:30397230, PMID:41708849]."},"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 all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CHD3"},"hgnc":{"alias_symbol":["Mi-2a","ZFH","Mi2-ALPHA"],"prev_symbol":[]},"alphafold":{"accession":"Q12873","domains":[{"cath_id":"3.30.40.10","chopping":"380-414","consensus_level":"medium","plddt":80.3109,"start":380,"end":414},{"cath_id":"3.40.50.10810","chopping":"710-966","consensus_level":"high","plddt":87.0602,"start":710,"end":966},{"cath_id":"3.40.50.300","chopping":"977-1233_1253-1269_1282-1292","consensus_level":"high","plddt":79.3449,"start":977,"end":1292},{"cath_id":"-","chopping":"1396-1468","consensus_level":"medium","plddt":72.0205,"start":1396,"end":1468},{"cath_id":"-","chopping":"1485-1515_1709-1811","consensus_level":"medium","plddt":83.8561,"start":1485,"end":1811},{"cath_id":"1.10.390","chopping":"135-198","consensus_level":"medium","plddt":83.4756,"start":135,"end":198}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q12873","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q12873-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q12873-F1-predicted_aligned_error_v6.png","plddt_mean":62.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CHD3","jax_strain_url":"https://www.jax.org/strain/search?query=CHD3"},"sequence":{"accession":"Q12873","fasta_url":"https://rest.uniprot.org/uniprotkb/Q12873.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q12873/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q12873"}},"corpus_meta":[{"pmid":"10570159","id":"PMC_10570159","title":"PICKLE is a CHD3 chromatin-remodeling factor that regulates the transition from embryonic to vegetative development in Arabidopsis.","date":"1999","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/10570159","citation_count":363,"is_preprint":false},{"pmid":"18593558","id":"PMC_18593558","title":"Zfh-1 controls somatic stem cell self-renewal in the Drosophila testis and nonautonomously influences germline stem cell self-renewal.","date":"2008","source":"Cell stem cell","url":"https://pubmed.ncbi.nlm.nih.gov/18593558","citation_count":256,"is_preprint":false},{"pmid":"21642969","id":"PMC_21642969","title":"KAP-1 phosphorylation regulates CHD3 nucleosome remodeling during the DNA double-strand break response.","date":"2011","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/21642969","citation_count":210,"is_preprint":false},{"pmid":"1680377","id":"PMC_1680377","title":"The 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CHD3 depletion or inactivation, or ablation of its interaction with KAP-1(SUMO1), bypassed the requirement for pKAP-1 in heterochromatic repair.\",\n      \"method\": \"siRNA depletion, mutagenesis of CHD3 SUMO-interacting motif, irradiation-induced foci imaging, chromatin relaxation assays, co-immunoprecipitation\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (mutagenesis, co-IP, live-cell imaging, functional repair assays) in a single rigorous study\",\n      \"pmids\": [\"21642969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CHD3 and CHD4 form distinct, isoform-specific NuRD complexes (each containing either CHD3 or CHD4 as a monomeric ATPase, not both simultaneously). CHD3-NuRD and CHD4-NuRD exhibit different nuclear localization patterns, different nucleosome remodeling and positioning behavior in vitro, and regulate overlapping but distinct sets of target genes. Both complexes interact with HP1 and rapidly accumulate at UV-induced DNA repair sites.\",\n      \"method\": \"Mass spectrometry-based interactome mapping, reciprocal co-immunoprecipitation, in vitro nucleosome remodeling assays, live-cell fluorescence imaging, UV laser micro-irradiation\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reciprocal Co-IP + MS interactome + in vitro remodeling assays + live-cell imaging, multiple orthogonal methods\",\n      \"pmids\": [\"28977666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CHD3 is recruited to DNA double-strand breaks in a PAR-dependent manner (dependent on prior PARP1 activity and initial chromatin relaxation by Alc1/CHD1L) and actively contributes to chromatin remodeling at break sites. Recruitment is not mediated by direct PAR binding but by DNA binding after initial relaxation.\",\n      \"method\": \"Live-cell fluorescence three-hybrid assay, laser micro-irradiation, siRNA knockdown, real-time recruitment kinetics imaging\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean live-cell assay with mechanistic dissection, single study\",\n      \"pmids\": [\"29733391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"De novo missense mutations clustering in the ATPase/helicase domain of CHD3 cause a neurodevelopmental syndrome (Snijders Blok-Campeau syndrome). Experimental assays of six identified mutations showed that a subset directly reduces ATPase activity and all but one alter chromatin remodeling activity in vitro.\",\n      \"method\": \"ATPase activity assays, chromatin remodeling assays, structural modeling of mutation impact on ATPase/helicase domain, whole genome sequencing\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro enzymatic assays + chromatin remodeling assays + structural modeling across multiple variants, replicated in large cohort\",\n      \"pmids\": [\"30397230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The tandem PHD fingers of CHD3 bind histone H3 tails, and posttranslational 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. CHD3 co-localizes with HDAC1 and other NuRD subunits near H3K9ac-enriched promoters of NuRD target genes.\",\n      \"method\": \"In vitro nucleosome unwrapping assay, histone peptide binding assays, co-immunoprecipitation, chromatin immunoprecipitation, in vivo heterochromatin imaging\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro biochemical reconstitution + in vivo functional consequence, multiple orthogonal methods\",\n      \"pmids\": [\"29020631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CHD3 localizes to early viral foci upon herpes simplex virus infection and suppresses viral gene expression. CHD3 can recognize repressive histone marks associated with the viral genome chromatin. Depletion of CHD3 results in enhanced viral immediate early gene expression and increased number of transcriptionally active viral genomes, establishing CHD3 as an antiviral chromatin repressor opposing the HCF-1 coactivator complex.\",\n      \"method\": \"siRNA depletion, viral gene expression assays, co-localization imaging, histone mark binding assays\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional KD with defined phenotypic readout plus binding data, single study\",\n      \"pmids\": [\"24425734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Two human proteins, Ki-1/57 and CGI-55, interact with the C-terminal region of CHD3 (human chromatin-remodeling factor). The CHD3–CGI-55 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 insect cells\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — multiple methods (Y2H + Co-IP) in single study for a binding partner identification\",\n      \"pmids\": [\"12505151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The C-terminal region of CHD3 (amino acids 1676–2000, with critical sequences between residues 1877–1955) interacts with the CIDD region (residues 96–349, critical at 200–343 and 279–299) of the Ets transcription factor ERM, as defined by yeast two-hybrid mapping and deletion analysis. This CHD3 C-terminal fragment represses transcription of the presenilin 1 (PS1) gene in transfection assays and reduces PS1 protein expression. Chromatin immunoprecipitation confirmed CHD3 occupancy at the PS1 promoter in vivo.\",\n      \"method\": \"Yeast two-hybrid, deletion mapping, transfection/reporter assays, western blot, chromatin immunoprecipitation\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Y2H + ChIP + functional reporter assays, single lab study\",\n      \"pmids\": [\"17489097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CHD3 interacts with the nuclear export signal 1 (NES1) of influenza A virus NS2 protein. This interaction localizes NS2 and Crm1 to dense chromatin and is required for efficient vRNP nuclear export. CHD3 knockdown impairs wild-type influenza propagation but not a NES1 mutant virus with weakened NS2-CHD3 interaction, establishing CHD3 as a host factor hijacked for viral vRNP export.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, viral propagation assays, site-directed mutagenesis of NES1, confocal localization\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP + mutagenesis + functional viral assay, single study\",\n      \"pmids\": [\"25213355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The ATPase domain of CHD3 is sufficient for basal nucleosome remodeling activity at lower ATP concentrations than SNF2H. Mutagenesis of conserved Q- and K-residues in the ATPase domain motifs abolished nucleosome translocation while preserving basal ATP hydrolysis, demonstrating that basal ATPase activity of CHD3 is sufficient for remodeling. CHD3 and SNF2H show differential sensitivity to inhibition by ADP and IP6 (competitive inhibition mode at CHD3 but not SNF2H).\",\n      \"method\": \"In vitro ATPase assays, in vitro nucleosome remodeling/translocation assays, site-directed mutagenesis, competitive inhibition assays with ADP and IP6\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with mutagenesis, multiple biochemical assays\",\n      \"pmids\": [\"33403747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Drosophila CHD3 proteins are found as monomers (not in multi-subunit complexes) and remodel chromatin in vitro as monomers. CHD3 co-localizes with elongating RNA polymerase II on salivary gland polytene chromosomes. Targeted gene replacement deletion of Drosophila Chd3 had no effect on viability or fertility.\",\n      \"method\": \"Protein complex analysis, in vitro chromatin remodeling assays, polytene chromosome immunostaining, targeted gene replacement\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro remodeling assay + in vivo localization + genetic KO, single study in Drosophila ortholog\",\n      \"pmids\": [\"20439780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Global homozygous deletion of Chd3 in mice results in partial lethality prior to weaning. Endothelial cell-specific deletion of Chd3 alone causes no vascular anomalies, and double deletion with Chd4 in endothelial cells does not worsen CHD4-KO phenotypes, indicating CHD3 is dispensable for early vascular development. CHD3 is highly expressed in adult gonads and brain.\",\n      \"method\": \"Conditional gene targeting (floxed allele), Cre-lox endothelial and epiblast deletion, embryonic viability analysis, tissue expression analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean in vivo KO with specific tissue-restricted deletions, single study\",\n      \"pmids\": [\"32658897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In C. elegans, the CHD3 ortholog CHD-3 (Mi2 homolog) and its paralog LET-418 are components of the NuRD complex and are required for faithful meiotic DSB repair through homologous recombination. Loss of CHD-3 results in elevated CHK-1-dependent germ-line apoptosis, persisting recombination intermediates in late pachytene, and chromosomal fusions indicative of non-homologous end joining, demonstrating a role in maintaining genome integrity during meiosis.\",\n      \"method\": \"Genetic analysis of chd-3 mutants, cytological assays for recombination intermediates, apoptosis assays, double mutant epistasis (chd-3; cku-80)\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis + cytological readouts in C. elegans ortholog, single study\",\n      \"pmids\": [\"29339410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CHD3 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 causes repression of BMP target genes, loss of chromatin accessibility at BMP-responsive enhancers, and an imbalance between BMP and Wnt signalling, resulting in aberrant early-mesoderm identity instead of CNCC fate. This failure could be partially rescued by titrating Wnt levels.\",\n      \"method\": \"CHD3 knockdown in human iPSC-derived CNCC differentiation, ATAC-seq (chromatin accessibility), RNA-seq, genetic rescue with Wnt titration\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD with ATAC-seq + RNA-seq + functional rescue, single study\",\n      \"pmids\": [\"40835974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Modeling the recurrent CHD3 variant p.R1025W in a humanized mouse (Chd3hR1025W/+) reduces CHD3 protein levels and recapitulates SNIBCPS behavioral features. In vivo adenine base editing (TadA-embedded ABE via dual AAV) correcting p.R1025W across cortical and hippocampal regions restored CHD3 protein levels and ameliorated behavioral abnormalities, establishing that CHD3 protein dosage is causally linked to the neurobehavioral phenotype.\",\n      \"method\": \"Humanized knock-in mouse model, in vivo dual AAV base editing, behavioral assays, immunostaining, protein quantification\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — humanized mouse model with in vivo gene correction restoring protein and rescuing phenotype, multiple orthogonal readouts\",\n      \"pmids\": [\"41708849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FBW7 targets CHD3 for ubiquitination and proteasomal degradation in hepatocellular carcinoma cells. FBW7 overexpression suppresses CHD3 protein levels, and the tumor-promoting effects of CHD3 overexpression (migration, invasion, stemness, oxaliplatin resistance) are attenuated by co-expression of FBW7, establishing FBW7 as an E3 ubiquitin ligase that writes ubiquitin on CHD3.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, FBW7 overexpression, cell functional assays (migration, invasion, sphere formation, drug sensitivity)\",\n      \"journal\": \"Frontiers in bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP + ubiquitination assay + functional rescue, single study\",\n      \"pmids\": [\"39473409\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CHD3 is an ATP-dependent chromatin remodeler that functions as the catalytic ATPase subunit of isoform-specific NuRD complexes; its PHD fingers bind H3K9me3/ac to target nucleosomes, its ATPase/helicase domain remodels chromatin (basal ATPase activity is sufficient for translocation), it is dispersed from heterochromatic DNA breaks by ATM-mediated KAP-1 phosphorylation (disrupting CHD3's SUMO-interacting motif–SUMO1 interaction) to permit repair, it is recruited to breaks via PARP1-dependent chromatin relaxation, it promotes BMP signalling and chromatin opening during cranial neural crest specification, and its protein dosage is causally linked to the Snijders Blok-Campeau neurodevelopmental syndrome, with FBW7 serving as an E3 ubiquitin ligase that targets CHD3 for degradation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CHD3 is an ATP-dependent chromatin remodeling enzyme that serves as the catalytic ATPase subunit of a distinct, isoform-specific NuRD complex and functions in transcriptional regulation, DNA damage repair, and developmental cell-fate specification. Its tandem PHD fingers recognize H3K9me3 and H3K9ac marks to target nucleosomes, and its ATPase/helicase domain is sufficient for basal nucleosome translocation, with activity differentially regulated by ADP and IP6 compared to other remodelers [PMID:29020631, PMID:33403747, PMID:28977666]. At heterochromatic DNA double-strand breaks, ATM-mediated phosphorylation of KAP-1 disrupts the CHD3 SUMO-interacting motif–SUMO1 interaction, dispersing CHD3 to permit chromatin relaxation and repair; CHD3 is subsequently recruited back to break sites through PARP1-dependent chromatin opening [PMID:21642969, PMID:29733391]. De novo missense mutations in the ATPase/helicase domain cause Snijders Blok–Campeau neurodevelopmental syndrome, and in vivo base-editing correction of a recurrent variant in a humanized mouse model restores CHD3 protein levels and rescues behavioral deficits, establishing that CHD3 protein dosage is causally linked to disease [PMID:30397230, PMID:41708849].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Identification of physical interactors (Ki-1/57, CGI-55) for CHD3's C-terminal region established that this domain serves as a protein–protein interaction platform beyond the catalytic core.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro pulldown, and co-immunoprecipitation from insect cells\",\n      \"pmids\": [\"12505151\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of Ki-1/57 and CGI-55 binding on CHD3 remodeling activity unknown\", \"No in vivo validation in mammalian cells\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Mapping the CHD3–ERM interaction and showing CHD3 occupancy at the PS1 promoter established CHD3 as a transcription-factor-recruited transcriptional repressor at specific gene loci.\",\n      \"evidence\": \"Yeast two-hybrid deletion mapping, reporter assays, and chromatin immunoprecipitation\",\n      \"pmids\": [\"17489097\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Dependence on NuRD complex versus CHD3 alone not tested\", \"Endogenous PS1 expression change not measured by orthogonal methods\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstration that Drosophila CHD3 remodels chromatin as a monomer and co-localizes with elongating RNA Pol II revealed that CHD3 can function independently of NuRD and participates in active transcription zones.\",\n      \"evidence\": \"Protein complex analysis, in vitro remodeling, polytene chromosome staining, and targeted gene replacement in Drosophila\",\n      \"pmids\": [\"20439780\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Drosophila ortholog dispensability may not translate to mammals\", \"Mechanism of CHD3 recruitment to active genes unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrating that ATM-dependent KAP-1 phosphorylation disperses CHD3 from heterochromatic DSBs by disrupting its SUMO-interacting motif–SUMO1 interaction resolved how heterochromatic DNA breaks become accessible for repair.\",\n      \"evidence\": \"siRNA depletion, SIM mutagenesis, irradiation-induced foci imaging, chromatin relaxation assays, and co-immunoprecipitation in human cells\",\n      \"pmids\": [\"21642969\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CHD3 dispersal is the sole mechanism enabling heterochromatic repair\", \"Role of other SIM-containing remodelers not excluded\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Two studies revealed CHD3 as a factor exploited by viruses: CHD3 silences incoming herpes simplex virus genomes via repressive chromatin, and influenza A NS2 hijacks CHD3 to facilitate vRNP nuclear export, broadening CHD3's roles to host–pathogen interactions.\",\n      \"evidence\": \"siRNA knockdown with viral gene expression and propagation assays, co-immunoprecipitation, NES1 mutagenesis, confocal imaging\",\n      \"pmids\": [\"24425734\", \"25213355\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of NS2–CHD3 interaction unresolved\", \"Whether CHD3's antiviral role against HSV extends to other DNA viruses not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Biochemical separation of CHD3-NuRD from CHD4-NuRD as distinct complexes with different remodeling activities, combined with the finding that CHD3's PHD fingers preferentially bind H3K9me3/ac and promote nucleosome unwrapping, defined CHD3-NuRD as a functionally autonomous remodeling complex targeted by histone marks.\",\n      \"evidence\": \"Mass spectrometry interactome, reciprocal co-IP, in vitro nucleosome unwrapping and remodeling assays, ChIP, heterochromatin imaging\",\n      \"pmids\": [\"28977666\", \"29020631\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide target specificity differences between CHD3-NuRD and CHD4-NuRD not comprehensively mapped\", \"Whether PHD-mark recognition is essential for all CHD3 functions in vivo\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstration that CHD3 is recruited to DSBs in a PARP1-dependent but PAR-binding-independent manner, and that CHD3 ortholog loss in C. elegans meiosis causes HR failure with chromosomal fusions, established CHD3 as an active participant in DNA repair at multiple levels.\",\n      \"evidence\": \"Live-cell fluorescence three-hybrid assay, laser micro-irradiation, siRNA knockdown (human); genetic epistasis, cytological assays (C. elegans)\",\n      \"pmids\": [\"29733391\", \"29339410\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Precise substrate specificity of CHD3 at DSBs (which nucleosomes it repositions) unresolved\", \"Whether meiotic role is conserved in mammals untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identification of de novo ATPase-domain mutations causing Snijders Blok–Campeau syndrome, with in vitro evidence that these mutations impair ATPase and remodeling activities, established CHD3 as a disease gene and linked its enzymatic activity to neurodevelopment.\",\n      \"evidence\": \"ATPase activity assays, chromatin remodeling assays, structural modeling, whole-genome sequencing of patient cohort\",\n      \"pmids\": [\"30397230\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type-specific downstream gene targets disrupted by SNIBCPS mutations not identified\", \"Gain-of-function versus loss-of-function spectrum across all variants not fully resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Reconstitution showing that CHD3's ATPase domain alone suffices for nucleosome translocation and that conserved motif mutations uncouple hydrolysis from translocation clarified the minimal catalytic mechanism and revealed differential regulation by IP6 and ADP compared to SNF2H.\",\n      \"evidence\": \"In vitro ATPase and nucleosome translocation assays with purified wild-type and mutant ATPase domains, competitive inhibition studies\",\n      \"pmids\": [\"33403747\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How flanking domains (PHD, chromodomains) allosterically regulate ATPase activity not reconstituted\", \"No structural data for CHD3-nucleosome complex\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of FBW7 as the E3 ubiquitin ligase that targets CHD3 for proteasomal degradation revealed a post-translational mechanism controlling CHD3 protein levels, with functional consequences for tumor cell migration and drug resistance.\",\n      \"evidence\": \"Co-immunoprecipitation, ubiquitination assay, FBW7 overexpression and knockdown in hepatocellular carcinoma cells\",\n      \"pmids\": [\"39473409\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Degron motif on CHD3 recognized by FBW7 not mapped\", \"Whether FBW7-mediated CHD3 turnover operates in non-cancer contexts unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showing that CHD3 opens chromatin at BMP-responsive enhancers during cranial neural crest specification linked its remodeling activity to a specific developmental signaling pathway and explained how SNIBCPS mutations may derail craniofacial development.\",\n      \"evidence\": \"CHD3 knockdown in human iPSC-derived CNCC differentiation, ATAC-seq, RNA-seq, Wnt titration rescue\",\n      \"pmids\": [\"40835974\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CHD3 acts at BMP enhancers as part of NuRD or independently not determined\", \"Direct CHD3 occupancy at BMP enhancers not shown by ChIP\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"In vivo base-editing correction of the recurrent SNIBCPS variant in a humanized mouse restored CHD3 protein and rescued behavioral deficits, causally linking CHD3 protein dosage to neurodevelopmental outcome and providing therapeutic proof-of-concept.\",\n      \"evidence\": \"Humanized Chd3hR1025W/+ knock-in mouse, dual-AAV adenine base editing, behavioral assays, protein quantification\",\n      \"pmids\": [\"41708849\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Long-term safety and off-target profile of in vivo base editing not characterized\", \"Whether correction in other brain regions or at other developmental stages would improve rescue\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A high-resolution structure of CHD3 (or CHD3-NuRD) bound to a nucleosome is lacking, the allosteric regulation of CHD3 ATPase activity by its PHD and chromodomains remains unresolved, and the full spectrum of gain- versus loss-of-function consequences across all SNIBCPS variants has not been systematically defined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No cryo-EM or crystal structure of CHD3–nucleosome complex\", \"Allosteric coupling between reader domains and ATPase motor not reconstituted\", \"Cell-type-specific target gene programs of CHD3 versus CHD4 NuRD largely uncharacterized\"]\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\": [4]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 1, 4, 9, 13]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [0, 2, 12]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [7, 13]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [13, 14]}\n    ],\n    \"complexes\": [\n      \"NuRD (CHD3-specific isoform)\"\n    ],\n    \"partners\": [\n      \"KAP1\",\n      \"HDAC1\",\n      \"FBW7\",\n      \"GATAD2A\",\n      \"HP1\",\n      \"PARP1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}