{"gene":"CHD7","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2010,"finding":"CHD7 associates with PBAF (polybromo- and BRG1-associated factor-containing complex) in human neural crest cells; both remodelers occupy a neural crest-specific distal SOX9 enhancer and a conserved element upstream of TWIST1, cooperating to promote neural crest gene expression and cell migration. Catalytically inactive CHD7 overexpression or CHD7 knockdown in Xenopus recapitulates CHARGE syndrome features, establishing CHD7 ATPase activity as essential for neural crest transcriptional circuitry (Sox9, Twist, Slug activation).","method":"Co-immunoprecipitation, ChIP, Xenopus loss-of-function (morpholino knockdown and catalytic mutant overexpression), human neural crest cell functional assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reciprocal Co-IP, ChIP at specific enhancers, catalytic mutant rescue, replicated in two model systems (Xenopus and human cells)","pmids":["20130577"],"is_preprint":false},{"year":2009,"finding":"CHD7 localizes to discrete, cell-type-specific chromatin sites that correlate with histone H3K4 methylation (H3K4me); these sites are predominantly distal to transcription start sites, overlap with DNase hypersensitive sites, and shift concomitantly with H3K4me patterns during ES cell differentiation—consistent with CHD7 functioning at enhancer elements.","method":"ChIP-chip (chromatin immunoprecipitation on tiled microarrays) in human colorectal carcinoma cells, human neuroblastoma cells, and mouse ES cells before and after neural precursor differentiation","journal":"Genome research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-chip across multiple cell types and conditions in one rigorous study, correlated with H3K4me dynamics","pmids":["19251738"],"is_preprint":false},{"year":2011,"finding":"CHD7 physically interacts with the HMG-box transcription factor SOX2 in neural stem cells; the two proteins have overlapping genome-wide binding sites and co-regulate a common set of target genes including Jag1, Gli3, and Mycn. Chd7-haploinsufficient embryos show severely reduced Jag1 expression in the developing inner ear.","method":"Proteomic interaction screen (Sox2 pulldown + mass spectrometry), genome-wide ChIP (ChIP-seq), co-immunoprecipitation, expression analysis in Chd7 haploinsufficient embryos","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, genome-wide ChIP-seq overlap, confirmed in vivo phenotype; multiple orthogonal methods in one study","pmids":["21532573"],"is_preprint":false},{"year":2012,"finding":"Purified recombinant CHD7 is an ATP-dependent nucleosome remodeling factor with biochemical characteristics distinct from SWI/SNF- and ISWI-type remodelers. Patient-derived CHARGE syndrome mutations have consequences ranging from subtle to complete inactivation of remodeling activity; truncations upstream of amino acid 1899 likely cause a hypomorphic remodeling phenotype.","method":"Dual-tag purification of intact recombinant CHD7; in vitro nucleosome remodeling assays; mutagenesis analysis of patient mutations","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical reconstitution with purified protein, mutagenesis of multiple disease alleles, single lab but multiple orthogonal methods","pmids":["23134727"],"is_preprint":false},{"year":2010,"finding":"CHD7 localizes constitutively to the nucleolus and physically associates with hypomethylated, actively transcribed rDNA. siRNA-mediated depletion of CHD7 causes hypermethylation of the rDNA promoter and reduction of 45S pre-rRNA levels, while CHD7 overexpression increases 45S pre-rRNA. CHD7 depletion also reduces cell proliferation and protein synthesis. Reduced pre-rRNA is observed in Chd7+/− and Chd7−/− mouse ES cells and embryos.","method":"Immunofluorescence and subcellular fractionation western blot; ChIP (standard and ChIP-chop); ChIP-seq rDNA alignment; siRNA knockdown; CHD7 overexpression; Chd7 mouse genetic models","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (immunofluorescence, fractionation, ChIP, siRNA, overexpression, in vivo mouse models) in one rigorous study","pmids":["20591827"],"is_preprint":false},{"year":2010,"finding":"CHD7 interacts directly with CHD8; the interaction was identified by yeast two-hybrid screen and confirmed by co-immunoprecipitation and bimolecular fluorescence complementation. Specific CHARGE syndrome missense mutations in CHD7 (p.Trp2091Arg, p.His2096Arg, p.Gly2108Arg) disrupt the direct CHD7–CHD8 interaction in yeast two-hybrid assays.","method":"Yeast two-hybrid library screen and direct yeast two-hybrid; co-immunoprecipitation; bimolecular fluorescence complementation; missense mutation functional testing","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — yeast two-hybrid plus Co-IP plus BiFC, single lab; disruption of direct interaction by patient mutations confirmed in one assay system but not fully confirmed in Co-IP","pmids":["20453063"],"is_preprint":false},{"year":2016,"finding":"CHD7 directly interacts with SOX10 in oligodendrocyte precursors; genome-wide occupancy analysis coupled with transcriptome profiling shows that CHD7 targets the enhancers of key myelinogenic genes. Chd7 is a direct transcriptional target of Olig2 and Smarca4/Brg1. Loss of Chd7 impairs proper onset of CNS myelination and remyelination, with CHD7 also targeting bone formation regulators Osterix (Sp7) and Creb3l2 required for oligodendrocyte maturation.","method":"ChIP-seq (genome-wide occupancy), RNA-seq (transcriptome profiling), co-immunoprecipitation (CHD7–SOX10 interaction), conditional genetic knockout in mice","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, genome-wide ChIP-seq, transcriptomics, and conditional KO phenotype; multiple orthogonal methods","pmids":["26928066"],"is_preprint":false},{"year":2013,"finding":"CHD7 promotes transcription of Sox4 and Sox11 by remodeling their promoters to an open chromatin state in neural stem cells. Genetic inactivation of CHD7 in NSCs reduces neuronal differentiation and causes aberrant dendritic development of newborn neurons. Physical exercise rescues the CHD7 mutant phenotype in the adult hippocampal dentate gyrus.","method":"Conditional genetic knockout in mice; ATAC/chromatin accessibility assays at Sox4/Sox11 promoters; neurosphere assays; BrdU/EdU proliferation; in vivo rescue by exercise","journal":"Cell stem cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean conditional KO with defined phenotype, chromatin accessibility evidence at specific loci, single lab","pmids":["23827709"],"is_preprint":false},{"year":2017,"finding":"CHD7 is required for maintenance of open chromatin and activation of genes essential for granule neuron differentiation; it cooperates with Top2b for transcription of long neuronal genes in cerebellar granule neurons. Genetic inactivation of Chd7 in cerebellar granule neuron progenitors causes cerebellar hypoplasia due to impaired differentiation and apoptosis.","method":"Conditional genetic knockout in mice; ATAC-seq (open chromatin profiling); RNA-seq; molecular analysis of Top2b co-dependence","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with ATAC-seq and RNA-seq, multiple orthogonal methods identifying mechanistic basis for chromatin opening and transcriptional control","pmids":["28317875"],"is_preprint":false},{"year":2017,"finding":"CHD7 directly regulates Reln (reelin) expression by maintaining an open, accessible chromatin state at the Reln locus in cerebellar granule cell progenitors. Reduction in Reln expression contributes to GCP proliferative defects and cerebellar hypoplasia in Chd7 conditional mutant mice.","method":"Conditional knockout in mice; genome-wide expression profiling; chromatin accessibility assays at the Reln locus; genetic rescue by Reln expression","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO, chromatin accessibility at specific locus, molecular and genetic rescue, multiple orthogonal methods","pmids":["28165338"],"is_preprint":false},{"year":2020,"finding":"CHD7 is recruited to DNA double-strand break sites via PARP1-triggered chromatin remodeling; it stimulates chromatin relaxation around break sites and recruits HDAC1/2 for localized chromatin de-acetylation. This coordinated 'chromatin breathing' fosters efficient non-homologous end-joining (NHEJ) by controlling Ku and LIG4/XRCC4 activities. Loss of CHD7-HDAC1/2-dependent canonical NHEJ shifts repair to 53BP1-dependent mutagenic NHEJ.","method":"Live-cell imaging of CHD7 recruitment to DSBs; co-immunoprecipitation (CHD7–HDAC1/2 interaction); ChIP at break sites; functional NHEJ assays; epistasis with 53BP1","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, ChIP, functional repair assays, epistasis), mechanistic pathway placement, single lab with rigorous controls","pmids":["33188175"],"is_preprint":false},{"year":2020,"finding":"CHD7 directly interacts with WDR5, a core component of H3K4 methyltransferase complexes (identified by protein-array screen with recombinant CHD7). An ATPase-dead CHD7 knock-in mouse model retains the ability to recruit H3K4 methyltransferase activity to its target loci, demonstrating that CHD7 regulates cardiovascular development through both ATP-dependent (chromatin remodeling) and ATP-independent (recruitment of H3K4 methyltransferase activity) mechanisms.","method":"Protein-array screen with purified recombinant CHD7; Co-IP (CHD7–WDR5); ATPase-deficient knock-in mouse model; ChIP for H3K4me marks; RNA-seq in neural crest cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct protein-array interaction with recombinant protein, Co-IP confirmation, ATPase-dead knock-in mouse model, ChIP for histone marks; multiple orthogonal methods","pmids":["33127760"],"is_preprint":false},{"year":2021,"finding":"CHD7 robustly promotes chromatin accessibility, active histone modifications (H3K27ac, H3K4me1), and RNA Pol II recruitment at enhancers in cerebellar granule cell precursors. In vivo genome architecture profiling shows CHD7 concordantly regulates epigenomic modifications and expression of topologically-interacting genes. Loss of CHD7 in GCPs triggers cerebellar polymicrogyria and alters preferred orientation of GCP division.","method":"Conditional KO in mice; ATAC-seq; ChIP-seq (H3K27ac, H3K4me1, Pol II); Hi-C genome architecture; cell division orientation analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with ATAC-seq, ChIP-seq, Hi-C, multiple orthogonal methods in one study; mechanistic link between enhancer activation and gene expression established","pmids":["34588434"],"is_preprint":false},{"year":2017,"finding":"CHD7 and CHD8 exhibit distinct nucleosome remodeling activities: CHD7 binds with high affinity to short linker DNA whereas CHD8 requires longer linker DNA. As a result, CHD7 and CHD8 slide nucleosomes into different positions; CHD6 disrupts nucleosomes without sliding. These distinct biochemical activities likely underlie their non-redundant in vivo roles.","method":"In vitro biochemical assays with purified CHD6, CHD7, CHD8; nucleosome binding assays; nucleosome sliding assays on defined substrates","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with purified proteins, multiple substrate conditions, single lab but rigorous biochemical characterization","pmids":["28533432"],"is_preprint":false},{"year":2009,"finding":"Chd7 and Tbx1 show a synergistic genetic interaction: Tbx1+/−;Chd7+/− double heterozygotes display synergistic defects in fourth pharyngeal arch artery, thymus, and ear morphogenesis. Biallelic expression of Chd7 and Tbx1 specifically in the pharyngeal ectoderm (not neural crest) is required for normal great vessel development.","method":"Mouse genetic epistasis (double heterozygote cross); tissue-specific Cre rescue (neural crest vs. pharyngeal ectoderm); paint-filling of pharyngeal arch arteries","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic epistasis with tissue-specific Cre rescue, multiple phenotypic readouts, single lab with thorough controls","pmids":["19855134"],"is_preprint":false},{"year":2015,"finding":"CHD7 is required to maintain neural stem cell quiescence in the hippocampus; inducible CHD7 inactivation in adult NSCs causes loss of quiescence, transient increase in cell divisions, followed by NSC depletion in middle-aged mice. CHD7 represses positive regulators of cell cycle progression and is required for full induction of the Notch target gene Hes5 in quiescent NSCs.","method":"Inducible conditional KO in mice (adult NSC-specific Cre); BrdU pulse-chase; immunofluorescence; gene expression analysis of Hes5 and cell cycle genes","journal":"Stem cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — inducible conditional KO with defined NSC quiescence phenotype and molecular readout (Hes5, cell cycle gene expression); single lab","pmids":["25183173"],"is_preprint":false},{"year":2014,"finding":"CHD7 and retinoic acid (RA) signaling cooperate in a common pathway: CHD7 directly binds and represses the RA synthesis gene Aldh1a3; loss of Aldh1a3 partially rescues Chd7 mutant mouse inner ear defects. CHD7 loss causes cell-autonomous proliferative, neurogenic, and self-renewal defects in the perinatal and mature SVZ stem cell niche.","method":"Conditional KO mouse models (Chd7); ChIP for CHD7 at Aldh1a3 locus; genetic rescue (Aldh1a3 loss in Chd7 mutant background); in vitro RA modulation of neural stem cells","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP, genetic epistasis rescue, conditional KO, in vitro modulation; multiple orthogonal methods establishing direct regulatory relationship","pmids":["24026680"],"is_preprint":false},{"year":2022,"finding":"Conditional knockout of Chd7 in bone marrow mesenchymal stem cells/preosteoblasts leads to enhanced PPAR-γ signaling; loss of Chd7 reduces restriction of PPAR-γ, which then associates with H3K4me3 marks to activate downstream adipogenic gene transcription, disrupting osteogenic/adipogenic balance.","method":"Conditional KO in mice (MSC/preosteoblast-specific Cre); RNA-seq; ChIP (H3K4me3, PPAR-γ binding); in vitro differentiation assays; loss-of-function and rescue experiments","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with RNA-seq, ChIP for PPAR-γ and H3K4me3, multiple orthogonal methods establishing mechanistic link","pmids":["35418650"],"is_preprint":false},{"year":2016,"finding":"CHD7 interacts with SMAD1, a downstream effector of BMP signaling, in mesenchymal stem cells; BMP2 stimulates binding of CHD7 to the enhancer region of SP7 (Osterix), promoting osteogenic differentiation. CHD7 depletion inhibits key osteogenic transcription factors and impairs osteogenic capability of MSCs.","method":"Co-immunoprecipitation (CHD7–SMAD1); ChIP (CHD7 at SP7 enhancer after BMP2 treatment); siRNA knockdown; overexpression; in vivo scaffold assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP and ChIP establishing direct interaction and genomic binding, with functional loss/gain-of-function; single lab","pmids":["27586276"],"is_preprint":false},{"year":2012,"finding":"FAM124B is a novel component of a CHD7- and CHD8-containing complex; identified by SILAC mass spectrometry and confirmed by co-immunoprecipitation. FAM124B shows direct binding to CHD8 by yeast two-hybrid. FAM124B is a nuclear protein with overlapping embryonic expression with Chd7.","method":"SILAC mass spectrometry; co-immunoprecipitation; direct yeast two-hybrid; immunofluorescence (nuclear localization); in situ hybridization (mouse expression)","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — SILAC MS plus Co-IP plus yeast two-hybrid; interaction confirmed by multiple methods but functional consequence not deeply characterized","pmids":["23285124"],"is_preprint":false},{"year":2020,"finding":"CHD7 physically interacts with RUNX1 and suppresses RUNX1-induced expansion of hematopoietic stem and progenitor cells during development. CHD7 occupancy correlates with RUNX1 binding motifs genome-wide; decreased RUNX1 occupancy correlates with loss of CHD7 localization. CHD7 loss leads to expanded HSPCs, erythroid, and myeloid lineages in zebrafish and mouse embryos.","method":"Co-immunoprecipitation (CHD7–RUNX1); ChIP-seq; genetic KO in zebrafish and mouse (conditional); flow cytometry of hematopoietic populations","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, ChIP-seq, genetic KO in two model organisms, multiple orthogonal methods; replicated across labs (corroborated by Zhen et al. 2017)","pmids":["32883883"],"is_preprint":false},{"year":2017,"finding":"CHD7 interacts with CBFβ-SMMHC through RUNX1 and enhances transcriptional activity of RUNX1 and CBFβ-SMMHC on the Csf1r target gene. CHD7 deficiency delays CBFB-MYH11-induced leukemia and alters expression of RUNX1 target genes.","method":"Co-immunoprecipitation; reporter transcription assays; RNA-seq; conditional KO mouse (Mx1-Cre); BrdU proliferation assay","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP and transcriptional reporter assays with in vivo genetic validation; single lab","pmids":["29018080"],"is_preprint":false},{"year":2018,"finding":"CHD7 is required for epigenetic activation of superenhancers and CNS-specific enhancers in human neuroepithelial cells, maintaining NE and CNS lineage identity. CHD7 shapes cellular identity by activating BRN2 and SOX21 as downstream effectors via superenhancer interactions. Loss of CHD7 causes neuroepithelial-to-neural crest cell fate shift.","method":"CHARGE patient-derived iPSCs; H3K27ac ChIP-seq (superenhancer mapping); siRNA knockdown in human NE cells; transcriptome profiling; BRN2 and SOX21 functional rescue","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — patient-derived cells plus ChIP-seq plus functional rescue, multiple orthogonal methods in one study","pmids":["29440260"],"is_preprint":false},{"year":2017,"finding":"Chd7 forms a complex with Sox2 in oligodendrocyte precursor cells and together they bind the promoters/enhancers of Rgcc and PKCθ to induce their expression, promoting OPC proliferation after spinal cord injury. Ablation of Chd7 or Sox2 in OPCs leads to similar phenotypes (reduced proliferation, loss of OPC identity). Overexpression of Rgcc and PKCθ rescues Chd7 deletion phenotypes.","method":"OPC-specific Cre KO in mice; co-immunoprecipitation (Chd7–Sox2); ChIP at Rgcc and PKCθ loci; overexpression rescue; in vitro OPC culture","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, ChIP, genetic KO, overexpression rescue; single lab with multiple methods","pmids":["28931573"],"is_preprint":false},{"year":2021,"finding":"CHD7 directly activates paqr3b expression in GABAergic neuron progenitors; loss of CHD7 downregulates paqr3b and causes upregulation of MAPK/ERK signaling. CHD7 deficiency leads to fewer GABAergic neurons and hyperactivity behavior in zebrafish. Ephedrine restores MAPK/ERK signaling and rescues GABAergic defects in chd7−/− zebrafish.","method":"chd7 knockout zebrafish; ChIP (CHD7 at paqr3b locus); transcriptomics; pharmacological rescue with ephedrine; C. elegans phenotype-based screen","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — ChIP establishing direct target, KO phenotype, pharmacological rescue; single lab","pmids":["33900016"],"is_preprint":false},{"year":2013,"finding":"Morpholino knockdown of chd7 in zebrafish elevates expression of cell-cycle inhibitors (p16/p15, p21, p27) with concomitant reduced cell proliferation and defects in neural crest-derived craniofacial cartilage. Knockdown of the histone demethylase fbxl10/kdm2bb (a repressor of rRNA genes) rescues chd7 morphant CHARGE-like phenotypes, placing CHD7 in a genetic pathway with rDNA regulation.","method":"Morpholino knockdown in zebrafish; genetic epistasis (double knockdown rescue); cell proliferation assays; gene expression analysis; cartilage staining","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — zebrafish genetic epistasis with clean phenotypic rescue, multiple phenotypic readouts; single lab","pmids":["23920116"],"is_preprint":false},{"year":2015,"finding":"CHD7 localizes to the Sema3c promoter in vivo in the cardiogenic mesoderm and its loss alters local chromatin structure at this locus, suggesting direct transcriptional regulation. Conditional deletion of Chd7 in Mesp1-expressing anterior mesoderm causes major structural cardiovascular defects, loss of cardiac innervation, and aberrant expression of Class 3 Semaphorin and Slit-Robo signaling pathway genes. CHD7 also regulates calcium handling genes in cardiomyocytes, with a functional defect in excitation-contraction coupling.","method":"Mesp1-Cre conditional KO in mice; ChIP (CHD7 at Sema3c promoter); chromatin structure analysis; genome-wide transcriptional profiling; functional excitation-contraction coupling assay","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with ChIP, chromatin structure analysis, genome-wide profiling, and functional readout; multiple orthogonal methods","pmids":["26102480"],"is_preprint":false},{"year":2022,"finding":"In human pluripotent stem cell-derived inner ear organoids, loss of CHD7 or its chromatin remodeling activity leads to complete absence of hair cells and supporting cells via dysregulation of key otic development-associated genes in otic progenitors. CHD7 can also regulate otic genes through a chromatin remodeling-independent mechanism. Co-differentiating CHD7 KO and wild-type cells in chimeric organoids partially rescues mutant phenotypes by restoring otic gene expression.","method":"Human PSC-derived inner ear organoids; CRISPR KO and ATPase-dead CHD7 mutant; transcriptome profiling (RNA-seq); chimeric organoid rescue assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — human organoid model with CRISPR KO and catalytic mutant, transcriptomics, chimeric rescue; multiple orthogonal methods in one study","pmids":["36396635"],"is_preprint":false},{"year":2024,"finding":"CHD7 regulates Sox2 expression in the otocyst and acts early in a gene regulatory network controlling key otic patterning genes including Pax2 and Otx2. CHD7 and SOX2 independently and cooperatively bind at transcription start sites and enhancers to regulate otic progenitor gene expression. Combined haploinsufficiency for Chd7 and Sox2 results in reduced otic cell proliferation, severe semicircular canal malformations, and shortened cochleae with ectopic hair cells.","method":"Variable dosage Chd7/Sox2 mouse genetics; CUT&Tag (genome-wide binding profiling); RNA-seq; inducible conditional KO (critical period ~E9.5 identified)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — CUT&Tag, RNA-seq, multiple genetic models, critical period determination; multiple orthogonal methods in one rigorous study","pmids":["38408234"],"is_preprint":false},{"year":2016,"finding":"CHD7, Oct3/4, Sox2, and Nanog co-occupy multiple conserved regulatory regions (mE1, mE2, mE3) of the FoxD3 locus in mouse neural crest cells in response to BMP2/Wnt3a signaling, directly inducing FoxD3 expression. Histone H3K4 mono- and trimethylation at these elements is required for FoxD3 activation. FoxD3 in turn promotes Sox10 expression, regulating neural crest-derived stem cell formation.","method":"ChIP (CHD7, Oct3/4, Sox2, Nanog at FoxD3 regulatory elements); siRNA knockdown; histone methylation inhibition; expression analysis","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — ChIP at specific loci plus siRNA plus histone modification inhibition; single lab, mechanistic pathway placement","pmids":["27579714"],"is_preprint":false},{"year":2012,"finding":"In a Chd7 mutant mouse (COA1 nonsense mutation), CHD7 directly regulates Bmp4 expression by binding to an enhancer element downstream of the Bmp4 locus. Loss of CHD7 leads to misexpression (both downregulation and ectopic expansion) of Bmp4 in the forebrain, resulting in telencephalic midline developmental defects including corpus callosum crossing failure.","method":"Chd7 mutant mouse model; in vitro CHD7 binding to Bmp4 enhancer; in situ hybridization; immunohistochemistry; apoptosis analysis","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — in vitro enhancer binding plus in vivo mouse mutant analysis; single lab, partial mechanistic follow-up","pmids":["22658483"],"is_preprint":false},{"year":2021,"finding":"Embryonic deletion of CHD7 in auditory neurons or hair cells leads to postnatal sensorineural hearing loss due to degeneration. Mechanistically, CHD7 controls expression of major stress pathway components; in CHD7-deficient hair cells, exposure to stress inducers triggers rapid death, suggesting sound at hearing onset triggers their degeneration.","method":"Conditional KO in mice (auditory neuron-specific and hair cell-specific Cre); auditory brainstem response testing; stress-inducer exposure assays; gene expression analysis of stress pathway components","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with functional phenotype and gene expression evidence for stress pathway control; single lab","pmids":["34732824"],"is_preprint":false},{"year":2020,"finding":"let-7 microRNAs directly repress CHD7 expression via a conserved let-7-5p-binding site in the CHD7/Chd7 3'UTR, identified in chicken, mouse, and human. let-7g overexpression in mice reduces CHD7 protein in developing inner ear, retina, and brain, identifying CHD7 as a mediator of let-7's role in auditory sensory progenitor differentiation control.","method":"let-7 sponge construct in chicken basilar papilla; let-7b overexpression; let-7g overexpression in mice; immunofluorescence for CHD7 protein; conserved binding site identification","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct experimental manipulation (sponge and overexpression) plus protein-level readout in two species; single lab","pmids":["32816902"],"is_preprint":false},{"year":2019,"finding":"Drosophila Kismet (CHD7/CHD8 ortholog) limits intestinal stem cell (ISC) number and proliferation. Kismet colocalizes genome-wide with the Trithorax-related/MLL3/4 modifier in ISCs and co-regulates Cbl, a negative regulator of EGFR. Loss of kismet or trr leads to elevated EGFR protein and signaling, promoting ISC self-renewal.","method":"Drosophila genetics (kismet loss-of-function); stem-cell-specific ChIP-seq; RNA-seq; EGFR protein level measurement; genetic epistasis","journal":"Developmental cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Drosophila ortholog study, ChIP-seq and genetic epistasis; relevant to understanding mammalian CHD7 but in invertebrate model","pmids":["31112698"],"is_preprint":false},{"year":2014,"finding":"CHD7 silencing in pancreatic ductal adenocarcinoma cells impairs ATR-dependent phosphorylation of CHK1, suggesting CHD7 participates in the ATR-CHK1 DNA damage response pathway. CHD7 depletion sensitizes PDAC cells to gemcitabine and delays tumor growth in xenografts.","method":"siRNA knockdown in PDAC cell lines; ATR-CHK1 phosphorylation assay (western blot); xenograft tumor growth assay; synthetic lethal screen","journal":"Cancer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single cell-line knockdown with western blot readout for pathway; mechanism is inferred from indirect phosphorylation change, not directly reconstituted","pmids":["24626090"],"is_preprint":false}],"current_model":"CHD7 is an ATP-dependent chromodomain helicase DNA-binding protein that functions as a nucleosome remodeling factor with biochemical properties distinct from SWI/SNF and ISWI remodelers; it localizes to cell-type-specific enhancers marked by H3K4 methylation, where it opens chromatin to activate lineage-specific transcriptional programs, and additionally regulates rDNA transcription in the nucleolus, participates in non-homologous end-joining DNA repair by recruiting HDAC1/2 to break sites, interacts with partners including SOX2, SOX10, PBAF, WDR5/H3K4 methyltransferase complexes, RUNX1, SMAD1, and CHD8 to control neural crest formation, CNS myelination, neurogenesis, hematopoiesis, and inner ear development, and can regulate gene expression through both ATPase-dependent chromatin remodeling and ATPase-independent recruitment of histone-modifying enzymes."},"narrative":{"mechanistic_narrative":"CHD7 is an ATP-dependent nucleosome remodeling factor with biochemical properties distinct from SWI/SNF- and ISWI-type remodelers, and patient-derived CHARGE syndrome mutations range from subtle to complete inactivation of this remodeling activity [PMID:23134727]. It binds discrete, cell-type-specific chromatin sites distal to transcription start sites that correlate with H3K4 methylation and DNase hypersensitivity, functioning predominantly at enhancers and super-enhancers where it promotes chromatin accessibility, active histone marks (H3K27ac, H3K4me1), and RNA Pol II recruitment to activate lineage-specific transcription [PMID:19251738, PMID:34588434, PMID:29440260]. CHD7 directs cell-fate decisions across multiple developmental programs largely by partnering with sequence-specific transcription factors: it cooperates with the PBAF complex at neural crest enhancers (SOX9, TWIST1) to drive neural crest formation [PMID:20130577], with SOX2 in neural stem cells and the otocyst to co-regulate otic and neurogenic targets [PMID:21532573, PMID:38408234], with SOX10 at myelinogenic enhancers in oligodendrocyte precursors [PMID:26928066], with SMAD1 downstream of BMP signaling at the SP7/Osterix enhancer in osteogenesis [PMID:27586276], and with RUNX1 to restrain hematopoietic stem/progenitor expansion [PMID:32883883]. Across neural lineages it maintains open chromatin at specific targets including Sox4/Sox11, Reln, and Aldh1a3 to control neuronal differentiation, cerebellar granule cell development, and neural stem cell quiescence [PMID:23827709, PMID:28165338, PMID:24026680, PMID:25183173]. CHD7 acts through both ATPase-dependent remodeling and an ATPase-independent mode that recruits H3K4 methyltransferase activity via direct interaction with WDR5 [PMID:33127760]. Beyond transcriptional enhancer control, CHD7 localizes to the nucleolus where it binds hypomethylated active rDNA to promote 45S pre-rRNA synthesis [PMID:20591827], and is recruited by PARP1 to DNA double-strand breaks where it relaxes chromatin and recruits HDAC1/2 to promote canonical non-homologous end-joining [PMID:33188175]. CHD7 directly interacts with the related remodeler CHD8, and CHARGE-associated missense mutations disrupt this interaction [PMID:20453063].","teleology":[{"year":2009,"claim":"Establishing where CHD7 acts in the genome was the first step toward defining its function; mapping showed it occupies cell-type-specific enhancer-like sites that track with H3K4 methylation.","evidence":"ChIP-chip across multiple human and mouse cell types before and after ES cell differentiation","pmids":["19251738"],"confidence":"High","gaps":["Did not establish what CHD7 does biochemically at these sites","Did not identify recruiting transcription factors"]},{"year":2009,"claim":"Genetic interaction studies began to connect CHD7 dosage to specific developmental defects, showing a synergistic requirement with Tbx1 in pharyngeal ectoderm for great vessel development.","evidence":"Mouse double-heterozygote epistasis with tissue-specific Cre rescue","pmids":["19855134"],"confidence":"High","gaps":["No molecular mechanism linking CHD7 and Tbx1","Direct chromatin targets unidentified"]},{"year":2010,"claim":"Identifying CHD7's protein partners and direct enhancer targets clarified how it activates lineage programs; CHD7 cooperates with PBAF at neural crest enhancers and ATPase activity is essential for neural crest transcription.","evidence":"Co-IP, ChIP at SOX9/TWIST1 enhancers, Xenopus knockdown and catalytic-mutant rescue, human neural crest assays","pmids":["20130577"],"confidence":"High","gaps":["Mechanism of PBAF cooperation not resolved","Generality beyond neural crest enhancers untested at the time"]},{"year":2010,"claim":"CHD7 was found to have a distinct nucleolar role; it binds active rDNA and promotes pre-rRNA synthesis, linking it to ribosome biogenesis and cell proliferation.","evidence":"Immunofluorescence/fractionation, ChIP, siRNA, overexpression, Chd7 mouse models","pmids":["20591827"],"confidence":"High","gaps":["Whether rDNA regulation requires remodeling ATPase activity not defined","Relationship to enhancer function unclear"]},{"year":2010,"claim":"A direct CHD7-CHD8 interaction was identified and shown to be disrupted by CHARGE missense mutations, suggesting a shared remodeler complex relevant to disease.","evidence":"Yeast two-hybrid, Co-IP, BiFC, missense mutation testing","pmids":["20453063"],"confidence":"Medium","gaps":["Mutation effect on interaction confirmed in Y2H but not in Co-IP","Functional consequence of the complex not defined"]},{"year":2011,"claim":"A SOX2 partnership was defined, showing CHD7 and SOX2 co-occupy and co-regulate shared targets in neural stem cells, with in vivo relevance to inner ear development.","evidence":"Sox2 pulldown/MS, ChIP-seq overlap, Co-IP, Chd7 haploinsufficient embryo expression","pmids":["21532573"],"confidence":"High","gaps":["Order of recruitment between CHD7 and SOX2 unresolved","Whether interaction is direct or complex-mediated unclear"]},{"year":2012,"claim":"Biochemical reconstitution proved CHD7 is itself an ATP-dependent nucleosome remodeler distinct from other families, and graded CHARGE mutations impair this activity to varying degrees.","evidence":"Purified recombinant CHD7 in vitro remodeling assays and patient-mutation mutagenesis","pmids":["23134727"],"confidence":"High","gaps":["Did not define in vivo substrates or directional outcome of remodeling","No structural model of the active enzyme"]},{"year":2012,"claim":"CHD7's complex composition was extended by identifying FAM124B as a CHD7/CHD8-associated nuclear protein with overlapping embryonic expression.","evidence":"SILAC MS, Co-IP, yeast two-hybrid, in situ hybridization","pmids":["23285124"],"confidence":"Medium","gaps":["Functional role of FAM124B in the complex uncharacterized","FAM124B binds CHD8 directly; direct contact with CHD7 not shown"]},{"year":2012,"claim":"Direct enhancer-level control of a developmental morphogen was demonstrated; CHD7 binds a Bmp4 enhancer and its loss misregulates Bmp4 to cause telencephalic midline defects.","evidence":"Chd7 mutant mouse, in vitro enhancer binding, in situ hybridization","pmids":["22658483"],"confidence":"Medium","gaps":["Binding shown in vitro; in vivo occupancy not established","Mechanism producing both loss and ectopic expression unexplained"]},{"year":2013,"claim":"CHD7 was shown to remodel specific promoters to an open state to drive neuronal differentiation, linking chromatin opening to a defined cellular phenotype.","evidence":"Conditional mouse KO, chromatin accessibility at Sox4/Sox11, neurosphere and differentiation assays, exercise rescue","pmids":["23827709"],"confidence":"Medium","gaps":["Direct vs indirect remodeling at these promoters not fully separated","Mechanism of exercise rescue unknown"]},{"year":2013,"claim":"Genetic epistasis in zebrafish placed CHD7 in a pathway with rDNA regulation, as knockdown of the rRNA repressor fbxl10/kdm2bb rescued CHARGE-like craniofacial phenotypes.","evidence":"Zebrafish morpholino knockdown, double-knockdown rescue, proliferation and cartilage assays","pmids":["23920116"],"confidence":"Medium","gaps":["Morpholino-based knockdown carries off-target risk","Direct molecular link between CHD7 and kdm2bb not shown"]},{"year":2014,"claim":"CHD7 was shown to repress retinoic acid synthesis through direct binding to Aldh1a3, integrating it with RA signaling in stem cell niches and inner ear development.","evidence":"Conditional KO, ChIP at Aldh1a3, genetic rescue by Aldh1a3 loss, in vitro RA modulation","pmids":["24026680"],"confidence":"High","gaps":["How CHD7 represses rather than activates this target mechanistically unresolved"]},{"year":2014,"claim":"A candidate role in the DNA damage response was raised, with CHD7 depletion impairing ATR-dependent CHK1 phosphorylation and sensitizing pancreatic cancer cells to gemcitabine.","evidence":"siRNA knockdown in PDAC cell lines, phospho-CHK1 western blot, xenografts","pmids":["24626090"],"confidence":"Low","gaps":["Mechanism inferred from a phosphorylation change in a single cell line, not reconstituted","No direct CHD7 role at ATR/CHK1 demonstrated"]},{"year":2015,"claim":"CHD7 was shown to maintain adult hippocampal NSC quiescence, repressing cell-cycle drivers and enabling full Hes5 induction, defining a stem-cell maintenance function.","evidence":"Inducible adult NSC-specific KO, BrdU pulse-chase, Hes5 and cell-cycle gene expression","pmids":["25183173"],"confidence":"Medium","gaps":["Direct chromatin targets for quiescence not mapped","Connection to Notch pathway mechanism incomplete"]},{"year":2015,"claim":"Direct cardiac enhancer regulation was demonstrated; CHD7 binds the Sema3c promoter in cardiogenic mesoderm and controls semaphorin/Slit-Robo and calcium-handling genes for cardiovascular development.","evidence":"Mesp1-Cre conditional KO, ChIP at Sema3c, chromatin structure and transcriptome profiling, excitation-contraction assay","pmids":["26102480"],"confidence":"High","gaps":["Partner transcription factors at cardiac enhancers not identified here"]},{"year":2016,"claim":"A SOX10 partnership in oligodendrocyte precursors was established, defining CHD7's role in CNS myelination through enhancer targeting of myelinogenic genes.","evidence":"Co-IP, ChIP-seq, RNA-seq, conditional KO in mice","pmids":["26928066"],"confidence":"High","gaps":["Whether SOX10 recruits CHD7 or vice versa not resolved"]},{"year":2016,"claim":"CHD7 was linked to BMP-driven osteogenesis via a SMAD1 interaction and BMP2-stimulated binding to the SP7/Osterix enhancer.","evidence":"Co-IP, ChIP at SP7 enhancer after BMP2, siRNA, overexpression, in vivo scaffold assay","pmids":["27586276"],"confidence":"Medium","gaps":["Whether SMAD1-CHD7 interaction is direct not established","Single-lab data"]},{"year":2016,"claim":"CHD7 was placed in a pluripotency-factor regulatory module at the FoxD3 locus, co-occupying enhancers with Oct3/4, Sox2, and Nanog and requiring H3K4 methylation for neural crest gene activation.","evidence":"ChIP at FoxD3 regulatory elements, siRNA, histone methylation inhibition","pmids":["27579714"],"confidence":"Medium","gaps":["Direct physical interactions among these factors not shown","Single-lab study"]},{"year":2017,"claim":"Comparative biochemistry distinguished CHD6/7/8 remodeling activities, showing CHD7 prefers short linker DNA and slides nucleosomes differently than CHD8, providing a basis for their non-redundant roles.","evidence":"In vitro binding and sliding assays with purified CHD6, CHD7, CHD8","pmids":["28533432"],"confidence":"High","gaps":["In vivo correlation of these biochemical preferences not demonstrated"]},{"year":2017,"claim":"CHD7 was shown to open chromatin for cerebellar granule neuron differentiation, cooperating with Top2b to transcribe long neuronal genes.","evidence":"Conditional KO, ATAC-seq, RNA-seq, Top2b co-dependence analysis","pmids":["28317875"],"confidence":"High","gaps":["Molecular nature of CHD7-Top2b functional cooperation not detailed"]},{"year":2017,"claim":"A specific direct target, Reln, was identified as CHD7-dependent in cerebellar granule cell progenitors, with genetic rescue confirming its role in the proliferative defect.","evidence":"Conditional KO, chromatin accessibility at Reln, genetic rescue","pmids":["28165338"],"confidence":"High","gaps":["How CHD7 selects this locus among many enhancers unresolved"]},{"year":2017,"claim":"A CHD7-Sox2 complex was shown to drive OPC proliferation after spinal cord injury via Rgcc and PKCθ, extending the SOX2 partnership to injury repair.","evidence":"OPC-specific KO, Co-IP, ChIP at Rgcc/PKCθ, overexpression rescue","pmids":["28931573"],"confidence":"Medium","gaps":["Single lab","Directness of CHD7-Sox2 contact not biochemically resolved"]},{"year":2017,"claim":"An oncogenic-cofactor role in leukemia was identified; CHD7 interacts with CBFβ-SMMHC through RUNX1 and enhances RUNX1 target transcription, with CHD7 loss delaying CBFB-MYH11 leukemia.","evidence":"Co-IP, reporter assays, RNA-seq, conditional KO mouse, proliferation assay","pmids":["29018080"],"confidence":"Medium","gaps":["Single lab","Mechanism of transcriptional enhancement not fully defined"]},{"year":2018,"claim":"Using CHARGE patient iPSCs, CHD7 was shown to activate super-enhancers maintaining neuroepithelial/CNS identity, with its loss causing a fate shift to neural crest.","evidence":"Patient iPSCs, H3K27ac ChIP-seq, siRNA, transcriptome profiling, BRN2/SOX21 rescue","pmids":["29440260"],"confidence":"High","gaps":["Mechanism by which CHD7 selects super-enhancers not defined"]},{"year":2020,"claim":"CHD7 was placed in DNA double-strand break repair; PARP1 recruits CHD7, which relaxes chromatin and recruits HDAC1/2 to promote canonical NHEJ, with loss shifting repair to mutagenic 53BP1-dependent NHEJ.","evidence":"Live-cell imaging of recruitment, Co-IP with HDAC1/2, ChIP at breaks, NHEJ assays, 53BP1 epistasis","pmids":["33188175"],"confidence":"High","gaps":["Whether DSB recruitment uses the same domains as transcriptional targeting unknown"]},{"year":2020,"claim":"The ATPase-independent mode of CHD7 was defined; it directly binds WDR5 and an ATPase-dead knock-in still recruits H3K4 methyltransferase activity, separating remodeling from histone-modification recruitment.","evidence":"Protein-array screen, Co-IP, ATPase-dead knock-in mouse, ChIP for H3K4me, RNA-seq","pmids":["33127760"],"confidence":"High","gaps":["Which target genes depend on each mode not comprehensively mapped"]},{"year":2020,"claim":"A RUNX1 partnership in development was established showing CHD7 restrains hematopoietic stem/progenitor expansion, with genome-wide co-occupancy at RUNX1 motifs.","evidence":"Co-IP, ChIP-seq, conditional KO in zebrafish and mouse, hematopoietic flow cytometry","pmids":["32883883"],"confidence":"High","gaps":["Mechanism of repression of RUNX1-driven expansion not fully defined"]},{"year":2020,"claim":"CHD7 was identified as a let-7 microRNA target, defining a post-transcriptional control layer regulating CHD7 protein in sensory progenitor differentiation.","evidence":"let-7 sponge and overexpression in chicken and mouse, conserved 3'UTR site, CHD7 protein immunofluorescence","pmids":["32816902"],"confidence":"Medium","gaps":["Physiological dynamics of let-7-CHD7 regulation in normal development not quantified"]},{"year":2021,"claim":"CHD7 was shown to robustly establish active enhancer chromatin and coordinate topologically interacting gene expression in cerebellar granule cell precursors, connecting enhancer activation to 3D genome architecture.","evidence":"Conditional KO, ATAC-seq, ChIP-seq (H3K27ac, H3K4me1, Pol II), Hi-C, division-orientation analysis","pmids":["34588434"],"confidence":"High","gaps":["Direct role of CHD7 in shaping genome topology vs downstream consequence unresolved"]},{"year":2021,"claim":"A direct target, paqr3b, was identified in GABAergic neuron progenitors, with CHD7 loss elevating MAPK/ERK signaling and a pharmacological rescue restoring the phenotype.","evidence":"chd7 KO zebrafish, ChIP at paqr3b, transcriptomics, ephedrine rescue, C. elegans screen","pmids":["33900016"],"confidence":"Medium","gaps":["Single lab","Conservation of the paqr3b axis to mammals not tested"]},{"year":2021,"claim":"CHD7 was shown to protect auditory neurons and hair cells postnatally by controlling stress pathway gene expression, explaining sensorineural hearing loss as stress-triggered degeneration.","evidence":"Cell-type-specific conditional KO, auditory brainstem response, stress-inducer assays, expression analysis","pmids":["34732824"],"confidence":"Medium","gaps":["Direct CHD7 targets among stress genes not mapped","Single lab"]},{"year":2022,"claim":"A metabolic/lineage-balance role was defined; loss of CHD7 in mesenchymal progenitors de-represses PPAR-γ, which engages H3K4me3 to activate adipogenesis at the expense of osteogenesis.","evidence":"Conditional KO, RNA-seq, ChIP for PPAR-γ and H3K4me3, differentiation and rescue assays","pmids":["35418650"],"confidence":"High","gaps":["Direct vs indirect restraint of PPAR-γ by CHD7 not resolved"]},{"year":2022,"claim":"Human inner ear organoids showed CHD7 and its remodeling activity are essential for hair cell and supporting cell formation, while a remodeling-independent mode also regulates otic genes, with non-cell-autonomous partial rescue.","evidence":"Human PSC organoids, CRISPR KO and ATPase-dead mutant, RNA-seq, chimeric rescue","pmids":["36396635"],"confidence":"High","gaps":["Identity of the remodeling-independent mechanism in otic cells unresolved","Basis of non-cell-autonomous rescue unknown"]},{"year":2024,"claim":"The CHD7-SOX2 partnership was resolved at the gene-regulatory-network level in the otocyst, with both factors binding independently and cooperatively to control otic patterning genes during a defined critical period.","evidence":"Variable-dosage Chd7/Sox2 mouse genetics, CUT&Tag, RNA-seq, inducible KO defining E9.5 critical period","pmids":["38408234"],"confidence":"High","gaps":["Structural basis of cooperative vs independent binding not addressed"]},{"year":null,"claim":"How CHD7 is targeted to specific enhancers and super-enhancers in different cell types, and how it allocates between its ATPase-dependent remodeling and ATPase-independent histone-modifier recruitment modes at each target, remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of CHD7 engaging a nucleosome or partner factor","Rules governing choice of remodeling vs recruitment mode at a given locus undefined","Determinants of cell-type-specific recruitment not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[3,13]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,22,26]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[4,26,30]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3,13]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[10,11]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,19]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[4]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[1,12]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[1,3,12,22]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2,26]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,6,14,28]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[10]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[4]}],"complexes":["PBAF","CHD7-CHD8 complex"],"partners":["SOX2","SOX10","CHD8","WDR5","RUNX1","SMAD1","HDAC1","FAM124B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9P2D1","full_name":"ATP-dependent chromatin remodeler CHD7","aliases":["Chromo domain-containing protein 7","CHD-7"],"length_aa":2997,"mass_kda":335.9,"function":"ATP-dependent chromatin-remodeling factor, slides nucleosomes along DNA; nucleosome sliding requires ATP (PubMed:28533432). Probable transcription regulator. May be involved in the in 45S precursor rRNA production","subcellular_location":"Nucleus, nucleolus","url":"https://www.uniprot.org/uniprotkb/Q9P2D1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CHD7","classification":"Not Classified","n_dependent_lines":36,"n_total_lines":1208,"dependency_fraction":0.029801324503311258},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"FKBP5","stoichiometry":10.0},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"PARP1","stoichiometry":0.2},{"gene":"PTGES3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CHD7","total_profiled":1310},"omim":[{"mim_id":"621249","title":"ARB2 COTRANSCRIPTIONAL REGULATOR A; ARB2A","url":"https://www.omim.org/entry/621249"},{"mim_id":"618403","title":"FAMILY WITH SEQUENCE SIMILARITY 124, MEMBER B; FAM124B","url":"https://www.omim.org/entry/618403"},{"mim_id":"617159","title":"SIFRIM-HITZ-WEISS SYNDROME; SIHIWES","url":"https://www.omim.org/entry/617159"},{"mim_id":"615369","title":"DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 94; DEE94","url":"https://www.omim.org/entry/615369"},{"mim_id":"612370","title":"HYPOGONADOTROPIC HYPOGONADISM 5 WITH OR WITHOUT ANOSMIA; HH5","url":"https://www.omim.org/entry/612370"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":28.5}],"url":"https://www.proteinatlas.org/search/CHD7"},"hgnc":{"alias_symbol":["KIAA1416","FLJ20357","FLJ20361"],"prev_symbol":["CRG"]},"alphafold":{"accession":"Q9P2D1","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P2D1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P2D1-4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P2D1-4-F1-predicted_aligned_error_v6.png","plddt_mean":46.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CHD7","jax_strain_url":"https://www.jax.org/strain/search?query=CHD7"},"sequence":{"accession":"Q9P2D1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9P2D1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9P2D1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P2D1"}},"corpus_meta":[{"pmid":"20130577","id":"PMC_20130577","title":"CHD7 cooperates with PBAF to control multipotent neural crest formation.","date":"2010","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/20130577","citation_count":497,"is_preprint":false},{"pmid":"16155193","id":"PMC_16155193","title":"CHARGE syndrome: the phenotypic spectrum of mutations in the CHD7 gene.","date":"2005","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16155193","citation_count":313,"is_preprint":false},{"pmid":"16400610","id":"PMC_16400610","title":"Spectrum of CHD7 mutations in 110 individuals with CHARGE syndrome and genotype-phenotype correlation.","date":"2005","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16400610","citation_count":276,"is_preprint":false},{"pmid":"18834967","id":"PMC_18834967","title":"Mutations in CHD7, encoding a chromatin-remodeling protein, cause idiopathic hypogonadotropic hypogonadism and Kallmann syndrome.","date":"2008","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18834967","citation_count":241,"is_preprint":false},{"pmid":"20186815","id":"PMC_20186815","title":"Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome.","date":"2010","source":"American journal of medical genetics. 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development.","date":"2024","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/38408234","citation_count":11,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":48941,"output_tokens":9630,"usd":0.145637,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":20130,"output_tokens":8788,"usd":0.160175,"stage2_stop_reason":"end_turn"},"total_usd":0.305812,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"CHD7 associates with PBAF (polybromo- and BRG1-associated factor-containing complex) in human neural crest cells; both remodelers occupy a neural crest-specific distal SOX9 enhancer and a conserved element upstream of TWIST1, cooperating to promote neural crest gene expression and cell migration. Catalytically inactive CHD7 overexpression or CHD7 knockdown in Xenopus recapitulates CHARGE syndrome features, establishing CHD7 ATPase activity as essential for neural crest transcriptional circuitry (Sox9, Twist, Slug activation).\",\n      \"method\": \"Co-immunoprecipitation, ChIP, Xenopus loss-of-function (morpholino knockdown and catalytic mutant overexpression), human neural crest cell functional assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reciprocal Co-IP, ChIP at specific enhancers, catalytic mutant rescue, replicated in two model systems (Xenopus and human cells)\",\n      \"pmids\": [\"20130577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CHD7 localizes to discrete, cell-type-specific chromatin sites that correlate with histone H3K4 methylation (H3K4me); these sites are predominantly distal to transcription start sites, overlap with DNase hypersensitive sites, and shift concomitantly with H3K4me patterns during ES cell differentiation—consistent with CHD7 functioning at enhancer elements.\",\n      \"method\": \"ChIP-chip (chromatin immunoprecipitation on tiled microarrays) in human colorectal carcinoma cells, human neuroblastoma cells, and mouse ES cells before and after neural precursor differentiation\",\n      \"journal\": \"Genome research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-chip across multiple cell types and conditions in one rigorous study, correlated with H3K4me dynamics\",\n      \"pmids\": [\"19251738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CHD7 physically interacts with the HMG-box transcription factor SOX2 in neural stem cells; the two proteins have overlapping genome-wide binding sites and co-regulate a common set of target genes including Jag1, Gli3, and Mycn. Chd7-haploinsufficient embryos show severely reduced Jag1 expression in the developing inner ear.\",\n      \"method\": \"Proteomic interaction screen (Sox2 pulldown + mass spectrometry), genome-wide ChIP (ChIP-seq), co-immunoprecipitation, expression analysis in Chd7 haploinsufficient embryos\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, genome-wide ChIP-seq overlap, confirmed in vivo phenotype; multiple orthogonal methods in one study\",\n      \"pmids\": [\"21532573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Purified recombinant CHD7 is an ATP-dependent nucleosome remodeling factor with biochemical characteristics distinct from SWI/SNF- and ISWI-type remodelers. Patient-derived CHARGE syndrome mutations have consequences ranging from subtle to complete inactivation of remodeling activity; truncations upstream of amino acid 1899 likely cause a hypomorphic remodeling phenotype.\",\n      \"method\": \"Dual-tag purification of intact recombinant CHD7; in vitro nucleosome remodeling assays; mutagenesis analysis of patient mutations\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical reconstitution with purified protein, mutagenesis of multiple disease alleles, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"23134727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CHD7 localizes constitutively to the nucleolus and physically associates with hypomethylated, actively transcribed rDNA. siRNA-mediated depletion of CHD7 causes hypermethylation of the rDNA promoter and reduction of 45S pre-rRNA levels, while CHD7 overexpression increases 45S pre-rRNA. CHD7 depletion also reduces cell proliferation and protein synthesis. Reduced pre-rRNA is observed in Chd7+/− and Chd7−/− mouse ES cells and embryos.\",\n      \"method\": \"Immunofluorescence and subcellular fractionation western blot; ChIP (standard and ChIP-chop); ChIP-seq rDNA alignment; siRNA knockdown; CHD7 overexpression; Chd7 mouse genetic models\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (immunofluorescence, fractionation, ChIP, siRNA, overexpression, in vivo mouse models) in one rigorous study\",\n      \"pmids\": [\"20591827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CHD7 interacts directly with CHD8; the interaction was identified by yeast two-hybrid screen and confirmed by co-immunoprecipitation and bimolecular fluorescence complementation. Specific CHARGE syndrome missense mutations in CHD7 (p.Trp2091Arg, p.His2096Arg, p.Gly2108Arg) disrupt the direct CHD7–CHD8 interaction in yeast two-hybrid assays.\",\n      \"method\": \"Yeast two-hybrid library screen and direct yeast two-hybrid; co-immunoprecipitation; bimolecular fluorescence complementation; missense mutation functional testing\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — yeast two-hybrid plus Co-IP plus BiFC, single lab; disruption of direct interaction by patient mutations confirmed in one assay system but not fully confirmed in Co-IP\",\n      \"pmids\": [\"20453063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CHD7 directly interacts with SOX10 in oligodendrocyte precursors; genome-wide occupancy analysis coupled with transcriptome profiling shows that CHD7 targets the enhancers of key myelinogenic genes. Chd7 is a direct transcriptional target of Olig2 and Smarca4/Brg1. Loss of Chd7 impairs proper onset of CNS myelination and remyelination, with CHD7 also targeting bone formation regulators Osterix (Sp7) and Creb3l2 required for oligodendrocyte maturation.\",\n      \"method\": \"ChIP-seq (genome-wide occupancy), RNA-seq (transcriptome profiling), co-immunoprecipitation (CHD7–SOX10 interaction), conditional genetic knockout in mice\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, genome-wide ChIP-seq, transcriptomics, and conditional KO phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"26928066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CHD7 promotes transcription of Sox4 and Sox11 by remodeling their promoters to an open chromatin state in neural stem cells. Genetic inactivation of CHD7 in NSCs reduces neuronal differentiation and causes aberrant dendritic development of newborn neurons. Physical exercise rescues the CHD7 mutant phenotype in the adult hippocampal dentate gyrus.\",\n      \"method\": \"Conditional genetic knockout in mice; ATAC/chromatin accessibility assays at Sox4/Sox11 promoters; neurosphere assays; BrdU/EdU proliferation; in vivo rescue by exercise\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean conditional KO with defined phenotype, chromatin accessibility evidence at specific loci, single lab\",\n      \"pmids\": [\"23827709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CHD7 is required for maintenance of open chromatin and activation of genes essential for granule neuron differentiation; it cooperates with Top2b for transcription of long neuronal genes in cerebellar granule neurons. Genetic inactivation of Chd7 in cerebellar granule neuron progenitors causes cerebellar hypoplasia due to impaired differentiation and apoptosis.\",\n      \"method\": \"Conditional genetic knockout in mice; ATAC-seq (open chromatin profiling); RNA-seq; molecular analysis of Top2b co-dependence\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with ATAC-seq and RNA-seq, multiple orthogonal methods identifying mechanistic basis for chromatin opening and transcriptional control\",\n      \"pmids\": [\"28317875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CHD7 directly regulates Reln (reelin) expression by maintaining an open, accessible chromatin state at the Reln locus in cerebellar granule cell progenitors. Reduction in Reln expression contributes to GCP proliferative defects and cerebellar hypoplasia in Chd7 conditional mutant mice.\",\n      \"method\": \"Conditional knockout in mice; genome-wide expression profiling; chromatin accessibility assays at the Reln locus; genetic rescue by Reln expression\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO, chromatin accessibility at specific locus, molecular and genetic rescue, multiple orthogonal methods\",\n      \"pmids\": [\"28165338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CHD7 is recruited to DNA double-strand break sites via PARP1-triggered chromatin remodeling; it stimulates chromatin relaxation around break sites and recruits HDAC1/2 for localized chromatin de-acetylation. This coordinated 'chromatin breathing' fosters efficient non-homologous end-joining (NHEJ) by controlling Ku and LIG4/XRCC4 activities. Loss of CHD7-HDAC1/2-dependent canonical NHEJ shifts repair to 53BP1-dependent mutagenic NHEJ.\",\n      \"method\": \"Live-cell imaging of CHD7 recruitment to DSBs; co-immunoprecipitation (CHD7–HDAC1/2 interaction); ChIP at break sites; functional NHEJ assays; epistasis with 53BP1\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, ChIP, functional repair assays, epistasis), mechanistic pathway placement, single lab with rigorous controls\",\n      \"pmids\": [\"33188175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CHD7 directly interacts with WDR5, a core component of H3K4 methyltransferase complexes (identified by protein-array screen with recombinant CHD7). An ATPase-dead CHD7 knock-in mouse model retains the ability to recruit H3K4 methyltransferase activity to its target loci, demonstrating that CHD7 regulates cardiovascular development through both ATP-dependent (chromatin remodeling) and ATP-independent (recruitment of H3K4 methyltransferase activity) mechanisms.\",\n      \"method\": \"Protein-array screen with purified recombinant CHD7; Co-IP (CHD7–WDR5); ATPase-deficient knock-in mouse model; ChIP for H3K4me marks; RNA-seq in neural crest cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct protein-array interaction with recombinant protein, Co-IP confirmation, ATPase-dead knock-in mouse model, ChIP for histone marks; multiple orthogonal methods\",\n      \"pmids\": [\"33127760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CHD7 robustly promotes chromatin accessibility, active histone modifications (H3K27ac, H3K4me1), and RNA Pol II recruitment at enhancers in cerebellar granule cell precursors. In vivo genome architecture profiling shows CHD7 concordantly regulates epigenomic modifications and expression of topologically-interacting genes. Loss of CHD7 in GCPs triggers cerebellar polymicrogyria and alters preferred orientation of GCP division.\",\n      \"method\": \"Conditional KO in mice; ATAC-seq; ChIP-seq (H3K27ac, H3K4me1, Pol II); Hi-C genome architecture; cell division orientation analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with ATAC-seq, ChIP-seq, Hi-C, multiple orthogonal methods in one study; mechanistic link between enhancer activation and gene expression established\",\n      \"pmids\": [\"34588434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CHD7 and CHD8 exhibit distinct nucleosome remodeling activities: CHD7 binds with high affinity to short linker DNA whereas CHD8 requires longer linker DNA. As a result, CHD7 and CHD8 slide nucleosomes into different positions; CHD6 disrupts nucleosomes without sliding. These distinct biochemical activities likely underlie their non-redundant in vivo roles.\",\n      \"method\": \"In vitro biochemical assays with purified CHD6, CHD7, CHD8; nucleosome binding assays; nucleosome sliding assays on defined substrates\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with purified proteins, multiple substrate conditions, single lab but rigorous biochemical characterization\",\n      \"pmids\": [\"28533432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Chd7 and Tbx1 show a synergistic genetic interaction: Tbx1+/−;Chd7+/− double heterozygotes display synergistic defects in fourth pharyngeal arch artery, thymus, and ear morphogenesis. Biallelic expression of Chd7 and Tbx1 specifically in the pharyngeal ectoderm (not neural crest) is required for normal great vessel development.\",\n      \"method\": \"Mouse genetic epistasis (double heterozygote cross); tissue-specific Cre rescue (neural crest vs. pharyngeal ectoderm); paint-filling of pharyngeal arch arteries\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic epistasis with tissue-specific Cre rescue, multiple phenotypic readouts, single lab with thorough controls\",\n      \"pmids\": [\"19855134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CHD7 is required to maintain neural stem cell quiescence in the hippocampus; inducible CHD7 inactivation in adult NSCs causes loss of quiescence, transient increase in cell divisions, followed by NSC depletion in middle-aged mice. CHD7 represses positive regulators of cell cycle progression and is required for full induction of the Notch target gene Hes5 in quiescent NSCs.\",\n      \"method\": \"Inducible conditional KO in mice (adult NSC-specific Cre); BrdU pulse-chase; immunofluorescence; gene expression analysis of Hes5 and cell cycle genes\",\n      \"journal\": \"Stem cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — inducible conditional KO with defined NSC quiescence phenotype and molecular readout (Hes5, cell cycle gene expression); single lab\",\n      \"pmids\": [\"25183173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CHD7 and retinoic acid (RA) signaling cooperate in a common pathway: CHD7 directly binds and represses the RA synthesis gene Aldh1a3; loss of Aldh1a3 partially rescues Chd7 mutant mouse inner ear defects. CHD7 loss causes cell-autonomous proliferative, neurogenic, and self-renewal defects in the perinatal and mature SVZ stem cell niche.\",\n      \"method\": \"Conditional KO mouse models (Chd7); ChIP for CHD7 at Aldh1a3 locus; genetic rescue (Aldh1a3 loss in Chd7 mutant background); in vitro RA modulation of neural stem cells\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP, genetic epistasis rescue, conditional KO, in vitro modulation; multiple orthogonal methods establishing direct regulatory relationship\",\n      \"pmids\": [\"24026680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Conditional knockout of Chd7 in bone marrow mesenchymal stem cells/preosteoblasts leads to enhanced PPAR-γ signaling; loss of Chd7 reduces restriction of PPAR-γ, which then associates with H3K4me3 marks to activate downstream adipogenic gene transcription, disrupting osteogenic/adipogenic balance.\",\n      \"method\": \"Conditional KO in mice (MSC/preosteoblast-specific Cre); RNA-seq; ChIP (H3K4me3, PPAR-γ binding); in vitro differentiation assays; loss-of-function and rescue experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with RNA-seq, ChIP for PPAR-γ and H3K4me3, multiple orthogonal methods establishing mechanistic link\",\n      \"pmids\": [\"35418650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CHD7 interacts with SMAD1, a downstream effector of BMP signaling, in mesenchymal stem cells; BMP2 stimulates binding of CHD7 to the enhancer region of SP7 (Osterix), promoting osteogenic differentiation. CHD7 depletion inhibits key osteogenic transcription factors and impairs osteogenic capability of MSCs.\",\n      \"method\": \"Co-immunoprecipitation (CHD7–SMAD1); ChIP (CHD7 at SP7 enhancer after BMP2 treatment); siRNA knockdown; overexpression; in vivo scaffold assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP and ChIP establishing direct interaction and genomic binding, with functional loss/gain-of-function; single lab\",\n      \"pmids\": [\"27586276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"FAM124B is a novel component of a CHD7- and CHD8-containing complex; identified by SILAC mass spectrometry and confirmed by co-immunoprecipitation. FAM124B shows direct binding to CHD8 by yeast two-hybrid. FAM124B is a nuclear protein with overlapping embryonic expression with Chd7.\",\n      \"method\": \"SILAC mass spectrometry; co-immunoprecipitation; direct yeast two-hybrid; immunofluorescence (nuclear localization); in situ hybridization (mouse expression)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — SILAC MS plus Co-IP plus yeast two-hybrid; interaction confirmed by multiple methods but functional consequence not deeply characterized\",\n      \"pmids\": [\"23285124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CHD7 physically interacts with RUNX1 and suppresses RUNX1-induced expansion of hematopoietic stem and progenitor cells during development. CHD7 occupancy correlates with RUNX1 binding motifs genome-wide; decreased RUNX1 occupancy correlates with loss of CHD7 localization. CHD7 loss leads to expanded HSPCs, erythroid, and myeloid lineages in zebrafish and mouse embryos.\",\n      \"method\": \"Co-immunoprecipitation (CHD7–RUNX1); ChIP-seq; genetic KO in zebrafish and mouse (conditional); flow cytometry of hematopoietic populations\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, ChIP-seq, genetic KO in two model organisms, multiple orthogonal methods; replicated across labs (corroborated by Zhen et al. 2017)\",\n      \"pmids\": [\"32883883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CHD7 interacts with CBFβ-SMMHC through RUNX1 and enhances transcriptional activity of RUNX1 and CBFβ-SMMHC on the Csf1r target gene. CHD7 deficiency delays CBFB-MYH11-induced leukemia and alters expression of RUNX1 target genes.\",\n      \"method\": \"Co-immunoprecipitation; reporter transcription assays; RNA-seq; conditional KO mouse (Mx1-Cre); BrdU proliferation assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP and transcriptional reporter assays with in vivo genetic validation; single lab\",\n      \"pmids\": [\"29018080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CHD7 is required for epigenetic activation of superenhancers and CNS-specific enhancers in human neuroepithelial cells, maintaining NE and CNS lineage identity. CHD7 shapes cellular identity by activating BRN2 and SOX21 as downstream effectors via superenhancer interactions. Loss of CHD7 causes neuroepithelial-to-neural crest cell fate shift.\",\n      \"method\": \"CHARGE patient-derived iPSCs; H3K27ac ChIP-seq (superenhancer mapping); siRNA knockdown in human NE cells; transcriptome profiling; BRN2 and SOX21 functional rescue\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — patient-derived cells plus ChIP-seq plus functional rescue, multiple orthogonal methods in one study\",\n      \"pmids\": [\"29440260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Chd7 forms a complex with Sox2 in oligodendrocyte precursor cells and together they bind the promoters/enhancers of Rgcc and PKCθ to induce their expression, promoting OPC proliferation after spinal cord injury. Ablation of Chd7 or Sox2 in OPCs leads to similar phenotypes (reduced proliferation, loss of OPC identity). Overexpression of Rgcc and PKCθ rescues Chd7 deletion phenotypes.\",\n      \"method\": \"OPC-specific Cre KO in mice; co-immunoprecipitation (Chd7–Sox2); ChIP at Rgcc and PKCθ loci; overexpression rescue; in vitro OPC culture\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, ChIP, genetic KO, overexpression rescue; single lab with multiple methods\",\n      \"pmids\": [\"28931573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CHD7 directly activates paqr3b expression in GABAergic neuron progenitors; loss of CHD7 downregulates paqr3b and causes upregulation of MAPK/ERK signaling. CHD7 deficiency leads to fewer GABAergic neurons and hyperactivity behavior in zebrafish. Ephedrine restores MAPK/ERK signaling and rescues GABAergic defects in chd7−/− zebrafish.\",\n      \"method\": \"chd7 knockout zebrafish; ChIP (CHD7 at paqr3b locus); transcriptomics; pharmacological rescue with ephedrine; C. elegans phenotype-based screen\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — ChIP establishing direct target, KO phenotype, pharmacological rescue; single lab\",\n      \"pmids\": [\"33900016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Morpholino knockdown of chd7 in zebrafish elevates expression of cell-cycle inhibitors (p16/p15, p21, p27) with concomitant reduced cell proliferation and defects in neural crest-derived craniofacial cartilage. Knockdown of the histone demethylase fbxl10/kdm2bb (a repressor of rRNA genes) rescues chd7 morphant CHARGE-like phenotypes, placing CHD7 in a genetic pathway with rDNA regulation.\",\n      \"method\": \"Morpholino knockdown in zebrafish; genetic epistasis (double knockdown rescue); cell proliferation assays; gene expression analysis; cartilage staining\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — zebrafish genetic epistasis with clean phenotypic rescue, multiple phenotypic readouts; single lab\",\n      \"pmids\": [\"23920116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CHD7 localizes to the Sema3c promoter in vivo in the cardiogenic mesoderm and its loss alters local chromatin structure at this locus, suggesting direct transcriptional regulation. Conditional deletion of Chd7 in Mesp1-expressing anterior mesoderm causes major structural cardiovascular defects, loss of cardiac innervation, and aberrant expression of Class 3 Semaphorin and Slit-Robo signaling pathway genes. CHD7 also regulates calcium handling genes in cardiomyocytes, with a functional defect in excitation-contraction coupling.\",\n      \"method\": \"Mesp1-Cre conditional KO in mice; ChIP (CHD7 at Sema3c promoter); chromatin structure analysis; genome-wide transcriptional profiling; functional excitation-contraction coupling assay\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with ChIP, chromatin structure analysis, genome-wide profiling, and functional readout; multiple orthogonal methods\",\n      \"pmids\": [\"26102480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In human pluripotent stem cell-derived inner ear organoids, loss of CHD7 or its chromatin remodeling activity leads to complete absence of hair cells and supporting cells via dysregulation of key otic development-associated genes in otic progenitors. CHD7 can also regulate otic genes through a chromatin remodeling-independent mechanism. Co-differentiating CHD7 KO and wild-type cells in chimeric organoids partially rescues mutant phenotypes by restoring otic gene expression.\",\n      \"method\": \"Human PSC-derived inner ear organoids; CRISPR KO and ATPase-dead CHD7 mutant; transcriptome profiling (RNA-seq); chimeric organoid rescue assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human organoid model with CRISPR KO and catalytic mutant, transcriptomics, chimeric rescue; multiple orthogonal methods in one study\",\n      \"pmids\": [\"36396635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CHD7 regulates Sox2 expression in the otocyst and acts early in a gene regulatory network controlling key otic patterning genes including Pax2 and Otx2. CHD7 and SOX2 independently and cooperatively bind at transcription start sites and enhancers to regulate otic progenitor gene expression. Combined haploinsufficiency for Chd7 and Sox2 results in reduced otic cell proliferation, severe semicircular canal malformations, and shortened cochleae with ectopic hair cells.\",\n      \"method\": \"Variable dosage Chd7/Sox2 mouse genetics; CUT&Tag (genome-wide binding profiling); RNA-seq; inducible conditional KO (critical period ~E9.5 identified)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CUT&Tag, RNA-seq, multiple genetic models, critical period determination; multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"38408234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CHD7, Oct3/4, Sox2, and Nanog co-occupy multiple conserved regulatory regions (mE1, mE2, mE3) of the FoxD3 locus in mouse neural crest cells in response to BMP2/Wnt3a signaling, directly inducing FoxD3 expression. Histone H3K4 mono- and trimethylation at these elements is required for FoxD3 activation. FoxD3 in turn promotes Sox10 expression, regulating neural crest-derived stem cell formation.\",\n      \"method\": \"ChIP (CHD7, Oct3/4, Sox2, Nanog at FoxD3 regulatory elements); siRNA knockdown; histone methylation inhibition; expression analysis\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — ChIP at specific loci plus siRNA plus histone modification inhibition; single lab, mechanistic pathway placement\",\n      \"pmids\": [\"27579714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In a Chd7 mutant mouse (COA1 nonsense mutation), CHD7 directly regulates Bmp4 expression by binding to an enhancer element downstream of the Bmp4 locus. Loss of CHD7 leads to misexpression (both downregulation and ectopic expansion) of Bmp4 in the forebrain, resulting in telencephalic midline developmental defects including corpus callosum crossing failure.\",\n      \"method\": \"Chd7 mutant mouse model; in vitro CHD7 binding to Bmp4 enhancer; in situ hybridization; immunohistochemistry; apoptosis analysis\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — in vitro enhancer binding plus in vivo mouse mutant analysis; single lab, partial mechanistic follow-up\",\n      \"pmids\": [\"22658483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Embryonic deletion of CHD7 in auditory neurons or hair cells leads to postnatal sensorineural hearing loss due to degeneration. Mechanistically, CHD7 controls expression of major stress pathway components; in CHD7-deficient hair cells, exposure to stress inducers triggers rapid death, suggesting sound at hearing onset triggers their degeneration.\",\n      \"method\": \"Conditional KO in mice (auditory neuron-specific and hair cell-specific Cre); auditory brainstem response testing; stress-inducer exposure assays; gene expression analysis of stress pathway components\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with functional phenotype and gene expression evidence for stress pathway control; single lab\",\n      \"pmids\": [\"34732824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"let-7 microRNAs directly repress CHD7 expression via a conserved let-7-5p-binding site in the CHD7/Chd7 3'UTR, identified in chicken, mouse, and human. let-7g overexpression in mice reduces CHD7 protein in developing inner ear, retina, and brain, identifying CHD7 as a mediator of let-7's role in auditory sensory progenitor differentiation control.\",\n      \"method\": \"let-7 sponge construct in chicken basilar papilla; let-7b overexpression; let-7g overexpression in mice; immunofluorescence for CHD7 protein; conserved binding site identification\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct experimental manipulation (sponge and overexpression) plus protein-level readout in two species; single lab\",\n      \"pmids\": [\"32816902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Drosophila Kismet (CHD7/CHD8 ortholog) limits intestinal stem cell (ISC) number and proliferation. Kismet colocalizes genome-wide with the Trithorax-related/MLL3/4 modifier in ISCs and co-regulates Cbl, a negative regulator of EGFR. Loss of kismet or trr leads to elevated EGFR protein and signaling, promoting ISC self-renewal.\",\n      \"method\": \"Drosophila genetics (kismet loss-of-function); stem-cell-specific ChIP-seq; RNA-seq; EGFR protein level measurement; genetic epistasis\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Drosophila ortholog study, ChIP-seq and genetic epistasis; relevant to understanding mammalian CHD7 but in invertebrate model\",\n      \"pmids\": [\"31112698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CHD7 silencing in pancreatic ductal adenocarcinoma cells impairs ATR-dependent phosphorylation of CHK1, suggesting CHD7 participates in the ATR-CHK1 DNA damage response pathway. CHD7 depletion sensitizes PDAC cells to gemcitabine and delays tumor growth in xenografts.\",\n      \"method\": \"siRNA knockdown in PDAC cell lines; ATR-CHK1 phosphorylation assay (western blot); xenograft tumor growth assay; synthetic lethal screen\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single cell-line knockdown with western blot readout for pathway; mechanism is inferred from indirect phosphorylation change, not directly reconstituted\",\n      \"pmids\": [\"24626090\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CHD7 is an ATP-dependent chromodomain helicase DNA-binding protein that functions as a nucleosome remodeling factor with biochemical properties distinct from SWI/SNF and ISWI remodelers; it localizes to cell-type-specific enhancers marked by H3K4 methylation, where it opens chromatin to activate lineage-specific transcriptional programs, and additionally regulates rDNA transcription in the nucleolus, participates in non-homologous end-joining DNA repair by recruiting HDAC1/2 to break sites, interacts with partners including SOX2, SOX10, PBAF, WDR5/H3K4 methyltransferase complexes, RUNX1, SMAD1, and CHD8 to control neural crest formation, CNS myelination, neurogenesis, hematopoiesis, and inner ear development, and can regulate gene expression through both ATPase-dependent chromatin remodeling and ATPase-independent recruitment of histone-modifying enzymes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CHD7 is an ATP-dependent nucleosome remodeling factor with biochemical properties distinct from SWI/SNF- and ISWI-type remodelers, and patient-derived CHARGE syndrome mutations range from subtle to complete inactivation of this remodeling activity [#3]. It binds discrete, cell-type-specific chromatin sites distal to transcription start sites that correlate with H3K4 methylation and DNase hypersensitivity, functioning predominantly at enhancers and super-enhancers where it promotes chromatin accessibility, active histone marks (H3K27ac, H3K4me1), and RNA Pol II recruitment to activate lineage-specific transcription [#1, #12, #22]. CHD7 directs cell-fate decisions across multiple developmental programs largely by partnering with sequence-specific transcription factors: it cooperates with the PBAF complex at neural crest enhancers (SOX9, TWIST1) to drive neural crest formation [#0], with SOX2 in neural stem cells and the otocyst to co-regulate otic and neurogenic targets [#2, #28], with SOX10 at myelinogenic enhancers in oligodendrocyte precursors [#6], with SMAD1 downstream of BMP signaling at the SP7/Osterix enhancer in osteogenesis [#18], and with RUNX1 to restrain hematopoietic stem/progenitor expansion [#20]. Across neural lineages it maintains open chromatin at specific targets including Sox4/Sox11, Reln, and Aldh1a3 to control neuronal differentiation, cerebellar granule cell development, and neural stem cell quiescence [#7, #9, #16, #15]. CHD7 acts through both ATPase-dependent remodeling and an ATPase-independent mode that recruits H3K4 methyltransferase activity via direct interaction with WDR5 [#11]. Beyond transcriptional enhancer control, CHD7 localizes to the nucleolus where it binds hypomethylated active rDNA to promote 45S pre-rRNA synthesis [#4], and is recruited by PARP1 to DNA double-strand breaks where it relaxes chromatin and recruits HDAC1/2 to promote canonical non-homologous end-joining [#10]. CHD7 directly interacts with the related remodeler CHD8, and CHARGE-associated missense mutations disrupt this interaction [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Establishing where CHD7 acts in the genome was the first step toward defining its function; mapping showed it occupies cell-type-specific enhancer-like sites that track with H3K4 methylation.\",\n      \"evidence\": \"ChIP-chip across multiple human and mouse cell types before and after ES cell differentiation\",\n      \"pmids\": [\"19251738\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish what CHD7 does biochemically at these sites\", \"Did not identify recruiting transcription factors\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Genetic interaction studies began to connect CHD7 dosage to specific developmental defects, showing a synergistic requirement with Tbx1 in pharyngeal ectoderm for great vessel development.\",\n      \"evidence\": \"Mouse double-heterozygote epistasis with tissue-specific Cre rescue\",\n      \"pmids\": [\"19855134\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No molecular mechanism linking CHD7 and Tbx1\", \"Direct chromatin targets unidentified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identifying CHD7's protein partners and direct enhancer targets clarified how it activates lineage programs; CHD7 cooperates with PBAF at neural crest enhancers and ATPase activity is essential for neural crest transcription.\",\n      \"evidence\": \"Co-IP, ChIP at SOX9/TWIST1 enhancers, Xenopus knockdown and catalytic-mutant rescue, human neural crest assays\",\n      \"pmids\": [\"20130577\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of PBAF cooperation not resolved\", \"Generality beyond neural crest enhancers untested at the time\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"CHD7 was found to have a distinct nucleolar role; it binds active rDNA and promotes pre-rRNA synthesis, linking it to ribosome biogenesis and cell proliferation.\",\n      \"evidence\": \"Immunofluorescence/fractionation, ChIP, siRNA, overexpression, Chd7 mouse models\",\n      \"pmids\": [\"20591827\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether rDNA regulation requires remodeling ATPase activity not defined\", \"Relationship to enhancer function unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"A direct CHD7-CHD8 interaction was identified and shown to be disrupted by CHARGE missense mutations, suggesting a shared remodeler complex relevant to disease.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, BiFC, missense mutation testing\",\n      \"pmids\": [\"20453063\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mutation effect on interaction confirmed in Y2H but not in Co-IP\", \"Functional consequence of the complex not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"A SOX2 partnership was defined, showing CHD7 and SOX2 co-occupy and co-regulate shared targets in neural stem cells, with in vivo relevance to inner ear development.\",\n      \"evidence\": \"Sox2 pulldown/MS, ChIP-seq overlap, Co-IP, Chd7 haploinsufficient embryo expression\",\n      \"pmids\": [\"21532573\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Order of recruitment between CHD7 and SOX2 unresolved\", \"Whether interaction is direct or complex-mediated unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Biochemical reconstitution proved CHD7 is itself an ATP-dependent nucleosome remodeler distinct from other families, and graded CHARGE mutations impair this activity to varying degrees.\",\n      \"evidence\": \"Purified recombinant CHD7 in vitro remodeling assays and patient-mutation mutagenesis\",\n      \"pmids\": [\"23134727\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define in vivo substrates or directional outcome of remodeling\", \"No structural model of the active enzyme\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"CHD7's complex composition was extended by identifying FAM124B as a CHD7/CHD8-associated nuclear protein with overlapping embryonic expression.\",\n      \"evidence\": \"SILAC MS, Co-IP, yeast two-hybrid, in situ hybridization\",\n      \"pmids\": [\"23285124\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of FAM124B in the complex uncharacterized\", \"FAM124B binds CHD8 directly; direct contact with CHD7 not shown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Direct enhancer-level control of a developmental morphogen was demonstrated; CHD7 binds a Bmp4 enhancer and its loss misregulates Bmp4 to cause telencephalic midline defects.\",\n      \"evidence\": \"Chd7 mutant mouse, in vitro enhancer binding, in situ hybridization\",\n      \"pmids\": [\"22658483\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding shown in vitro; in vivo occupancy not established\", \"Mechanism producing both loss and ectopic expression unexplained\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"CHD7 was shown to remodel specific promoters to an open state to drive neuronal differentiation, linking chromatin opening to a defined cellular phenotype.\",\n      \"evidence\": \"Conditional mouse KO, chromatin accessibility at Sox4/Sox11, neurosphere and differentiation assays, exercise rescue\",\n      \"pmids\": [\"23827709\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect remodeling at these promoters not fully separated\", \"Mechanism of exercise rescue unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Genetic epistasis in zebrafish placed CHD7 in a pathway with rDNA regulation, as knockdown of the rRNA repressor fbxl10/kdm2bb rescued CHARGE-like craniofacial phenotypes.\",\n      \"evidence\": \"Zebrafish morpholino knockdown, double-knockdown rescue, proliferation and cartilage assays\",\n      \"pmids\": [\"23920116\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Morpholino-based knockdown carries off-target risk\", \"Direct molecular link between CHD7 and kdm2bb not shown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"CHD7 was shown to repress retinoic acid synthesis through direct binding to Aldh1a3, integrating it with RA signaling in stem cell niches and inner ear development.\",\n      \"evidence\": \"Conditional KO, ChIP at Aldh1a3, genetic rescue by Aldh1a3 loss, in vitro RA modulation\",\n      \"pmids\": [\"24026680\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CHD7 represses rather than activates this target mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"A candidate role in the DNA damage response was raised, with CHD7 depletion impairing ATR-dependent CHK1 phosphorylation and sensitizing pancreatic cancer cells to gemcitabine.\",\n      \"evidence\": \"siRNA knockdown in PDAC cell lines, phospho-CHK1 western blot, xenografts\",\n      \"pmids\": [\"24626090\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Mechanism inferred from a phosphorylation change in a single cell line, not reconstituted\", \"No direct CHD7 role at ATR/CHK1 demonstrated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"CHD7 was shown to maintain adult hippocampal NSC quiescence, repressing cell-cycle drivers and enabling full Hes5 induction, defining a stem-cell maintenance function.\",\n      \"evidence\": \"Inducible adult NSC-specific KO, BrdU pulse-chase, Hes5 and cell-cycle gene expression\",\n      \"pmids\": [\"25183173\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct chromatin targets for quiescence not mapped\", \"Connection to Notch pathway mechanism incomplete\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Direct cardiac enhancer regulation was demonstrated; CHD7 binds the Sema3c promoter in cardiogenic mesoderm and controls semaphorin/Slit-Robo and calcium-handling genes for cardiovascular development.\",\n      \"evidence\": \"Mesp1-Cre conditional KO, ChIP at Sema3c, chromatin structure and transcriptome profiling, excitation-contraction assay\",\n      \"pmids\": [\"26102480\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Partner transcription factors at cardiac enhancers not identified here\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"A SOX10 partnership in oligodendrocyte precursors was established, defining CHD7's role in CNS myelination through enhancer targeting of myelinogenic genes.\",\n      \"evidence\": \"Co-IP, ChIP-seq, RNA-seq, conditional KO in mice\",\n      \"pmids\": [\"26928066\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SOX10 recruits CHD7 or vice versa not resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"CHD7 was linked to BMP-driven osteogenesis via a SMAD1 interaction and BMP2-stimulated binding to the SP7/Osterix enhancer.\",\n      \"evidence\": \"Co-IP, ChIP at SP7 enhancer after BMP2, siRNA, overexpression, in vivo scaffold assay\",\n      \"pmids\": [\"27586276\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SMAD1-CHD7 interaction is direct not established\", \"Single-lab data\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"CHD7 was placed in a pluripotency-factor regulatory module at the FoxD3 locus, co-occupying enhancers with Oct3/4, Sox2, and Nanog and requiring H3K4 methylation for neural crest gene activation.\",\n      \"evidence\": \"ChIP at FoxD3 regulatory elements, siRNA, histone methylation inhibition\",\n      \"pmids\": [\"27579714\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical interactions among these factors not shown\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Comparative biochemistry distinguished CHD6/7/8 remodeling activities, showing CHD7 prefers short linker DNA and slides nucleosomes differently than CHD8, providing a basis for their non-redundant roles.\",\n      \"evidence\": \"In vitro binding and sliding assays with purified CHD6, CHD7, CHD8\",\n      \"pmids\": [\"28533432\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo correlation of these biochemical preferences not demonstrated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"CHD7 was shown to open chromatin for cerebellar granule neuron differentiation, cooperating with Top2b to transcribe long neuronal genes.\",\n      \"evidence\": \"Conditional KO, ATAC-seq, RNA-seq, Top2b co-dependence analysis\",\n      \"pmids\": [\"28317875\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular nature of CHD7-Top2b functional cooperation not detailed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"A specific direct target, Reln, was identified as CHD7-dependent in cerebellar granule cell progenitors, with genetic rescue confirming its role in the proliferative defect.\",\n      \"evidence\": \"Conditional KO, chromatin accessibility at Reln, genetic rescue\",\n      \"pmids\": [\"28165338\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CHD7 selects this locus among many enhancers unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"A CHD7-Sox2 complex was shown to drive OPC proliferation after spinal cord injury via Rgcc and PKCθ, extending the SOX2 partnership to injury repair.\",\n      \"evidence\": \"OPC-specific KO, Co-IP, ChIP at Rgcc/PKCθ, overexpression rescue\",\n      \"pmids\": [\"28931573\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Directness of CHD7-Sox2 contact not biochemically resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"An oncogenic-cofactor role in leukemia was identified; CHD7 interacts with CBFβ-SMMHC through RUNX1 and enhances RUNX1 target transcription, with CHD7 loss delaying CBFB-MYH11 leukemia.\",\n      \"evidence\": \"Co-IP, reporter assays, RNA-seq, conditional KO mouse, proliferation assay\",\n      \"pmids\": [\"29018080\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanism of transcriptional enhancement not fully defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Using CHARGE patient iPSCs, CHD7 was shown to activate super-enhancers maintaining neuroepithelial/CNS identity, with its loss causing a fate shift to neural crest.\",\n      \"evidence\": \"Patient iPSCs, H3K27ac ChIP-seq, siRNA, transcriptome profiling, BRN2/SOX21 rescue\",\n      \"pmids\": [\"29440260\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which CHD7 selects super-enhancers not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"CHD7 was placed in DNA double-strand break repair; PARP1 recruits CHD7, which relaxes chromatin and recruits HDAC1/2 to promote canonical NHEJ, with loss shifting repair to mutagenic 53BP1-dependent NHEJ.\",\n      \"evidence\": \"Live-cell imaging of recruitment, Co-IP with HDAC1/2, ChIP at breaks, NHEJ assays, 53BP1 epistasis\",\n      \"pmids\": [\"33188175\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether DSB recruitment uses the same domains as transcriptional targeting unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The ATPase-independent mode of CHD7 was defined; it directly binds WDR5 and an ATPase-dead knock-in still recruits H3K4 methyltransferase activity, separating remodeling from histone-modification recruitment.\",\n      \"evidence\": \"Protein-array screen, Co-IP, ATPase-dead knock-in mouse, ChIP for H3K4me, RNA-seq\",\n      \"pmids\": [\"33127760\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which target genes depend on each mode not comprehensively mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"A RUNX1 partnership in development was established showing CHD7 restrains hematopoietic stem/progenitor expansion, with genome-wide co-occupancy at RUNX1 motifs.\",\n      \"evidence\": \"Co-IP, ChIP-seq, conditional KO in zebrafish and mouse, hematopoietic flow cytometry\",\n      \"pmids\": [\"32883883\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of repression of RUNX1-driven expansion not fully defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"CHD7 was identified as a let-7 microRNA target, defining a post-transcriptional control layer regulating CHD7 protein in sensory progenitor differentiation.\",\n      \"evidence\": \"let-7 sponge and overexpression in chicken and mouse, conserved 3'UTR site, CHD7 protein immunofluorescence\",\n      \"pmids\": [\"32816902\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological dynamics of let-7-CHD7 regulation in normal development not quantified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"CHD7 was shown to robustly establish active enhancer chromatin and coordinate topologically interacting gene expression in cerebellar granule cell precursors, connecting enhancer activation to 3D genome architecture.\",\n      \"evidence\": \"Conditional KO, ATAC-seq, ChIP-seq (H3K27ac, H3K4me1, Pol II), Hi-C, division-orientation analysis\",\n      \"pmids\": [\"34588434\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct role of CHD7 in shaping genome topology vs downstream consequence unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"A direct target, paqr3b, was identified in GABAergic neuron progenitors, with CHD7 loss elevating MAPK/ERK signaling and a pharmacological rescue restoring the phenotype.\",\n      \"evidence\": \"chd7 KO zebrafish, ChIP at paqr3b, transcriptomics, ephedrine rescue, C. elegans screen\",\n      \"pmids\": [\"33900016\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Conservation of the paqr3b axis to mammals not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"CHD7 was shown to protect auditory neurons and hair cells postnatally by controlling stress pathway gene expression, explaining sensorineural hearing loss as stress-triggered degeneration.\",\n      \"evidence\": \"Cell-type-specific conditional KO, auditory brainstem response, stress-inducer assays, expression analysis\",\n      \"pmids\": [\"34732824\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct CHD7 targets among stress genes not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A metabolic/lineage-balance role was defined; loss of CHD7 in mesenchymal progenitors de-represses PPAR-γ, which engages H3K4me3 to activate adipogenesis at the expense of osteogenesis.\",\n      \"evidence\": \"Conditional KO, RNA-seq, ChIP for PPAR-γ and H3K4me3, differentiation and rescue assays\",\n      \"pmids\": [\"35418650\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect restraint of PPAR-γ by CHD7 not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Human inner ear organoids showed CHD7 and its remodeling activity are essential for hair cell and supporting cell formation, while a remodeling-independent mode also regulates otic genes, with non-cell-autonomous partial rescue.\",\n      \"evidence\": \"Human PSC organoids, CRISPR KO and ATPase-dead mutant, RNA-seq, chimeric rescue\",\n      \"pmids\": [\"36396635\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the remodeling-independent mechanism in otic cells unresolved\", \"Basis of non-cell-autonomous rescue unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The CHD7-SOX2 partnership was resolved at the gene-regulatory-network level in the otocyst, with both factors binding independently and cooperatively to control otic patterning genes during a defined critical period.\",\n      \"evidence\": \"Variable-dosage Chd7/Sox2 mouse genetics, CUT&Tag, RNA-seq, inducible KO defining E9.5 critical period\",\n      \"pmids\": [\"38408234\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of cooperative vs independent binding not addressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CHD7 is targeted to specific enhancers and super-enhancers in different cell types, and how it allocates between its ATPase-dependent remodeling and ATPase-independent histone-modifier recruitment modes at each target, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of CHD7 engaging a nucleosome or partner factor\", \"Rules governing choice of remodeling vs recruitment mode at a given locus undefined\", \"Determinants of cell-type-specific recruitment not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [3, 13]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 22, 26]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [4, 26, 30]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 13]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [10, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 19]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [1, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1, 3, 12, 22]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 26]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 6, 14, 28]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [\"PBAF\", \"CHD7-CHD8 complex\"],\n    \"partners\": [\"SOX2\", \"SOX10\", \"CHD8\", \"WDR5\", \"RUNX1\", \"SMAD1\", \"HDAC1\", \"FAM124B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}