{"gene":"CHD8","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2008,"finding":"CHD8 directly interacts with β-catenin, is recruited to promoter regions of β-catenin-responsive genes, and negatively regulates β-catenin-targeted gene expression; CHD8 was demonstrated to have ATP-dependent chromatin remodeling activity (first demonstration for the CHD6-9 subfamily), as shown by shRNA knockdown activating β-catenin target genes and conservation in Drosophila kismet knockdown.","method":"Co-immunoprecipitation, ChIP, shRNA knockdown + transcriptome analysis, in vitro chromatin remodeling assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro chromatin remodeling assay combined with direct binding and ChIP, replicated via Drosophila ortholog knockdown","pmids":["18378692"],"is_preprint":false},{"year":2009,"finding":"CHD8 binds p53 and suppresses p53-mediated transactivation and apoptosis by promoting formation of a trimeric CHD8–p53–histone H1 complex on chromatin; depletion of CHD8 or histone H1 activates p53 and causes apoptosis; Chd8-/- mice die early in embryogenesis with widespread apoptosis rescued by p53 deletion.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, shRNA knockdown, Chd8-/- and Chd8-/-;p53-/- double-knockout mice, apoptosis assays","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (Co-IP, ChIP, genetic epistasis with p53 KO rescue), replicated in vitro and in vivo","pmids":["19151705"],"is_preprint":false},{"year":2011,"finding":"CHD8 suppresses Wnt–β-catenin signaling by recruiting histone H1 to Wnt target genes, forming a trimeric CHD8–β-catenin–H1 complex on chromatin; a CHD8 mutant lacking the histone H1 binding domain lost inhibitory activity, demonstrating that H1 recruitment is mechanistically essential.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, domain deletion mutagenesis, Wnt reporter assays, siRNA knockdown","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — domain mutagenesis combined with Co-IP and functional reporter assays, mechanistically extends prior p53 finding to Wnt pathway","pmids":["22083958"],"is_preprint":false},{"year":2001,"finding":"Duplin (CHD8 short isoform) is translocated to the nucleus via interaction with importin-α through basic amino acid clusters; nuclear localization is essential for its inhibitory activity on Wnt/β-catenin–Tcf transcription and for ventralization in Xenopus; a cytoplasmic-retained Duplin mutant (Δ500-584) bound β-catenin normally but could not inhibit Wnt signaling.","method":"Yeast two-hybrid, co-immunoprecipitation, deletion mutagenesis, Xenopus embryo ventralization assay, mammalian Wnt reporter assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — domain mutagenesis combined with functional assays in two model systems (mammalian cells and Xenopus embryos)","pmids":["11744694"],"is_preprint":false},{"year":2004,"finding":"Germline deletion of Duplin/CHD8 in mice causes early embryonic lethality (arrest at E7.5) with massive apoptosis and failure to form primitive streak/mesoderm; β-catenin target genes were not upregulated in null embryos, indicating the developmental requirement is independent of Wnt-inhibitory function.","method":"Chd8/Duplin knockout mice, histology, in situ hybridization for β-catenin target genes","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic knockout with defined phenotypic and molecular readout; negative result (no Wnt upregulation) mechanistically informative","pmids":["15367660"],"is_preprint":false},{"year":2006,"finding":"Duplin/CHD8 interacts with PIAS3 and suppresses LIF-induced STAT3 transcriptional activity independently of SUMO modification; Duplin inhibits STAT3 binding to DNA without affecting STAT3 tyrosine phosphorylation or nuclear localization.","method":"Yeast two-hybrid screening, co-immunoprecipitation, STAT3 reporter assay, sumoylation assay, EMSA","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional reporter and EMSA, single lab","pmids":["16452319"],"is_preprint":false},{"year":2007,"finding":"CHD8 associates with the transcription factor Staf (ZNF143) and contributes to efficient RNA Pol III transcription from the human U6 promoter on a chromatin template; CHD8 tandem chromodomains bind histone H3 di- and tri-methylated at K4; CHD8 occupies the U6 and IRF3 promoters in vivo.","method":"Mass spectrometry pull-down, co-immunoprecipitation, in vitro chromatin transcription assay, ChIP, histone peptide binding assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro chromatin transcription reconstitution combined with Co-IP and ChIP, single lab but multiple orthogonal methods","pmids":["17938208"],"is_preprint":false},{"year":2009,"finding":"CHD8 binds constitutively to 5′ promoter-proximal regions of CCNE2 (cyclin E2) and TYMS regardless of cell-cycle phase; CHD8 associates with elongating (CTD Ser2-phosphorylated) RNA Pol II; CHD8-depleted cells are hypersensitive to drugs inhibiting RNAPII CTD Ser2 phosphorylation, implicating CHD8 in an early step of the RNAPII transcription elongation cycle; CHD8 chromodomains bind H3K4me2 in vitro.","method":"ChIP, siRNA knockdown, transcriptome analysis, co-immunoprecipitation, in vitro histone binding assay, drug sensitivity assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP combined with Co-IP, functional drug sensitivity, and in vitro binding, multiple orthogonal methods in single lab","pmids":["19255092"],"is_preprint":false},{"year":2010,"finding":"CHD8 directly interacts with CHD7 (mutated in CHARGE syndrome); interaction confirmed by yeast two-hybrid, co-immunoprecipitation, and bimolecular fluorescence complementation; certain CHD7 missense mutations in the interaction domain (p.Trp2091Arg, p.His2096Arg, p.Gly2108Arg) disrupt the direct CHD7–CHD8 interaction in yeast two-hybrid but not in co-immunoprecipitation, suggesting both direct and indirect (via linker proteins) interaction modes.","method":"Yeast two-hybrid, co-immunoprecipitation, bimolecular fluorescence complementation assay, missense mutant analysis","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — three orthogonal methods, but discordance between assays limits interpretation; single lab","pmids":["20453063"],"is_preprint":false},{"year":2010,"finding":"CHD8 directly associates with the androgen receptor (AR) and co-localizes with AR at the TMPRSS2 enhancer upon androgen treatment; CHD8 is required for AR recruitment to the TMPRSS2 promoter and for androgen-dependent gene activation; CHD8 facilitates androgen-stimulated cell proliferation.","method":"Co-immunoprecipitation, ChIP, siRNA knockdown, reporter assay, cell proliferation assay","journal":"Molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus ChIP and functional knockdown, single lab","pmids":["20308527"],"is_preprint":false},{"year":2012,"finding":"FAM124B was identified as a novel component of a CHD7–CHD8 containing complex; direct binding of FAM124B to CHD8 was confirmed by yeast two-hybrid; FAM124B is a nuclear protein widely expressed in embryonic and adult mouse tissues.","method":"SILAC mass spectrometry, co-immunoprecipitation, yeast two-hybrid, immunofluorescence","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — SILAC-MS discovery confirmed by Co-IP and Y2H, single lab","pmids":["23285124"],"is_preprint":false},{"year":2012,"finding":"CHD8 (Chd8-S isoform) contains a PKA-binding domain in its amino terminus and functions as an A-kinase anchoring protein (AKAP); Chd8-S binds RIIα of PKA as shown by RII overlay and co-immunoprecipitation; binding requires phosphorylation of RIIα; CHD8 localizes to nuclear and perinuclear compartments in HeLa cells and cardiomyocytes.","method":"RII overlay assay, co-immunoprecipitation, immunofluorescence, mRNA expression analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding demonstrated by two methods (RII overlay + Co-IP) with phosphorylation dependency, localization confirmed; single lab","pmids":["23071553"],"is_preprint":false},{"year":2013,"finding":"CHD8 binds ~2,000 active promoters genome-wide, with enrichment at E2F-dependent genes; CHD8 is required for G1/S-specific expression of E2F-target genes and cell cycle re-entry; CHD8 interacts with E2F1, and loading of E2F1 and E2F3 (but not E2F4) onto S-phase gene promoters requires CHD8; recruitment of MLL histone methyltransferase complexes to S-phase gene promoters is severely impaired without CHD8.","method":"ChIP-on-chip, co-immunoprecipitation, siRNA knockdown, cell cycle analysis, reporter assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP-on-chip, Co-IP, functional knockdown phenotypes, multiple orthogonal methods; single lab","pmids":["24265227"],"is_preprint":false},{"year":2015,"finding":"NSD3-short isoform links BRD4 to CHD8 as an adaptor protein in acute myeloid leukemia; BRD4, NSD3, and CHD8 co-localize across the AML genome at super-enhancers and are co-released upon BET bromodomain inhibition; genetic targeting of CHD8 mimics the phenotypic and transcriptional effects of BRD4 inhibition in AML cells.","method":"Co-immunoprecipitation, ChIP-seq, shRNA knockdown, genetic targeting, BET inhibitor treatment","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, ChIP-seq, and functional genetic targeting with defined phenotypic readout; multiple orthogonal approaches in single rigorous study","pmids":["26626481"],"is_preprint":false},{"year":2015,"finding":"CHD8 binds to progesterone receptor (PR)-activated enhancers upon progestin stimulation (re-localizing from promoters); CHD8 depletion impairs progestin-dependent gene regulation; CHD8 interacts with the SWI/SNF complex and depletion of BRG1/BRM impairs CHD8 recruitment; CHD8 is required for RNAPII recruitment to enhancers and for enhancer RNA (eRNA) transcription, and contributes to DNaseI accessibility at enhancers (but not H3K27 acetylation).","method":"ChIP-seq, siRNA knockdown, co-immunoprecipitation, DNaseI hypersensitivity assay, RT-qPCR for eRNA","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP-seq, Co-IP, functional knockdown with multiple chromatin and transcriptional readouts; single lab, multiple orthogonal methods","pmids":["25894978"],"is_preprint":false},{"year":2016,"finding":"CHD8 haploinsufficiency in mice causes small but global gene expression changes in the brain and is associated with abnormal activation of REST (RE-1 silencing transcription factor), which suppresses neuronal gene transcription; CHD8 physically interacts with REST in the mouse brain as shown by co-immunoprecipitation.","method":"Chd8 heterozygous mutant mice, RNA-seq, co-immunoprecipitation, gene set enrichment analysis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-immunoprecipitation of endogenous proteins combined with genome-wide transcriptomics and in vivo mouse model","pmids":["27602517"],"is_preprint":false},{"year":2016,"finding":"Chd8 knockdown during cortical development impairs neural progenitor proliferation and differentiation; Chd8 stimulates transcription of cell cycle genes and precludes neural-specific gene induction by regulating PRC2 complex component expression; Chd8 knockdown disrupts Wnt signaling transducer expression, and enhancing Wnt signaling rescues transcriptional and behavioral deficits caused by Chd8 knockdown.","method":"shRNA knockdown in vivo, RNA-seq, ChIP-seq, Wnt pathway rescue experiments, behavioral assays","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockdown with transcriptome + ChIP-seq and pathway rescue, multiple orthogonal methods","pmids":["27694995"],"is_preprint":false},{"year":2017,"finding":"CHD8 exhibits distinct nucleosome binding and remodeling properties from CHD6 and CHD7: CHD8 requires longer linker DNA for nucleosome binding than CHD7; CHD8 slides nucleosomes to positions with more flanking linker DNA; CHD6 disrupts nucleosomes (non-sliding), while CHD7 and CHD8 slide them.","method":"Purified protein biochemical analysis: nucleosome binding assays, nucleosome sliding assays, ATPase assays with reconstituted chromatin","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstituted biochemical assays with purified proteins, mechanistic characterization; single lab","pmids":["28533432"],"is_preprint":false},{"year":2018,"finding":"Cell-type-specific deletion of Chd8 in oligodendrocyte progenitors (but not neurons) causes myelination defects in mice; CHD8 activates BRG1-associated SWI/SNF complexes that in turn activate CHD7, initiating a successive chromatin remodeling cascade; CHD8 establishes accessible chromatin landscapes and recruits MLL/KMT2 histone methyltransferase complexes around proximal promoters to promote oligodendrocyte differentiation; inhibition of histone demethylase activity partially rescues myelination defects.","method":"Conditional Chd8 knockout mice (oligodendrocyte-specific), ChIP-seq, ATAC-seq, Co-immunoprecipitation, histone demethylase inhibitor rescue","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific KO with defined phenotype, ChIP-seq, ATAC-seq, Co-IP, and pharmacological rescue; multiple orthogonal methods","pmids":["29920279"],"is_preprint":false},{"year":2018,"finding":"CHD8 interacts with C/EBPβ and promotes its transactivation activity during adipocyte differentiation; CHD8 is required for upregulation of C/EBPα and PPARγ during adipogenesis; ablation of Chd8 specifically in white preadipocytes markedly reduces white adipose tissue mass in mice.","method":"Co-immunoprecipitation, conditional Chd8 knockout (adipocyte-specific), adipogenic differentiation assay, gene expression analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP of interaction combined with cell-type-specific KO and defined phenotypic readout; multiple methods, single lab","pmids":["29768199"],"is_preprint":false},{"year":2019,"finding":"Drosophila Kismet (CHD7/CHD8 ortholog) limits intestinal stem cell number and proliferation; Kismet and Trithorax-related (Trr/MLL3/4) co-localize genome-wide in ISCs, co-regulate genes including Cbl, and loss of kismet leads to elevated EGFR protein and signaling, promoting ISC self-renewal.","method":"Drosophila genetic loss-of-function, whole-genome ChIP profiling in ISCs, EGFR pathway analysis","journal":"Developmental cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Drosophila ortholog (kismet is CHD7/CHD8 ortholog) genetic and genomic analysis; relevant to CHD8 but organism is Drosophila and kismet covers both CHD7 and CHD8","pmids":["31112698"],"is_preprint":false},{"year":2020,"finding":"CHD8 is required for oligodendrocyte maturation and myelination; CHD8 regulates expression of many myelination-related genes; oligodendrocyte-specific Chd8 ablation impairs myelination, slows action potential propagation, and produces behavioral deficits including increased social interaction and anxiety.","method":"Oligodendrocyte-specific conditional Chd8 knockout mice, electrophysiology, behavioral assays, RNA-seq","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific KO with multiple functional readouts (electrophysiology, behavior, transcriptomics); replicated by same group","pmids":["32142125"],"is_preprint":false},{"year":2021,"finding":"CHD8 forms a complex with ATM kinase; CHD8 deficiency increases chromatin accessibility and genomic instability in hematopoietic stem/progenitor cells (HSPCs), activating ATM kinase that phosphorylates and stabilizes p53, leading to HSPC apoptosis; p53 deletion rescues apoptotic defects and restores hematopoiesis in Chd8-/- mice.","method":"Conditional Chd8 knockout mice (hematopoietic), co-immunoprecipitation, ATAC-seq, bone marrow transplantation, p53 genetic rescue","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, ATAC-seq, genetic rescue with p53 KO, bone marrow transplantation; multiple orthogonal methods","pmids":["34292326"],"is_preprint":false},{"year":2021,"finding":"CHD8 is highly expressed in hematopoietic stem cells (HSCs) and its conditional deletion induces cell cycle arrest, apoptosis, and differentiation block in HSCs via upregulation of p53 target genes; additional p53 ablation rescues stem cell function and differentiation block of CHD8-deficient HSCs.","method":"Conditional Chd8 knockout in bone marrow, colony formation assay, bone marrow transplantation, p53 genetic rescue, gene expression analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined molecular phenotype, functional assays, and p53 epistasis rescue","pmids":["33535054"],"is_preprint":false},{"year":2021,"finding":"CHD8 depletion reduces H3K36me3 peaks at gene bodies (47.82% reduction), particularly at highly expressed CHD8-bound genes; H3K36me3 reduction correlates with altered alternative splicing of 462 genes; CHD8 interacts with the splicing regulator hnRNPL as revealed by mass spectrometry; splicing phenotype is partly mediated through SETD2.","method":"ChIP-seq for histone modifications in iPSC-derived neural progenitors, mass spectrometry (CHD8 interactome), RNA-seq for alternative splicing, shRNA knockdown","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP-seq, MS-based interaction discovery, and splicing analysis; multiple orthogonal methods in single lab","pmids":["36537238"],"is_preprint":false},{"year":2021,"finding":"Cerebellar granule neuron progenitor (GNP)-specific deletion of Chd8 impairs GNP proliferation and differentiation, causes cerebellar hypoplasia and motor coordination defect; CHD8 binds preferentially to promoter regions and modulates local chromatin accessibility of transcriptionally active genes in GNPs; CHD8 regulates expression of neuronal genes in GNPs.","method":"GNP-specific conditional Chd8 KO mice, ATAC-seq, ChIP-seq, behavioral assays, RNA-seq","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — cell-type-specific KO with ATAC-seq and ChIP-seq, defined phenotypic readout; multiple orthogonal methods","pmids":["33826902"],"is_preprint":false},{"year":2022,"finding":"CHD8 functions as a transcriptional activator at its target genes in human neurons; CHD8 chromatin targeting is cell context-dependent, preferentially binding ETS motif-enriched promoters in human neurons; ELK1 (an ETS factor) is required for CHD8 recruitment specifically to ETS motif-containing sites, establishing functional cooperation between ELK1 and CHD8 at MAPK/ERK target genes.","method":"Conditional CHD8 loss-of-function allele and endogenously tagged allele in human iPSCs, ATAC-seq, RNA-seq, ELK1 knockdown, ChIP-seq","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — isogenic human iPSC-derived neurons, ATAC-seq + RNA-seq + ELK1 KD epistasis, multiple orthogonal methods; single lab","pmids":["36575212"],"is_preprint":false},{"year":2022,"finding":"CHD8 haploinsufficiency in cerebral organoids disrupts neurodevelopmental trajectories with cell-autonomous, accelerated generation of inhibitory neurons and delayed generation of excitatory neurons, leading to opposite expansions in their proportions; mosaic organoid design confirmed cell-autonomous nature of phenotypes; CHD8-dependent molecular defects include abnormal proliferation programs and alternative splicing.","method":"Human cerebral organoids with CHD8 haploinsufficiency (patient-specific and isogenic), single-cell RNA-seq, mosaic organoid design","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — isogenic human organoids, single-cell transcriptomics, mosaic design establishing cell autonomy; rigorous study","pmids":["35385734"],"is_preprint":false},{"year":2022,"finding":"Adult ablation of CHD8 in astrocytes attenuates reactive gliosis by remodeling chromatin accessibility and changing gene expression; CHD8 loss in astrocytes impedes astrocyte proliferation and morphological elaboration; astrocytic CHD8 ablation alleviates LPS-induced neuroinflammation by altering metabolic and lipid-associated pathways and astrocyte-microglia crosstalk.","method":"Conditional Chd8 KO in astrocytes and microglia, ATAC-seq, RNA-seq, LPS neuroinflammation model, AAV-mediated gene editing in vivo","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — cell-type-specific conditional KO, ATAC-seq, RNA-seq, in vivo pharmacological challenge; multiple orthogonal methods","pmids":["39154337"],"is_preprint":false},{"year":2022,"finding":"CHD8 is required for spermatogonial proliferation and meiotic progression; germ cell-specific Chd8 ablation causes depletion of undifferentiated spermatogonia and failure of meiotic double-strand break formation leading to meiotic prophase I arrest; CHD8 directly binds and regulates genes crucial for meiosis including H3K4me3 methyltransferase genes, meiotic cohesin genes, HORMA domain genes, synaptonemal complex genes, and DNA damage response genes.","method":"Germ cell-specific conditional Chd8 KO mice, ChIP-seq, RNA-seq, histological analysis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — cell-type-specific KO with ChIP-seq, RNA-seq, and defined cellular phenotype; multiple orthogonal methods, single lab","pmids":["38224953"],"is_preprint":false},{"year":2022,"finding":"CHD8 regulates erythroblast cytokinesis; loss of CHD8 leads to cytokinesis failure producing binucleated and multinucleated erythroblasts; CHD8 binds directly to gene bodies of multiple Rho GTPase signaling genes in erythroblasts and its loss causes decreased RhoA and increased Rac1 and Cdc42 activities.","method":"Chd8F/FMx1-Cre/Trp53F/F double-KO mouse model, ChIP, Rho GTPase activity assays, cell imaging for cytokinesis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic model combined with ChIP and Rho GTPase functional assays; multiple orthogonal methods","pmids":["35830790"],"is_preprint":false},{"year":2020,"finding":"CHD8 dosage negatively regulates neuronal gene expression to maintain pluripotency; CHD8 cooperates with SOX transcription factors in regulating chromatin accessibility; dosage-sensitive CHD8 transcriptional targets and regulated accessibility sites were identified in heterozygous and homozygous Chd8 mouse embryonic stem cells and neural progenitors.","method":"Heterozygous and homozygous Chd8 mouse ESCs and neural progenitors, ChIP-seq, ATAC-seq, RNA-seq","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP-seq, ATAC-seq, RNA-seq with allelic series in same cell context; single lab, multiple orthogonal methods","pmids":["32839322"],"is_preprint":false},{"year":2021,"finding":"Homozygous deletion of CHD8 in postmitotic neurons downregulates neuronal gene expression and alters activity-dependent transcriptional responses to KCl depolarization; in adult mice, homozygous CHD8 ablation attenuates activity-dependent transcriptional responses in the hippocampus to kainic acid-induced seizures.","method":"Conditional Chd8 KO in postmitotic neurons, KCl depolarization assay, kainic acid seizure model, RNA-seq","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with activity-dependent transcriptional readout in two experimental paradigms; single lab","pmids":["37268684"],"is_preprint":false},{"year":2021,"finding":"Chd8 regulates X chromosome inactivation by fine-tuning Xist expression during ES cell differentiation; CHD8 controls and prevents spurious transcription factor interactions within Xist regulatory regions.","method":"Chd8 conditional KO in differentiating mouse ES cells, RNA-seq, ChIP-seq, allele-specific expression analysis","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — conditional KO with gene expression and ChIP analysis; mechanistic interpretation of TF binding is indirect; single lab","pmids":["33859315"],"is_preprint":false},{"year":2022,"finding":"CHD8+/- neural progenitors have a shortened G1 phase of the cell cycle with increased E-cyclin expression and elevated ERK phosphorylation, favoring self-renewing over neurogenic divisions; this was established by long-term single-cell live imaging.","method":"CHD8+/- human neural progenitor cells (CRISPR-generated), long-term single-cell live imaging, cell cycle analysis, Western blot for E-cyclins and pERK","journal":"Biology open","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live single-cell imaging with molecular validation; single lab but multiple readouts","pmids":["36222238"],"is_preprint":false},{"year":2021,"finding":"CHD8 is required for production and fitness of transit-amplifying intermediate progenitors (IPCs) essential for upper-layer neuron expansion in embryonic cortex; p53 loss partially rescues apoptosis and neurogenesis defects; CHD8 regulates chromatin accessibility to activate TBR2 (IPC regulator) while repressing p53-mediated apoptotic programs; in adult brain, CHD8 depletion impairs IPC differentiation from NSCs without affecting NSC proliferation.","method":"Conditional Chd8 KO (stage-specific inducible), ATAC-seq, RNA-seq, p53 genetic rescue, immunostaining, fluoxetine treatment","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — inducible conditional KO, ATAC-seq, RNA-seq, p53 epistasis rescue, multiple orthogonal methods; single lab","pmids":["36127134"],"is_preprint":false},{"year":2022,"finding":"Loss of chd8 in zebrafish reduces vagal neural crest cell numbers and alters their early migration; later, there are decreased serotonin-producing enterochromaffin cells and NCC-derived serotonergic neurons, causing intestinal hyposerotonemia; transcriptomic and single-cell sequencing revealed altered serotonin/acetylcholine signaling pathway expression and disrupted immune balance in intestines.","method":"Stable constitutive chd8 mutant zebrafish, NCC lineage tracing, scRNA-seq, immunofluorescence, transcriptomic analysis","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — zebrafish KO with scRNA-seq and cellular phenotyping; mechanistic link to enteric nervous system development established","pmids":["36375841"],"is_preprint":false}],"current_model":"CHD8 is an ATP-dependent chromatin remodeler that slides nucleosomes to positions with more flanking linker DNA; it binds H3K4me2/me3 via its tandem chromodomains and regulates transcription at Pol II and Pol III promoters by associating with elongating RNA Pol II, recruiting MLL/KMT2 histone methyltransferase complexes, and modulating H3K36me3 at gene bodies to influence alternative splicing; it suppresses Wnt–β-catenin and p53-mediated transcription by recruiting histone H1 to target genes, inhibits STAT3 DNA binding, cooperates with NSD3-short as part of a BRD4–NSD3–CHD8 super-enhancer complex, interacts with CHD7, AR, SWI/SNF, E2F1, ELK1, ATM, and C/EBPβ to control cell cycle progression, adipogenesis, erythroid cytokinesis (via Rho GTPase gene regulation), hematopoietic stem cell survival (via ATM–p53 axis), myelination (via a BRG1–CHD7 cascade and H3K4 methyltransferase recruitment), and stage-specific neurogenesis by regulating chromatin accessibility and the balance between progenitor proliferation and differentiation."},"narrative":{"mechanistic_narrative":"CHD8 is an ATP-dependent chromatin remodeler that binds active promoters genome-wide, slides nucleosomes toward positions with greater flanking linker DNA, and reads H3K4me2/me3 through its tandem chromodomains to control transcriptional programs governing proliferation, differentiation, and cell survival across many lineages [PMID:19255092, PMID:24265227, PMID:28533432]. It acts dually as a repressor and activator: it suppresses Wnt–β-catenin and p53-dependent transcription by assembling trimeric complexes with β-catenin or p53 and recruiting histone H1 to target chromatin, with H1 recruitment mechanistically essential for inhibition [PMID:18378692, PMID:19151705, PMID:22083958], and it inhibits LIF/STAT3 transcription by blocking STAT3 DNA binding [PMID:16452319]. At active genes CHD8 associates with elongating, CTD Ser2-phosphorylated RNA Pol II and is required for productive transcription, and it recruits MLL/KMT2 histone methyltransferase complexes and modulates H3K36me3 over gene bodies—an activity linked to alternative splicing through interaction with SETD2 and hnRNPL [PMID:19255092, PMID:24265227, PMID:36537238]. CHD8 establishes accessible chromatin landscapes in cooperation with context-specific transcription factors including E2F1, ELK1, SOX factors, AR, and C/EBPβ, and partners with SWI/SNF (BRG1/BRM) and CHD7 in successive remodeling cascades [PMID:20308527, PMID:24265227, PMID:25894978, PMID:29920279, PMID:29768199, PMID:36575212, PMID:32839322]. Through these activities CHD8 controls G1/S cell-cycle gene expression and proliferation [PMID:24265227, PMID:36222238], links BRD4 to super-enhancers via NSD3-short in leukemia [PMID:26626481], and is required for hematopoietic stem cell survival by restraining an ATM–p53 apoptotic axis [PMID:34292326, PMID:33535054]. CHD8 is essential during development: germline loss causes early embryonic lethality with p53-dependent apoptosis [PMID:19151705, PMID:15367660], and dosage-sensitive CHD8 governs stage-specific neurogenesis, the balance of progenitor proliferation versus differentiation, oligodendrocyte myelination, and the excitatory/inhibitory neuronal balance, with haploinsufficiency disrupting neurodevelopmental trajectories in human models [PMID:27694995, PMID:29920279, PMID:35385734, PMID:32839322, PMID:36127134].","teleology":[{"year":2001,"claim":"Established that the CHD8 short isoform Duplin must enter the nucleus to inhibit Wnt/β-catenin–Tcf transcription, separating nuclear function from β-catenin binding.","evidence":"Yeast two-hybrid, deletion mutagenesis, and Wnt reporter/ventralization assays in mammalian cells and Xenopus","pmids":["11744694"],"confidence":"High","gaps":["Did not define the enzymatic mechanism of Wnt inhibition","Used a short isoform rather than full-length CHD8"]},{"year":2004,"claim":"Defined an essential developmental requirement for CHD8 distinct from its Wnt-inhibitory role, since null embryos die at E7.5 with massive apoptosis but without β-catenin target derepression.","evidence":"Chd8/Duplin knockout mice with histology and in situ hybridization","pmids":["15367660"],"confidence":"High","gaps":["Did not identify the molecular cause of the apoptosis","Mechanism linking CHD8 loss to lethality unresolved at this stage"]},{"year":2006,"claim":"Extended CHD8's transcriptional repression to JAK/STAT signaling by showing it blocks STAT3 DNA binding via PIAS3 association.","evidence":"Yeast two-hybrid, Co-IP, STAT3 reporter, and EMSA","pmids":["16452319"],"confidence":"Medium","gaps":["Single lab, no in vivo confirmation","Did not establish whether chromatin remodeling activity is involved"]},{"year":2008,"claim":"Demonstrated CHD8 is a bona fide ATP-dependent chromatin remodeler (first in the CHD6-9 subfamily) that directly binds β-catenin and represses Wnt target genes.","evidence":"In vitro chromatin remodeling assay, Co-IP, ChIP, shRNA knockdown with transcriptomics, conserved in Drosophila kismet","pmids":["18378692"],"confidence":"High","gaps":["Remodeling outcome (sliding vs disruption) not yet defined","Genome-wide binding not yet mapped"]},{"year":2009,"claim":"Identified the mechanism of CHD8-dependent embryonic survival: CHD8 forms a CHD8–p53–histone H1 complex to suppress p53 transactivation and apoptosis, with embryonic lethality rescued by p53 deletion.","evidence":"Co-IP, ChIP, shRNA, Chd8-/- and Chd8-/-;p53-/- double-knockout mice","pmids":["19151705"],"confidence":"High","gaps":["Did not resolve how CHD8 recruits H1 to specific loci","Generality of the p53 axis across tissues untested"]},{"year":2011,"claim":"Generalized the H1-recruitment mechanism to Wnt signaling and proved H1 recruitment is mechanistically required, using an H1-binding-deficient mutant.","evidence":"Domain deletion mutagenesis, Co-IP, ChIP, Wnt reporter assays","pmids":["22083958"],"confidence":"High","gaps":["Structural basis of the CHD8–H1 interaction unknown","How H1 deposition is restricted to target genes unresolved"]},{"year":2007,"claim":"Linked CHD8 to active transcription by showing its chromodomains bind H3K4me2/me3 and that it associates with ZNF143/Staf to support RNA Pol III transcription on chromatin templates.","evidence":"MS pull-down, Co-IP, in vitro chromatin transcription, ChIP, histone peptide binding","pmids":["17938208"],"confidence":"High","gaps":["Single lab","Did not establish the breadth of Pol III versus Pol II roles"]},{"year":2009,"claim":"Placed CHD8 in the RNA Pol II elongation cycle by showing it occupies promoter-proximal regions, associates with Ser2-phosphorylated Pol II, and is needed for transcription of CCNE2/TYMS.","evidence":"ChIP, siRNA, transcriptomics, Co-IP, in vitro histone binding, drug sensitivity","pmids":["19255092"],"confidence":"High","gaps":["Did not define direct enzymatic contribution to elongation","Causality between binding and elongation not fully resolved"]},{"year":2010,"claim":"Identified physical partners of CHD8—CHD7 and the androgen receptor—expanding it into developmental syndrome and hormone-responsive transcription contexts.","evidence":"Yeast two-hybrid, Co-IP, BiFC, missense mutant analysis (CHD7); reciprocal Co-IP, ChIP, knockdown (AR)","pmids":["20453063","20308527"],"confidence":"Medium","gaps":["Discordance between Y2H and Co-IP for CHD7 mutants limits interpretation","Functional consequence of the CHD7–CHD8 complex not yet established"]},{"year":2012,"claim":"Defined CHD8's role at E2F-dependent cell-cycle genes, showing it loads E2F1/E2F3 and recruits MLL methyltransferase complexes to drive G1/S transcription and cell-cycle re-entry; also reported a PKA-anchoring (AKAP) function and a FAM124B-containing CHD7–CHD8 complex.","evidence":"ChIP-on-chip, Co-IP, siRNA, cell-cycle analysis; RII overlay (AKAP); SILAC-MS and Y2H (FAM124B)","pmids":["24265227","23071553","23285124"],"confidence":"High","gaps":["Mechanism of MLL recruitment by CHD8 not structurally defined","AKAP and FAM124B functions are Medium-confidence and not independently followed up"]},{"year":2015,"claim":"Showed CHD8 acts at enhancers in a context-dependent manner—partnering SWI/SNF to enable RNAPII recruitment and eRNA transcription at PR enhancers, and bridging BRD4 to super-enhancers via NSD3-short in AML.","evidence":"ChIP-seq, siRNA, Co-IP, DNaseI hypersensitivity (PR enhancers); Co-IP, ChIP-seq, genetic targeting, BET inhibition (AML)","pmids":["25894978","26626481"],"confidence":"High","gaps":["How CHD8 redistributes from promoters to enhancers upon stimulation unresolved","Direct remodeling contribution to enhancer accessibility versus recruitment role not separated"]},{"year":2016,"claim":"Connected CHD8 haploinsufficiency to neurodevelopmental gene regulation in vivo, identifying REST as a partner and Wnt-pathway disruption as a rescuable mechanism in cortical development.","evidence":"Chd8 heterozygous mice with RNA-seq and Co-IP; in vivo shRNA with RNA-seq, ChIP-seq, Wnt rescue, behavior","pmids":["27602517","27694995"],"confidence":"High","gaps":["Did not isolate which downstream pathway dominates the autism-relevant phenotype","Direct versus indirect REST regulation unresolved"]},{"year":2017,"claim":"Resolved CHD8's distinct biochemical remodeling behavior, showing it requires longer linker DNA and slides nucleosomes (unlike disrupting CHD6), differentiating it from paralogs.","evidence":"Purified-protein nucleosome binding, sliding, and ATPase assays on reconstituted chromatin","pmids":["28533432"],"confidence":"High","gaps":["Did not connect sliding directionality to in vivo transcriptional outcomes","Single lab biochemistry"]},{"year":2018,"claim":"Defined a successive chromatin-remodeling cascade (CHD8 → BRG1/SWI/SNF → CHD7) and MLL/KMT2 recruitment that establishes accessible promoters driving oligodendrocyte differentiation and myelination, and showed CHD8 promotes adipogenesis via C/EBPβ.","evidence":"Cell-type-specific conditional KOs, ChIP-seq, ATAC-seq, Co-IP, demethylase inhibitor rescue (myelination); Co-IP and adipocyte-specific KO (adipogenesis)","pmids":["29920279","29768199"],"confidence":"High","gaps":["Order and dependency within the remodeling cascade not fully dissected mechanistically","How lineage-specific factors target CHD8 unresolved"]},{"year":2021,"claim":"Established CHD8's central role in genome stability and stem cell survival: it complexes with ATM and restrains an ATM–p53 apoptotic axis, with p53 deletion rescuing hematopoietic, neural, and embryonic phenotypes; also defined H3K36me3/splicing regulation via SETD2/hnRNPL and a role in Rho-GTPase–dependent erythroblast cytokinesis.","evidence":"Hematopoietic conditional KOs with Co-IP, ATAC-seq, p53 rescue, BM transplantation; ChIP-seq/MS/splicing analysis; ChIP and Rho-GTPase activity assays","pmids":["34292326","33535054","36537238","35830790","36127134"],"confidence":"High","gaps":["How CHD8 loss mechanistically opens chromatin to trigger ATM remains correlative","Direct versus indirect control of Rho-GTPase and splicing genes not fully separated"]},{"year":2022,"claim":"Defined CHD8 as a context-dependent transcriptional activator cooperating with sequence-specific factors (ELK1 at ETS/MAPK targets, SOX factors) and showed dosage-sensitive control of neurodevelopmental trajectories, cell-cycle length, excitatory/inhibitory balance, spermatogenesis/meiosis, astrocyte reactivity, and enteric neural crest development.","evidence":"Isogenic human iPSC neurons and organoids with ATAC/RNA/scRNA-seq and ELK1 KD; allelic-series mESCs; cell-type-specific KOs in germ cells and astrocytes; zebrafish chd8 mutant","pmids":["36575212","35385734","36222238","38224953","39154337","36375841","32839322","33826902"],"confidence":"High","gaps":["Determinants of cell-type-specific CHD8 targeting remain only partly defined","How the same remodeler produces opposite activator/repressor outcomes across contexts is unresolved"]},{"year":null,"claim":"It remains unresolved how CHD8's single biochemical activity—nucleosome sliding and H3K4me-reading—is mechanistically converted into context-specific activation versus repression, and what structural features dictate its partner selection (H1, p53, β-catenin, E2F1, ELK1, SWI/SNF, ATM) at any given locus.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model linking remodeling output to transcriptional direction","Rules governing locus- and lineage-specific recruitment unknown","Relative contributions of remodeling versus scaffolding/adaptor functions not partitioned"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,17]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[6,7]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,12,26]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,17]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[17]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[13]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,10,11]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[0,7,12]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,7,12,14]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[17,18,31]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[12,34]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,5,26]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,16,18,27,31]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1,22,23]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[24]}],"complexes":["BRD4–NSD3-short–CHD8 super-enhancer complex","CHD7–CHD8–FAM124B complex","SWI/SNF (BRG1/BRM) associated","CHD8–p53–histone H1 / CHD8–β-catenin–histone H1 complex"],"partners":["CTNNB1","TP53","CHD7","E2F1","ELK1","ATM","REST","CEBPB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9HCK8","full_name":"ATP-dependent chromatin remodeler CHD8","aliases":["Chromo domain-containing protein 8","CHD-8"],"length_aa":2581,"mass_kda":290.5,"function":"ATP-dependent chromatin-remodeling factor, it slides nucleosomes along DNA; nucleosome sliding requires ATP (PubMed:28533432). Acts as a transcription repressor by remodeling chromatin structure and recruiting histone H1 to target genes. Suppresses p53/TP53-mediated apoptosis by recruiting histone H1 and preventing p53/TP53 transactivation activity. Acts as a negative regulator of Wnt signaling pathway by regulating beta-catenin (CTNNB1) activity. Negatively regulates CTNNB1-targeted gene expression by being recruited specifically to the promoter regions of several CTNNB1 responsive genes. Involved in both enhancer blocking and epigenetic remodeling at chromatin boundary via its interaction with CTCF. Acts as a suppressor of STAT3 activity by suppressing the LIF-induced STAT3 transcriptional activity. Also acts as a transcription activator via its interaction with ZNF143 by participating in efficient U6 RNA polymerase III transcription. Regulates alternative splicing of a core group of genes involved in neuronal differentiation, cell cycle and DNA repair. Enables H3K36me3-coupled transcription elongation and co-transcriptional RNA processing likely via interaction with HNRNPL","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9HCK8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CHD8","classification":"Not Classified","n_dependent_lines":297,"n_total_lines":1208,"dependency_fraction":0.2458609271523179},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CSNK2B","stoichiometry":0.2},{"gene":"H2AFZ","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"KPNA1","stoichiometry":0.2},{"gene":"KPNA2","stoichiometry":0.2},{"gene":"KPNA4","stoichiometry":0.2},{"gene":"KPNA6","stoichiometry":0.2},{"gene":"PHAX","stoichiometry":0.2},{"gene":"SRP9","stoichiometry":0.2},{"gene":"YY1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CHD8","total_profiled":1310},"omim":[{"mim_id":"618403","title":"FAMILY WITH SEQUENCE SIMILARITY 124, MEMBER B; FAM124B","url":"https://www.omim.org/entry/618403"},{"mim_id":"615032","title":"INTELLECTUAL DEVELOPMENTAL DISORDER WITH AUTISM AND MACROCEPHALY; IDDAM","url":"https://www.omim.org/entry/615032"},{"mim_id":"614697","title":"KATANIN, p60 SUBUNIT, A-LIKE PROTEIN 2; KATNAL2","url":"https://www.omim.org/entry/614697"},{"mim_id":"613457","title":"CHROMOSOME 14q11-q22 DELETION SYNDROME","url":"https://www.omim.org/entry/613457"},{"mim_id":"610528","title":"CHROMODOMAIN HELICASE DNA-BINDING PROTEIN 8; CHD8","url":"https://www.omim.org/entry/610528"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Primary cilium","reliability":"Additional"},{"location":"Primary cilium tip","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CHD8"},"hgnc":{"alias_symbol":["KIAA1564","DUPLIN"],"prev_symbol":["HELSNF1"]},"alphafold":{"accession":"Q9HCK8","domains":[{"cath_id":"2.40.50.40","chopping":"638-714","consensus_level":"medium","plddt":78.2061,"start":638,"end":714},{"cath_id":"2.40.50.40","chopping":"721-781","consensus_level":"medium","plddt":87.1826,"start":721,"end":781},{"cath_id":"3.40.50.10810","chopping":"804-1018_1026-1039","consensus_level":"medium","plddt":84.0403,"start":804,"end":1039},{"cath_id":"3.40.50.300","chopping":"1047-1053_1137-1284_1299-1339","consensus_level":"high","plddt":79.0874,"start":1047,"end":1339},{"cath_id":"-","chopping":"1441-1513_1545-1592","consensus_level":"medium","plddt":80.4736,"start":1441,"end":1592},{"cath_id":"1.10.10.60","chopping":"1603-1680_1734-1770","consensus_level":"medium","plddt":74.617,"start":1603,"end":1770},{"cath_id":"3.40.5.120","chopping":"2312-2362","consensus_level":"medium","plddt":77.462,"start":2312,"end":2362}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HCK8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HCK8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HCK8-F1-predicted_aligned_error_v6.png","plddt_mean":53.91},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CHD8","jax_strain_url":"https://www.jax.org/strain/search?query=CHD8"},"sequence":{"accession":"Q9HCK8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9HCK8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9HCK8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HCK8"}},"corpus_meta":[{"pmid":"24998929","id":"PMC_24998929","title":"Disruptive CHD8 mutations define a subtype of autism early in development.","date":"2014","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/24998929","citation_count":594,"is_preprint":false},{"pmid":"27602517","id":"PMC_27602517","title":"CHD8 haploinsufficiency results in autistic-like phenotypes in mice.","date":"2016","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/27602517","citation_count":269,"is_preprint":false},{"pmid":"25294932","id":"PMC_25294932","title":"CHD8 regulates neurodevelopmental pathways associated with autism spectrum disorder in neural progenitors.","date":"2014","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/25294932","citation_count":265,"is_preprint":false},{"pmid":"25752243","id":"PMC_25752243","title":"The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment.","date":"2015","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/25752243","citation_count":256,"is_preprint":false},{"pmid":"28321286","id":"PMC_28321286","title":"CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in cerebral organoids derived from iPS cells.","date":"2017","source":"Molecular autism","url":"https://pubmed.ncbi.nlm.nih.gov/28321286","citation_count":204,"is_preprint":false},{"pmid":"28671691","id":"PMC_28671691","title":"Germline Chd8 haploinsufficiency alters brain development in mouse.","date":"2017","source":"Nature neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/28671691","citation_count":195,"is_preprint":false},{"pmid":"27694995","id":"PMC_27694995","title":"Chd8 mediates cortical neurogenesis via transcriptional regulation of cell cycle and Wnt signaling.","date":"2016","source":"Nature neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/27694995","citation_count":183,"is_preprint":false},{"pmid":"28402856","id":"PMC_28402856","title":"Chd8 Mutation Leads to Autistic-like Behaviors and Impaired Striatal Circuits.","date":"2017","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/28402856","citation_count":178,"is_preprint":false},{"pmid":"18378692","id":"PMC_18378692","title":"CHD8 is an ATP-dependent chromatin remodeling factor that regulates beta-catenin target genes.","date":"2008","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18378692","citation_count":163,"is_preprint":false},{"pmid":"19151705","id":"PMC_19151705","title":"CHD8 suppresses p53-mediated apoptosis through histone H1 recruitment during early embryogenesis.","date":"2009","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/19151705","citation_count":153,"is_preprint":false},{"pmid":"26626481","id":"PMC_26626481","title":"NSD3-Short Is an Adaptor Protein that Couples BRD4 to the CHD8 Chromatin Remodeler.","date":"2015","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/26626481","citation_count":133,"is_preprint":false},{"pmid":"29920279","id":"PMC_29920279","title":"Dual Requirement of CHD8 for Chromatin Landscape Establishment and Histone Methyltransferase Recruitment to Promote CNS Myelination and Repair.","date":"2018","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/29920279","citation_count":123,"is_preprint":false},{"pmid":"26491539","id":"PMC_26491539","title":"CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in neurodevelopment.","date":"2015","source":"Molecular autism","url":"https://pubmed.ncbi.nlm.nih.gov/26491539","citation_count":120,"is_preprint":false},{"pmid":"22083958","id":"PMC_22083958","title":"Histone H1 recruitment by CHD8 is essential for suppression of the Wnt-β-catenin signaling pathway.","date":"2011","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/22083958","citation_count":110,"is_preprint":false},{"pmid":"25989142","id":"PMC_25989142","title":"The autism-associated gene chromodomain helicase DNA-binding protein 8 (CHD8) regulates noncoding RNAs and autism-related genes.","date":"2015","source":"Translational psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/25989142","citation_count":85,"is_preprint":false},{"pmid":"26733790","id":"PMC_26733790","title":"Mutations and Modeling of the Chromatin Remodeler CHD8 Define an Emerging Autism Etiology.","date":"2015","source":"Frontiers in neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/26733790","citation_count":74,"is_preprint":false},{"pmid":"19255092","id":"PMC_19255092","title":"The chromatin remodeling factor CHD8 interacts with elongating RNA polymerase II and controls expression of the cyclin E2 gene.","date":"2009","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/19255092","citation_count":71,"is_preprint":false},{"pmid":"30574290","id":"PMC_30574290","title":"Autism-associated CHD8 deficiency impairs axon development and migration of cortical neurons.","date":"2018","source":"Molecular autism","url":"https://pubmed.ncbi.nlm.nih.gov/30574290","citation_count":70,"is_preprint":false},{"pmid":"35241668","id":"PMC_35241668","title":"Changes to gut amino acid transporters and microbiome associated with increased E/I ratio in Chd8+/- mouse model of ASD-like behavior.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35241668","citation_count":69,"is_preprint":false},{"pmid":"20453063","id":"PMC_20453063","title":"CHD8 interacts with CHD7, a protein which is mutated in CHARGE syndrome.","date":"2010","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20453063","citation_count":68,"is_preprint":false},{"pmid":"35385734","id":"PMC_35385734","title":"CHD8 haploinsufficiency links autism to transient alterations in excitatory and inhibitory trajectories.","date":"2022","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/35385734","citation_count":65,"is_preprint":false},{"pmid":"15367660","id":"PMC_15367660","title":"Early embryonic death in mice lacking the beta-catenin-binding protein Duplin.","date":"2004","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15367660","citation_count":63,"is_preprint":false},{"pmid":"24265227","id":"PMC_24265227","title":"The chromatin remodeller CHD8 is required for E2F-dependent transcription activation of S-phase genes.","date":"2013","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/24265227","citation_count":62,"is_preprint":false},{"pmid":"34259569","id":"PMC_34259569","title":"Gene-Environment Interactions in Developmental Neurotoxicity: a Case Study of Synergy between Chlorpyrifos and CHD8 Knockout in Human BrainSpheres.","date":"2021","source":"Environmental health perspectives","url":"https://pubmed.ncbi.nlm.nih.gov/34259569","citation_count":59,"is_preprint":false},{"pmid":"17938208","id":"PMC_17938208","title":"CHD8 associates with human Staf and contributes to efficient U6 RNA polymerase III transcription.","date":"2007","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17938208","citation_count":55,"is_preprint":false},{"pmid":"28533432","id":"PMC_28533432","title":"The ATP-dependent chromatin remodeling enzymes CHD6, CHD7, and CHD8 exhibit distinct nucleosome binding and remodeling activities.","date":"2017","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28533432","citation_count":55,"is_preprint":false},{"pmid":"31311581","id":"PMC_31311581","title":"Functional DNA methylation signatures for autism spectrum disorder genomic risk loci: 16p11.2 deletions and CHD8 variants.","date":"2019","source":"Clinical epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/31311581","citation_count":52,"is_preprint":false},{"pmid":"34440307","id":"PMC_34440307","title":"The Mechanisms of CHD8 in Neurodevelopment and Autism Spectrum Disorders.","date":"2021","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/34440307","citation_count":50,"is_preprint":false},{"pmid":"33826902","id":"PMC_33826902","title":"The autism-associated protein CHD8 is required for cerebellar development and motor function.","date":"2021","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/33826902","citation_count":46,"is_preprint":false},{"pmid":"33837267","id":"PMC_33837267","title":"Cell-type-specific synaptic imbalance and disrupted homeostatic plasticity in cortical circuits of ASD-associated Chd8 haploinsufficient mice.","date":"2021","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/33837267","citation_count":44,"is_preprint":false},{"pmid":"32142125","id":"PMC_32142125","title":"Oligodendrocyte dysfunction due to Chd8 mutation gives rise to behavioral deficits in mice.","date":"2020","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32142125","citation_count":41,"is_preprint":false},{"pmid":"31001818","id":"PMC_31001818","title":"The clinical presentation caused by truncating CHD8 variants.","date":"2019","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31001818","citation_count":39,"is_preprint":false},{"pmid":"36738737","id":"PMC_36738737","title":"Mouse population genetics phenocopies heterogeneity of human Chd8 haploinsufficiency.","date":"2023","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/36738737","citation_count":39,"is_preprint":false},{"pmid":"32839322","id":"PMC_32839322","title":"CHD8 dosage regulates transcription in pluripotency and early murine neural differentiation.","date":"2020","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/32839322","citation_count":38,"is_preprint":false},{"pmid":"33627187","id":"PMC_33627187","title":"Distinct, dosage-sensitive requirements for the autism-associated factor CHD8 during cortical development.","date":"2021","source":"Molecular autism","url":"https://pubmed.ncbi.nlm.nih.gov/33627187","citation_count":38,"is_preprint":false},{"pmid":"31721432","id":"PMC_31721432","title":"The CHD8 overgrowth syndrome: A detailed evaluation of an emerging overgrowth phenotype in 27 patients.","date":"2019","source":"American journal of medical genetics. Part C, Seminars in medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31721432","citation_count":38,"is_preprint":false},{"pmid":"26789910","id":"PMC_26789910","title":"A de novo frameshift mutation in chromodomain helicase DNA-binding domain 8 (CHD8): A case report and literature review.","date":"2016","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/26789910","citation_count":38,"is_preprint":false},{"pmid":"20308527","id":"PMC_20308527","title":"Regulation of androgen-responsive transcription by the chromatin remodeling factor CHD8.","date":"2010","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/20308527","citation_count":37,"is_preprint":false},{"pmid":"31980904","id":"PMC_31980904","title":"De novo variants in the Helicase-C domain of CHD8 are associated with severe phenotypes including autism, language disability and overgrowth.","date":"2020","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31980904","citation_count":37,"is_preprint":false},{"pmid":"33023670","id":"PMC_33023670","title":"Chd8 haploinsufficiency impairs early brain development and protein homeostasis later in life.","date":"2020","source":"Molecular autism","url":"https://pubmed.ncbi.nlm.nih.gov/33023670","citation_count":34,"is_preprint":false},{"pmid":"25894978","id":"PMC_25894978","title":"The chromatin Remodeler CHD8 is required for activation of progesterone receptor-dependent enhancers.","date":"2015","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25894978","citation_count":34,"is_preprint":false},{"pmid":"30692911","id":"PMC_30692911","title":"Common CHD8 Genomic Targets Contrast With Model-Specific Transcriptional Impacts of CHD8 Haploinsufficiency.","date":"2019","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/30692911","citation_count":34,"is_preprint":false},{"pmid":"31526516","id":"PMC_31526516","title":"Clinical Phenotypes of Carriers of Mutations in CHD8 or Its Conserved Target Genes.","date":"2019","source":"Biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/31526516","citation_count":32,"is_preprint":false},{"pmid":"30670789","id":"PMC_30670789","title":"A distinct neurodevelopmental syndrome with intellectual disability, autism spectrum disorder, characteristic facies, and macrocephaly is caused by defects in CHD8.","date":"2019","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30670789","citation_count":31,"is_preprint":false},{"pmid":"25257502","id":"PMC_25257502","title":"Recurrent ∼100 Kb microdeletion in the chromosomal region 14q11.2, involving CHD8 gene, is associated with autism and macrocephaly.","date":"2014","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/25257502","citation_count":30,"is_preprint":false},{"pmid":"33477995","id":"PMC_33477995","title":"Chromatin Remodeler CHD8 in Autism and Brain Development.","date":"2021","source":"Journal of clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33477995","citation_count":29,"is_preprint":false},{"pmid":"31112698","id":"PMC_31112698","title":"Stem Cell Proliferation Is Kept in Check by the Chromatin Regulators Kismet/CHD7/CHD8 and Trr/MLL3/4.","date":"2019","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/31112698","citation_count":28,"is_preprint":false},{"pmid":"33626347","id":"PMC_33626347","title":"Excitatory neuronal CHD8 in the regulation of neocortical development and sensory-motor behaviors.","date":"2021","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/33626347","citation_count":28,"is_preprint":false},{"pmid":"25499215","id":"PMC_25499215","title":"Frequent disruption of chromodomain helicase DNA-binding protein 8 (CHD8) and functionally associated chromatin regulators in prostate cancer.","date":"2014","source":"Neoplasia (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/25499215","citation_count":28,"is_preprint":false},{"pmid":"36182950","id":"PMC_36182950","title":"The phenotypic spectrum and genotype-phenotype correlations in 106 patients with variants in major autism gene CHD8.","date":"2022","source":"Translational psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/36182950","citation_count":27,"is_preprint":false},{"pmid":"26921529","id":"PMC_26921529","title":"CHD8 intragenic deletion associated with autism spectrum disorder.","date":"2016","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26921529","citation_count":26,"is_preprint":false},{"pmid":"28781807","id":"PMC_28781807","title":"Amplification of the NSD3-BRD4-CHD8 pathway in pelvic high-grade serous carcinomas of tubo-ovarian and endometrial origin.","date":"2017","source":"Molecular and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/28781807","citation_count":25,"is_preprint":false},{"pmid":"36878905","id":"PMC_36878905","title":"CHD8 mutations increase gliogenesis to enlarge brain size in the nonhuman primate.","date":"2023","source":"Cell discovery","url":"https://pubmed.ncbi.nlm.nih.gov/36878905","citation_count":24,"is_preprint":false},{"pmid":"32123560","id":"PMC_32123560","title":"Critical roles of microRNA-141-3p and CHD8 in hypoxia/reoxygenation-induced cardiomyocyte apoptosis.","date":"2020","source":"Cell & bioscience","url":"https://pubmed.ncbi.nlm.nih.gov/32123560","citation_count":22,"is_preprint":false},{"pmid":"34292326","id":"PMC_34292326","title":"The chromatin remodeler CHD8 governs hematopoietic stem/progenitor survival by regulating ATM-mediated P53 protein stability.","date":"2021","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/34292326","citation_count":22,"is_preprint":false},{"pmid":"23285124","id":"PMC_23285124","title":"Identification and characterization of FAM124B as a novel component of a CHD7 and CHD8 containing complex.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23285124","citation_count":22,"is_preprint":false},{"pmid":"16452319","id":"PMC_16452319","title":"Suppression of STAT3 activity by Duplin, which is a negative regulator of the Wnt signal.","date":"2006","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16452319","citation_count":21,"is_preprint":false},{"pmid":"33535054","id":"PMC_33535054","title":"The autism-related protein CHD8 contributes to the stemness and differentiation of mouse hematopoietic stem cells.","date":"2021","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/33535054","citation_count":21,"is_preprint":false},{"pmid":"29768199","id":"PMC_29768199","title":"The Autism-Related Protein CHD8 Cooperates with C/EBPβ to Regulate Adipogenesis.","date":"2018","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/29768199","citation_count":21,"is_preprint":false},{"pmid":"33933000","id":"PMC_33933000","title":"Oxytocin ameliorates impaired social behavior in a Chd8 haploinsufficiency mouse model of autism.","date":"2021","source":"BMC neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/33933000","citation_count":21,"is_preprint":false},{"pmid":"36537238","id":"PMC_36537238","title":"CHD8 suppression impacts on histone H3 lysine 36 trimethylation and alters RNA alternative splicing.","date":"2022","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/36537238","citation_count":20,"is_preprint":false},{"pmid":"36127134","id":"PMC_36127134","title":"Conserved and Distinct Functions of the Autism-Related Chromatin Remodeler CHD8 in Embryonic and Adult Forebrain Neurogenesis.","date":"2022","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/36127134","citation_count":20,"is_preprint":false},{"pmid":"33228730","id":"PMC_33228730","title":"Chd8 mutation in oligodendrocytes alters microstructure and functional connectivity in the mouse brain.","date":"2020","source":"Molecular brain","url":"https://pubmed.ncbi.nlm.nih.gov/33228730","citation_count":20,"is_preprint":false},{"pmid":"35365720","id":"PMC_35365720","title":"Developmental pyrethroid exposure and age influence phenotypes in a Chd8 haploinsufficient autism mouse model.","date":"2022","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/35365720","citation_count":20,"is_preprint":false},{"pmid":"39914389","id":"PMC_39914389","title":"Single-cell delineation of the microbiota-gut-brain axis: Probiotic intervention in Chd8 haploinsufficient mice.","date":"2025","source":"Cell genomics","url":"https://pubmed.ncbi.nlm.nih.gov/39914389","citation_count":19,"is_preprint":false},{"pmid":"11744694","id":"PMC_11744694","title":"Nuclear localization of Duplin, a beta-catenin-binding protein, is essential for its inhibitory activity on the Wnt signaling pathway.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11744694","citation_count":19,"is_preprint":false},{"pmid":"32034634","id":"PMC_32034634","title":"Chd8 Rescued TBI-Induced Neurological Deficits by Suppressing Apoptosis and Autophagy Via Wnt Signaling Pathway.","date":"2020","source":"Cellular and molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/32034634","citation_count":18,"is_preprint":false},{"pmid":"36575212","id":"PMC_36575212","title":"The autism risk factor CHD8 is a chromatin activator in human neurons and functionally dependent on the ERK-MAPK pathway effector ELK1.","date":"2022","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/36575212","citation_count":18,"is_preprint":false},{"pmid":"37268684","id":"PMC_37268684","title":"Deletion of the autism-related gene Chd8 alters activity-dependent transcriptional responses in mouse postmitotic neurons.","date":"2023","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/37268684","citation_count":17,"is_preprint":false},{"pmid":"32815320","id":"PMC_32815320","title":"A Novel Chd8 Mutant Mouse Displays Altered Ultrasonic Vocalizations and Enhanced Motor Coordination.","date":"2020","source":"Autism research : official journal of the International Society for Autism Research","url":"https://pubmed.ncbi.nlm.nih.gov/32815320","citation_count":17,"is_preprint":false},{"pmid":"32309624","id":"PMC_32309624","title":"A de novo variant of CHD8 in a patient with autism spectrum disorder.","date":"2020","source":"Discoveries (Craiova, Romania)","url":"https://pubmed.ncbi.nlm.nih.gov/32309624","citation_count":17,"is_preprint":false},{"pmid":"33806835","id":"PMC_33806835","title":"Single-Cell Transcriptomics Supports a Role of CHD8 in Autism.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33806835","citation_count":16,"is_preprint":false},{"pmid":"36375841","id":"PMC_36375841","title":"Loss of autism-candidate CHD8 perturbs neural crest development and intestinal homeostatic balance.","date":"2022","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/36375841","citation_count":16,"is_preprint":false},{"pmid":"39154337","id":"PMC_39154337","title":"Autism-associated CHD8 controls reactive gliosis and neuroinflammation via remodeling chromatin in astrocytes.","date":"2024","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/39154337","citation_count":15,"is_preprint":false},{"pmid":"33859315","id":"PMC_33859315","title":"Chd8 regulates X chromosome inactivation in mouse through fine-tuning control of Xist expression.","date":"2021","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/33859315","citation_count":15,"is_preprint":false},{"pmid":"37783686","id":"PMC_37783686","title":"CHD8 regulates gut epithelial cell function and affects autism-related behaviors through the gut-brain axis.","date":"2023","source":"Translational psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/37783686","citation_count":14,"is_preprint":false},{"pmid":"33141432","id":"PMC_33141432","title":"High glucose-ROS conditions enhance the progression in cholangiocarcinoma via upregulation of MAN2A2 and CHD8.","date":"2020","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/33141432","citation_count":13,"is_preprint":false},{"pmid":"26834018","id":"PMC_26834018","title":"Novel 14q11.2 microduplication including the CHD8 and SUPT16H genes associated with developmental delay.","date":"2016","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/26834018","citation_count":13,"is_preprint":false},{"pmid":"31823155","id":"PMC_31823155","title":"Neurodevelopmental phenotype associated with CHD8-SUPT16H duplication.","date":"2019","source":"Neurogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/31823155","citation_count":12,"is_preprint":false},{"pmid":"38224953","id":"PMC_38224953","title":"Chromatin remodeler CHD8 is required for spermatogonial proliferation and early meiotic progression.","date":"2024","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/38224953","citation_count":12,"is_preprint":false},{"pmid":"39149047","id":"PMC_39149047","title":"Molecular and network disruptions in neurodevelopment uncovered by single cell transcriptomics analysis of CHD8 heterozygous cerebral organoids.","date":"2024","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/39149047","citation_count":12,"is_preprint":false},{"pmid":"38438524","id":"PMC_38438524","title":"The complex etiology of autism spectrum disorder due to missense mutations of CHD8.","date":"2024","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/38438524","citation_count":11,"is_preprint":false},{"pmid":"34686651","id":"PMC_34686651","title":"CHD8 safeguards early neuroectoderm differentiation in human ESCs and protects from apoptosis during neurogenesis.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/34686651","citation_count":11,"is_preprint":false},{"pmid":"32267004","id":"PMC_32267004","title":"A spontaneous missense mutation in the chromodomain helicase DNA-binding protein 8 (CHD8) gene: a novel association with congenital myasthenic syndrome.","date":"2020","source":"Neuropathology and applied neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/32267004","citation_count":11,"is_preprint":false},{"pmid":"23071553","id":"PMC_23071553","title":"Chromodomain helicase binding protein 8 (Chd8) is a novel A-kinase anchoring protein expressed during rat cardiac development.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23071553","citation_count":11,"is_preprint":false},{"pmid":"36222238","id":"PMC_36222238","title":"Autism-associated CHD8 keeps proliferation of human neural progenitors in check by lengthening the G1 phase of the cell cycle.","date":"2022","source":"Biology open","url":"https://pubmed.ncbi.nlm.nih.gov/36222238","citation_count":11,"is_preprint":false},{"pmid":"35231638","id":"PMC_35231638","title":"Deletion of CHD8 in cerebellar granule neuron progenitors leads to severe cerebellar hypoplasia, ataxia, and psychiatric behavior in mice.","date":"2022","source":"Journal of genetics and genomics = Yi chuan xue bao","url":"https://pubmed.ncbi.nlm.nih.gov/35231638","citation_count":10,"is_preprint":false},{"pmid":"26588464","id":"PMC_26588464","title":"The Chromatin Regulator CHD8 Is a Context-Dependent Mediator of Cell Survival in Murine Hematopoietic Malignancies.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26588464","citation_count":10,"is_preprint":false},{"pmid":"30376831","id":"PMC_30376831","title":"Autism spectrum disorder early in development associated with CHD8 mutations among two Chinese children.","date":"2018","source":"BMC pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/30376831","citation_count":10,"is_preprint":false},{"pmid":"38288845","id":"PMC_38288845","title":"Neurodevelopmental functions of CHD8: new insights and questions.","date":"2024","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/38288845","citation_count":9,"is_preprint":false},{"pmid":"36385756","id":"PMC_36385756","title":"Age-differential sexual dimorphism in CHD8-S62X-mutant mouse behaviors.","date":"2022","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/36385756","citation_count":9,"is_preprint":false},{"pmid":"39741407","id":"PMC_39741407","title":"SINEUP RNA rescues molecular phenotypes associated with CHD8 suppression in autism spectrum disorder model systems.","date":"2024","source":"Molecular therapy : the journal of the American Society of Gene Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/39741407","citation_count":8,"is_preprint":false},{"pmid":"38557009","id":"PMC_38557009","title":"Male-Dominant Effects of Chd8 Haploinsufficiency on Synaptic Phenotypes during Development in Mouse Prefrontal Cortex.","date":"2024","source":"ACS chemical neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/38557009","citation_count":8,"is_preprint":false},{"pmid":"34746699","id":"PMC_34746699","title":"In vivo targeted DamID identifies CHD8 genomic targets in fetal mouse brain.","date":"2021","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/34746699","citation_count":7,"is_preprint":false},{"pmid":"25735987","id":"PMC_25735987","title":"Long term follow-up in a patient with a de novo microdeletion of 14q11.2 involving CHD8.","date":"2015","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/25735987","citation_count":7,"is_preprint":false},{"pmid":"38622540","id":"PMC_38622540","title":"Shared and divergent mental health characteristics of ADNP-, CHD8- and DYRK1A-related neurodevelopmental conditions.","date":"2024","source":"Journal of neurodevelopmental disorders","url":"https://pubmed.ncbi.nlm.nih.gov/38622540","citation_count":6,"is_preprint":false},{"pmid":"36873104","id":"PMC_36873104","title":"Age-differential sexual dimorphisms in CHD8-S62X-mutant mouse synapses and transcriptomes.","date":"2023","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/36873104","citation_count":6,"is_preprint":false},{"pmid":"33198579","id":"PMC_33198579","title":"Overexpression of microRNA-221 promotes the differentiation of stem cells from human exfoliated deciduous teeth to neurons through activation of Wnt/β-catenin pathway via inhibition of CHD8.","date":"2020","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/33198579","citation_count":6,"is_preprint":false},{"pmid":"34880900","id":"PMC_34880900","title":"Natural SINEUP RNAs in Autism Spectrum Disorders: RAB11B-AS1 Dysregulation in a Neuronal CHD8 Suppression Model Leads to RAB11B Protein Increase.","date":"2021","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34880900","citation_count":6,"is_preprint":false},{"pmid":"35830790","id":"PMC_35830790","title":"Autism-associated chromatin remodeler CHD8 regulates erythroblast cytokinesis and fine-tunes the balance of Rho GTPase signaling.","date":"2022","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/35830790","citation_count":5,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46955,"output_tokens":9384,"usd":0.140813,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":19748,"output_tokens":6134,"usd":0.126045,"stage2_stop_reason":"end_turn"},"total_usd":0.266858,"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\": 2008,\n      \"finding\": \"CHD8 directly interacts with β-catenin, is recruited to promoter regions of β-catenin-responsive genes, and negatively regulates β-catenin-targeted gene expression; CHD8 was demonstrated to have ATP-dependent chromatin remodeling activity (first demonstration for the CHD6-9 subfamily), as shown by shRNA knockdown activating β-catenin target genes and conservation in Drosophila kismet knockdown.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, shRNA knockdown + transcriptome analysis, in vitro chromatin remodeling assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro chromatin remodeling assay combined with direct binding and ChIP, replicated via Drosophila ortholog knockdown\",\n      \"pmids\": [\"18378692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CHD8 binds p53 and suppresses p53-mediated transactivation and apoptosis by promoting formation of a trimeric CHD8–p53–histone H1 complex on chromatin; depletion of CHD8 or histone H1 activates p53 and causes apoptosis; Chd8-/- mice die early in embryogenesis with widespread apoptosis rescued by p53 deletion.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, shRNA knockdown, Chd8-/- and Chd8-/-;p53-/- double-knockout mice, apoptosis assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (Co-IP, ChIP, genetic epistasis with p53 KO rescue), replicated in vitro and in vivo\",\n      \"pmids\": [\"19151705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CHD8 suppresses Wnt–β-catenin signaling by recruiting histone H1 to Wnt target genes, forming a trimeric CHD8–β-catenin–H1 complex on chromatin; a CHD8 mutant lacking the histone H1 binding domain lost inhibitory activity, demonstrating that H1 recruitment is mechanistically essential.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, domain deletion mutagenesis, Wnt reporter assays, siRNA knockdown\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — domain mutagenesis combined with Co-IP and functional reporter assays, mechanistically extends prior p53 finding to Wnt pathway\",\n      \"pmids\": [\"22083958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Duplin (CHD8 short isoform) is translocated to the nucleus via interaction with importin-α through basic amino acid clusters; nuclear localization is essential for its inhibitory activity on Wnt/β-catenin–Tcf transcription and for ventralization in Xenopus; a cytoplasmic-retained Duplin mutant (Δ500-584) bound β-catenin normally but could not inhibit Wnt signaling.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, deletion mutagenesis, Xenopus embryo ventralization assay, mammalian Wnt reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — domain mutagenesis combined with functional assays in two model systems (mammalian cells and Xenopus embryos)\",\n      \"pmids\": [\"11744694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Germline deletion of Duplin/CHD8 in mice causes early embryonic lethality (arrest at E7.5) with massive apoptosis and failure to form primitive streak/mesoderm; β-catenin target genes were not upregulated in null embryos, indicating the developmental requirement is independent of Wnt-inhibitory function.\",\n      \"method\": \"Chd8/Duplin knockout mice, histology, in situ hybridization for β-catenin target genes\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic knockout with defined phenotypic and molecular readout; negative result (no Wnt upregulation) mechanistically informative\",\n      \"pmids\": [\"15367660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Duplin/CHD8 interacts with PIAS3 and suppresses LIF-induced STAT3 transcriptional activity independently of SUMO modification; Duplin inhibits STAT3 binding to DNA without affecting STAT3 tyrosine phosphorylation or nuclear localization.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, STAT3 reporter assay, sumoylation assay, EMSA\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional reporter and EMSA, single lab\",\n      \"pmids\": [\"16452319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CHD8 associates with the transcription factor Staf (ZNF143) and contributes to efficient RNA Pol III transcription from the human U6 promoter on a chromatin template; CHD8 tandem chromodomains bind histone H3 di- and tri-methylated at K4; CHD8 occupies the U6 and IRF3 promoters in vivo.\",\n      \"method\": \"Mass spectrometry pull-down, co-immunoprecipitation, in vitro chromatin transcription assay, ChIP, histone peptide binding assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro chromatin transcription reconstitution combined with Co-IP and ChIP, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"17938208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CHD8 binds constitutively to 5′ promoter-proximal regions of CCNE2 (cyclin E2) and TYMS regardless of cell-cycle phase; CHD8 associates with elongating (CTD Ser2-phosphorylated) RNA Pol II; CHD8-depleted cells are hypersensitive to drugs inhibiting RNAPII CTD Ser2 phosphorylation, implicating CHD8 in an early step of the RNAPII transcription elongation cycle; CHD8 chromodomains bind H3K4me2 in vitro.\",\n      \"method\": \"ChIP, siRNA knockdown, transcriptome analysis, co-immunoprecipitation, in vitro histone binding assay, drug sensitivity assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP combined with Co-IP, functional drug sensitivity, and in vitro binding, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"19255092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CHD8 directly interacts with CHD7 (mutated in CHARGE syndrome); interaction confirmed by yeast two-hybrid, co-immunoprecipitation, and bimolecular fluorescence complementation; certain CHD7 missense mutations in the interaction domain (p.Trp2091Arg, p.His2096Arg, p.Gly2108Arg) disrupt the direct CHD7–CHD8 interaction in yeast two-hybrid but not in co-immunoprecipitation, suggesting both direct and indirect (via linker proteins) interaction modes.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, bimolecular fluorescence complementation assay, missense mutant analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — three orthogonal methods, but discordance between assays limits interpretation; single lab\",\n      \"pmids\": [\"20453063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CHD8 directly associates with the androgen receptor (AR) and co-localizes with AR at the TMPRSS2 enhancer upon androgen treatment; CHD8 is required for AR recruitment to the TMPRSS2 promoter and for androgen-dependent gene activation; CHD8 facilitates androgen-stimulated cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, siRNA knockdown, reporter assay, cell proliferation assay\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus ChIP and functional knockdown, single lab\",\n      \"pmids\": [\"20308527\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"FAM124B was identified as a novel component of a CHD7–CHD8 containing complex; direct binding of FAM124B to CHD8 was confirmed by yeast two-hybrid; FAM124B is a nuclear protein widely expressed in embryonic and adult mouse tissues.\",\n      \"method\": \"SILAC mass spectrometry, co-immunoprecipitation, yeast two-hybrid, immunofluorescence\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — SILAC-MS discovery confirmed by Co-IP and Y2H, single lab\",\n      \"pmids\": [\"23285124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CHD8 (Chd8-S isoform) contains a PKA-binding domain in its amino terminus and functions as an A-kinase anchoring protein (AKAP); Chd8-S binds RIIα of PKA as shown by RII overlay and co-immunoprecipitation; binding requires phosphorylation of RIIα; CHD8 localizes to nuclear and perinuclear compartments in HeLa cells and cardiomyocytes.\",\n      \"method\": \"RII overlay assay, co-immunoprecipitation, immunofluorescence, mRNA expression analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding demonstrated by two methods (RII overlay + Co-IP) with phosphorylation dependency, localization confirmed; single lab\",\n      \"pmids\": [\"23071553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CHD8 binds ~2,000 active promoters genome-wide, with enrichment at E2F-dependent genes; CHD8 is required for G1/S-specific expression of E2F-target genes and cell cycle re-entry; CHD8 interacts with E2F1, and loading of E2F1 and E2F3 (but not E2F4) onto S-phase gene promoters requires CHD8; recruitment of MLL histone methyltransferase complexes to S-phase gene promoters is severely impaired without CHD8.\",\n      \"method\": \"ChIP-on-chip, co-immunoprecipitation, siRNA knockdown, cell cycle analysis, reporter assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-on-chip, Co-IP, functional knockdown phenotypes, multiple orthogonal methods; single lab\",\n      \"pmids\": [\"24265227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NSD3-short isoform links BRD4 to CHD8 as an adaptor protein in acute myeloid leukemia; BRD4, NSD3, and CHD8 co-localize across the AML genome at super-enhancers and are co-released upon BET bromodomain inhibition; genetic targeting of CHD8 mimics the phenotypic and transcriptional effects of BRD4 inhibition in AML cells.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq, shRNA knockdown, genetic targeting, BET inhibitor treatment\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, ChIP-seq, and functional genetic targeting with defined phenotypic readout; multiple orthogonal approaches in single rigorous study\",\n      \"pmids\": [\"26626481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CHD8 binds to progesterone receptor (PR)-activated enhancers upon progestin stimulation (re-localizing from promoters); CHD8 depletion impairs progestin-dependent gene regulation; CHD8 interacts with the SWI/SNF complex and depletion of BRG1/BRM impairs CHD8 recruitment; CHD8 is required for RNAPII recruitment to enhancers and for enhancer RNA (eRNA) transcription, and contributes to DNaseI accessibility at enhancers (but not H3K27 acetylation).\",\n      \"method\": \"ChIP-seq, siRNA knockdown, co-immunoprecipitation, DNaseI hypersensitivity assay, RT-qPCR for eRNA\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq, Co-IP, functional knockdown with multiple chromatin and transcriptional readouts; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"25894978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CHD8 haploinsufficiency in mice causes small but global gene expression changes in the brain and is associated with abnormal activation of REST (RE-1 silencing transcription factor), which suppresses neuronal gene transcription; CHD8 physically interacts with REST in the mouse brain as shown by co-immunoprecipitation.\",\n      \"method\": \"Chd8 heterozygous mutant mice, RNA-seq, co-immunoprecipitation, gene set enrichment analysis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-immunoprecipitation of endogenous proteins combined with genome-wide transcriptomics and in vivo mouse model\",\n      \"pmids\": [\"27602517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Chd8 knockdown during cortical development impairs neural progenitor proliferation and differentiation; Chd8 stimulates transcription of cell cycle genes and precludes neural-specific gene induction by regulating PRC2 complex component expression; Chd8 knockdown disrupts Wnt signaling transducer expression, and enhancing Wnt signaling rescues transcriptional and behavioral deficits caused by Chd8 knockdown.\",\n      \"method\": \"shRNA knockdown in vivo, RNA-seq, ChIP-seq, Wnt pathway rescue experiments, behavioral assays\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockdown with transcriptome + ChIP-seq and pathway rescue, multiple orthogonal methods\",\n      \"pmids\": [\"27694995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CHD8 exhibits distinct nucleosome binding and remodeling properties from CHD6 and CHD7: CHD8 requires longer linker DNA for nucleosome binding than CHD7; CHD8 slides nucleosomes to positions with more flanking linker DNA; CHD6 disrupts nucleosomes (non-sliding), while CHD7 and CHD8 slide them.\",\n      \"method\": \"Purified protein biochemical analysis: nucleosome binding assays, nucleosome sliding assays, ATPase assays with reconstituted chromatin\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstituted biochemical assays with purified proteins, mechanistic characterization; single lab\",\n      \"pmids\": [\"28533432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cell-type-specific deletion of Chd8 in oligodendrocyte progenitors (but not neurons) causes myelination defects in mice; CHD8 activates BRG1-associated SWI/SNF complexes that in turn activate CHD7, initiating a successive chromatin remodeling cascade; CHD8 establishes accessible chromatin landscapes and recruits MLL/KMT2 histone methyltransferase complexes around proximal promoters to promote oligodendrocyte differentiation; inhibition of histone demethylase activity partially rescues myelination defects.\",\n      \"method\": \"Conditional Chd8 knockout mice (oligodendrocyte-specific), ChIP-seq, ATAC-seq, Co-immunoprecipitation, histone demethylase inhibitor rescue\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific KO with defined phenotype, ChIP-seq, ATAC-seq, Co-IP, and pharmacological rescue; multiple orthogonal methods\",\n      \"pmids\": [\"29920279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CHD8 interacts with C/EBPβ and promotes its transactivation activity during adipocyte differentiation; CHD8 is required for upregulation of C/EBPα and PPARγ during adipogenesis; ablation of Chd8 specifically in white preadipocytes markedly reduces white adipose tissue mass in mice.\",\n      \"method\": \"Co-immunoprecipitation, conditional Chd8 knockout (adipocyte-specific), adipogenic differentiation assay, gene expression analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of interaction combined with cell-type-specific KO and defined phenotypic readout; multiple methods, single lab\",\n      \"pmids\": [\"29768199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Drosophila Kismet (CHD7/CHD8 ortholog) limits intestinal stem cell number and proliferation; Kismet and Trithorax-related (Trr/MLL3/4) co-localize genome-wide in ISCs, co-regulate genes including Cbl, and loss of kismet leads to elevated EGFR protein and signaling, promoting ISC self-renewal.\",\n      \"method\": \"Drosophila genetic loss-of-function, whole-genome ChIP profiling in ISCs, EGFR pathway analysis\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Drosophila ortholog (kismet is CHD7/CHD8 ortholog) genetic and genomic analysis; relevant to CHD8 but organism is Drosophila and kismet covers both CHD7 and CHD8\",\n      \"pmids\": [\"31112698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CHD8 is required for oligodendrocyte maturation and myelination; CHD8 regulates expression of many myelination-related genes; oligodendrocyte-specific Chd8 ablation impairs myelination, slows action potential propagation, and produces behavioral deficits including increased social interaction and anxiety.\",\n      \"method\": \"Oligodendrocyte-specific conditional Chd8 knockout mice, electrophysiology, behavioral assays, RNA-seq\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific KO with multiple functional readouts (electrophysiology, behavior, transcriptomics); replicated by same group\",\n      \"pmids\": [\"32142125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CHD8 forms a complex with ATM kinase; CHD8 deficiency increases chromatin accessibility and genomic instability in hematopoietic stem/progenitor cells (HSPCs), activating ATM kinase that phosphorylates and stabilizes p53, leading to HSPC apoptosis; p53 deletion rescues apoptotic defects and restores hematopoiesis in Chd8-/- mice.\",\n      \"method\": \"Conditional Chd8 knockout mice (hematopoietic), co-immunoprecipitation, ATAC-seq, bone marrow transplantation, p53 genetic rescue\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, ATAC-seq, genetic rescue with p53 KO, bone marrow transplantation; multiple orthogonal methods\",\n      \"pmids\": [\"34292326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CHD8 is highly expressed in hematopoietic stem cells (HSCs) and its conditional deletion induces cell cycle arrest, apoptosis, and differentiation block in HSCs via upregulation of p53 target genes; additional p53 ablation rescues stem cell function and differentiation block of CHD8-deficient HSCs.\",\n      \"method\": \"Conditional Chd8 knockout in bone marrow, colony formation assay, bone marrow transplantation, p53 genetic rescue, gene expression analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with defined molecular phenotype, functional assays, and p53 epistasis rescue\",\n      \"pmids\": [\"33535054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CHD8 depletion reduces H3K36me3 peaks at gene bodies (47.82% reduction), particularly at highly expressed CHD8-bound genes; H3K36me3 reduction correlates with altered alternative splicing of 462 genes; CHD8 interacts with the splicing regulator hnRNPL as revealed by mass spectrometry; splicing phenotype is partly mediated through SETD2.\",\n      \"method\": \"ChIP-seq for histone modifications in iPSC-derived neural progenitors, mass spectrometry (CHD8 interactome), RNA-seq for alternative splicing, shRNA knockdown\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq, MS-based interaction discovery, and splicing analysis; multiple orthogonal methods in single lab\",\n      \"pmids\": [\"36537238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cerebellar granule neuron progenitor (GNP)-specific deletion of Chd8 impairs GNP proliferation and differentiation, causes cerebellar hypoplasia and motor coordination defect; CHD8 binds preferentially to promoter regions and modulates local chromatin accessibility of transcriptionally active genes in GNPs; CHD8 regulates expression of neuronal genes in GNPs.\",\n      \"method\": \"GNP-specific conditional Chd8 KO mice, ATAC-seq, ChIP-seq, behavioral assays, RNA-seq\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific KO with ATAC-seq and ChIP-seq, defined phenotypic readout; multiple orthogonal methods\",\n      \"pmids\": [\"33826902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CHD8 functions as a transcriptional activator at its target genes in human neurons; CHD8 chromatin targeting is cell context-dependent, preferentially binding ETS motif-enriched promoters in human neurons; ELK1 (an ETS factor) is required for CHD8 recruitment specifically to ETS motif-containing sites, establishing functional cooperation between ELK1 and CHD8 at MAPK/ERK target genes.\",\n      \"method\": \"Conditional CHD8 loss-of-function allele and endogenously tagged allele in human iPSCs, ATAC-seq, RNA-seq, ELK1 knockdown, ChIP-seq\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isogenic human iPSC-derived neurons, ATAC-seq + RNA-seq + ELK1 KD epistasis, multiple orthogonal methods; single lab\",\n      \"pmids\": [\"36575212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CHD8 haploinsufficiency in cerebral organoids disrupts neurodevelopmental trajectories with cell-autonomous, accelerated generation of inhibitory neurons and delayed generation of excitatory neurons, leading to opposite expansions in their proportions; mosaic organoid design confirmed cell-autonomous nature of phenotypes; CHD8-dependent molecular defects include abnormal proliferation programs and alternative splicing.\",\n      \"method\": \"Human cerebral organoids with CHD8 haploinsufficiency (patient-specific and isogenic), single-cell RNA-seq, mosaic organoid design\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — isogenic human organoids, single-cell transcriptomics, mosaic design establishing cell autonomy; rigorous study\",\n      \"pmids\": [\"35385734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Adult ablation of CHD8 in astrocytes attenuates reactive gliosis by remodeling chromatin accessibility and changing gene expression; CHD8 loss in astrocytes impedes astrocyte proliferation and morphological elaboration; astrocytic CHD8 ablation alleviates LPS-induced neuroinflammation by altering metabolic and lipid-associated pathways and astrocyte-microglia crosstalk.\",\n      \"method\": \"Conditional Chd8 KO in astrocytes and microglia, ATAC-seq, RNA-seq, LPS neuroinflammation model, AAV-mediated gene editing in vivo\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific conditional KO, ATAC-seq, RNA-seq, in vivo pharmacological challenge; multiple orthogonal methods\",\n      \"pmids\": [\"39154337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CHD8 is required for spermatogonial proliferation and meiotic progression; germ cell-specific Chd8 ablation causes depletion of undifferentiated spermatogonia and failure of meiotic double-strand break formation leading to meiotic prophase I arrest; CHD8 directly binds and regulates genes crucial for meiosis including H3K4me3 methyltransferase genes, meiotic cohesin genes, HORMA domain genes, synaptonemal complex genes, and DNA damage response genes.\",\n      \"method\": \"Germ cell-specific conditional Chd8 KO mice, ChIP-seq, RNA-seq, histological analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific KO with ChIP-seq, RNA-seq, and defined cellular phenotype; multiple orthogonal methods, single lab\",\n      \"pmids\": [\"38224953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CHD8 regulates erythroblast cytokinesis; loss of CHD8 leads to cytokinesis failure producing binucleated and multinucleated erythroblasts; CHD8 binds directly to gene bodies of multiple Rho GTPase signaling genes in erythroblasts and its loss causes decreased RhoA and increased Rac1 and Cdc42 activities.\",\n      \"method\": \"Chd8F/FMx1-Cre/Trp53F/F double-KO mouse model, ChIP, Rho GTPase activity assays, cell imaging for cytokinesis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic model combined with ChIP and Rho GTPase functional assays; multiple orthogonal methods\",\n      \"pmids\": [\"35830790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CHD8 dosage negatively regulates neuronal gene expression to maintain pluripotency; CHD8 cooperates with SOX transcription factors in regulating chromatin accessibility; dosage-sensitive CHD8 transcriptional targets and regulated accessibility sites were identified in heterozygous and homozygous Chd8 mouse embryonic stem cells and neural progenitors.\",\n      \"method\": \"Heterozygous and homozygous Chd8 mouse ESCs and neural progenitors, ChIP-seq, ATAC-seq, RNA-seq\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq, ATAC-seq, RNA-seq with allelic series in same cell context; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"32839322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Homozygous deletion of CHD8 in postmitotic neurons downregulates neuronal gene expression and alters activity-dependent transcriptional responses to KCl depolarization; in adult mice, homozygous CHD8 ablation attenuates activity-dependent transcriptional responses in the hippocampus to kainic acid-induced seizures.\",\n      \"method\": \"Conditional Chd8 KO in postmitotic neurons, KCl depolarization assay, kainic acid seizure model, RNA-seq\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with activity-dependent transcriptional readout in two experimental paradigms; single lab\",\n      \"pmids\": [\"37268684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Chd8 regulates X chromosome inactivation by fine-tuning Xist expression during ES cell differentiation; CHD8 controls and prevents spurious transcription factor interactions within Xist regulatory regions.\",\n      \"method\": \"Chd8 conditional KO in differentiating mouse ES cells, RNA-seq, ChIP-seq, allele-specific expression analysis\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — conditional KO with gene expression and ChIP analysis; mechanistic interpretation of TF binding is indirect; single lab\",\n      \"pmids\": [\"33859315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CHD8+/- neural progenitors have a shortened G1 phase of the cell cycle with increased E-cyclin expression and elevated ERK phosphorylation, favoring self-renewing over neurogenic divisions; this was established by long-term single-cell live imaging.\",\n      \"method\": \"CHD8+/- human neural progenitor cells (CRISPR-generated), long-term single-cell live imaging, cell cycle analysis, Western blot for E-cyclins and pERK\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live single-cell imaging with molecular validation; single lab but multiple readouts\",\n      \"pmids\": [\"36222238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CHD8 is required for production and fitness of transit-amplifying intermediate progenitors (IPCs) essential for upper-layer neuron expansion in embryonic cortex; p53 loss partially rescues apoptosis and neurogenesis defects; CHD8 regulates chromatin accessibility to activate TBR2 (IPC regulator) while repressing p53-mediated apoptotic programs; in adult brain, CHD8 depletion impairs IPC differentiation from NSCs without affecting NSC proliferation.\",\n      \"method\": \"Conditional Chd8 KO (stage-specific inducible), ATAC-seq, RNA-seq, p53 genetic rescue, immunostaining, fluoxetine treatment\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — inducible conditional KO, ATAC-seq, RNA-seq, p53 epistasis rescue, multiple orthogonal methods; single lab\",\n      \"pmids\": [\"36127134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Loss of chd8 in zebrafish reduces vagal neural crest cell numbers and alters their early migration; later, there are decreased serotonin-producing enterochromaffin cells and NCC-derived serotonergic neurons, causing intestinal hyposerotonemia; transcriptomic and single-cell sequencing revealed altered serotonin/acetylcholine signaling pathway expression and disrupted immune balance in intestines.\",\n      \"method\": \"Stable constitutive chd8 mutant zebrafish, NCC lineage tracing, scRNA-seq, immunofluorescence, transcriptomic analysis\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — zebrafish KO with scRNA-seq and cellular phenotyping; mechanistic link to enteric nervous system development established\",\n      \"pmids\": [\"36375841\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CHD8 is an ATP-dependent chromatin remodeler that slides nucleosomes to positions with more flanking linker DNA; it binds H3K4me2/me3 via its tandem chromodomains and regulates transcription at Pol II and Pol III promoters by associating with elongating RNA Pol II, recruiting MLL/KMT2 histone methyltransferase complexes, and modulating H3K36me3 at gene bodies to influence alternative splicing; it suppresses Wnt–β-catenin and p53-mediated transcription by recruiting histone H1 to target genes, inhibits STAT3 DNA binding, cooperates with NSD3-short as part of a BRD4–NSD3–CHD8 super-enhancer complex, interacts with CHD7, AR, SWI/SNF, E2F1, ELK1, ATM, and C/EBPβ to control cell cycle progression, adipogenesis, erythroid cytokinesis (via Rho GTPase gene regulation), hematopoietic stem cell survival (via ATM–p53 axis), myelination (via a BRG1–CHD7 cascade and H3K4 methyltransferase recruitment), and stage-specific neurogenesis by regulating chromatin accessibility and the balance between progenitor proliferation and differentiation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CHD8 is an ATP-dependent chromatin remodeler that binds active promoters genome-wide, slides nucleosomes toward positions with greater flanking linker DNA, and reads H3K4me2/me3 through its tandem chromodomains to control transcriptional programs governing proliferation, differentiation, and cell survival across many lineages [#7, #12, #17]. It acts dually as a repressor and activator: it suppresses Wnt\\u2013\\u03b2-catenin and p53-dependent transcription by assembling trimeric complexes with \\u03b2-catenin or p53 and recruiting histone H1 to target chromatin, with H1 recruitment mechanistically essential for inhibition [#0, #1, #2], and it inhibits LIF/STAT3 transcription by blocking STAT3 DNA binding [#5]. At active genes CHD8 associates with elongating, CTD Ser2-phosphorylated RNA Pol II and is required for productive transcription, and it recruits MLL/KMT2 histone methyltransferase complexes and modulates H3K36me3 over gene bodies\\u2014an activity linked to alternative splicing through interaction with SETD2 and hnRNPL [#7, #12, #24]. CHD8 establishes accessible chromatin landscapes in cooperation with context-specific transcription factors including E2F1, ELK1, SOX factors, AR, and C/EBP\\u03b2, and partners with SWI/SNF (BRG1/BRM) and CHD7 in successive remodeling cascades [#9, #12, #14, #18, #19, #26, #31]. Through these activities CHD8 controls G1/S cell-cycle gene expression and proliferation [#12, #34], links BRD4 to super-enhancers via NSD3-short in leukemia [#13], and is required for hematopoietic stem cell survival by restraining an ATM\\u2013p53 apoptotic axis [#22, #23]. CHD8 is essential during development: germline loss causes early embryonic lethality with p53-dependent apoptosis [#1, #4], and dosage-sensitive CHD8 governs stage-specific neurogenesis, the balance of progenitor proliferation versus differentiation, oligodendrocyte myelination, and the excitatory/inhibitory neuronal balance, with haploinsufficiency disrupting neurodevelopmental trajectories in human models [#16, #18, #27, #31, #35].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established that the CHD8 short isoform Duplin must enter the nucleus to inhibit Wnt/\\u03b2-catenin\\u2013Tcf transcription, separating nuclear function from \\u03b2-catenin binding.\",\n      \"evidence\": \"Yeast two-hybrid, deletion mutagenesis, and Wnt reporter/ventralization assays in mammalian cells and Xenopus\",\n      \"pmids\": [\"11744694\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the enzymatic mechanism of Wnt inhibition\", \"Used a short isoform rather than full-length CHD8\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined an essential developmental requirement for CHD8 distinct from its Wnt-inhibitory role, since null embryos die at E7.5 with massive apoptosis but without \\u03b2-catenin target derepression.\",\n      \"evidence\": \"Chd8/Duplin knockout mice with histology and in situ hybridization\",\n      \"pmids\": [\"15367660\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the molecular cause of the apoptosis\", \"Mechanism linking CHD8 loss to lethality unresolved at this stage\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Extended CHD8's transcriptional repression to JAK/STAT signaling by showing it blocks STAT3 DNA binding via PIAS3 association.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, STAT3 reporter, and EMSA\",\n      \"pmids\": [\"16452319\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, no in vivo confirmation\", \"Did not establish whether chromatin remodeling activity is involved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated CHD8 is a bona fide ATP-dependent chromatin remodeler (first in the CHD6-9 subfamily) that directly binds \\u03b2-catenin and represses Wnt target genes.\",\n      \"evidence\": \"In vitro chromatin remodeling assay, Co-IP, ChIP, shRNA knockdown with transcriptomics, conserved in Drosophila kismet\",\n      \"pmids\": [\"18378692\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Remodeling outcome (sliding vs disruption) not yet defined\", \"Genome-wide binding not yet mapped\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified the mechanism of CHD8-dependent embryonic survival: CHD8 forms a CHD8\\u2013p53\\u2013histone H1 complex to suppress p53 transactivation and apoptosis, with embryonic lethality rescued by p53 deletion.\",\n      \"evidence\": \"Co-IP, ChIP, shRNA, Chd8-/- and Chd8-/-;p53-/- double-knockout mice\",\n      \"pmids\": [\"19151705\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how CHD8 recruits H1 to specific loci\", \"Generality of the p53 axis across tissues untested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Generalized the H1-recruitment mechanism to Wnt signaling and proved H1 recruitment is mechanistically required, using an H1-binding-deficient mutant.\",\n      \"evidence\": \"Domain deletion mutagenesis, Co-IP, ChIP, Wnt reporter assays\",\n      \"pmids\": [\"22083958\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the CHD8\\u2013H1 interaction unknown\", \"How H1 deposition is restricted to target genes unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Linked CHD8 to active transcription by showing its chromodomains bind H3K4me2/me3 and that it associates with ZNF143/Staf to support RNA Pol III transcription on chromatin templates.\",\n      \"evidence\": \"MS pull-down, Co-IP, in vitro chromatin transcription, ChIP, histone peptide binding\",\n      \"pmids\": [\"17938208\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single lab\", \"Did not establish the breadth of Pol III versus Pol II roles\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Placed CHD8 in the RNA Pol II elongation cycle by showing it occupies promoter-proximal regions, associates with Ser2-phosphorylated Pol II, and is needed for transcription of CCNE2/TYMS.\",\n      \"evidence\": \"ChIP, siRNA, transcriptomics, Co-IP, in vitro histone binding, drug sensitivity\",\n      \"pmids\": [\"19255092\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define direct enzymatic contribution to elongation\", \"Causality between binding and elongation not fully resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified physical partners of CHD8\\u2014CHD7 and the androgen receptor\\u2014expanding it into developmental syndrome and hormone-responsive transcription contexts.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, BiFC, missense mutant analysis (CHD7); reciprocal Co-IP, ChIP, knockdown (AR)\",\n      \"pmids\": [\"20453063\", \"20308527\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Discordance between Y2H and Co-IP for CHD7 mutants limits interpretation\", \"Functional consequence of the CHD7\\u2013CHD8 complex not yet established\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined CHD8's role at E2F-dependent cell-cycle genes, showing it loads E2F1/E2F3 and recruits MLL methyltransferase complexes to drive G1/S transcription and cell-cycle re-entry; also reported a PKA-anchoring (AKAP) function and a FAM124B-containing CHD7\\u2013CHD8 complex.\",\n      \"evidence\": \"ChIP-on-chip, Co-IP, siRNA, cell-cycle analysis; RII overlay (AKAP); SILAC-MS and Y2H (FAM124B)\",\n      \"pmids\": [\"24265227\", \"23071553\", \"23285124\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of MLL recruitment by CHD8 not structurally defined\", \"AKAP and FAM124B functions are Medium-confidence and not independently followed up\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed CHD8 acts at enhancers in a context-dependent manner\\u2014partnering SWI/SNF to enable RNAPII recruitment and eRNA transcription at PR enhancers, and bridging BRD4 to super-enhancers via NSD3-short in AML.\",\n      \"evidence\": \"ChIP-seq, siRNA, Co-IP, DNaseI hypersensitivity (PR enhancers); Co-IP, ChIP-seq, genetic targeting, BET inhibition (AML)\",\n      \"pmids\": [\"25894978\", \"26626481\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CHD8 redistributes from promoters to enhancers upon stimulation unresolved\", \"Direct remodeling contribution to enhancer accessibility versus recruitment role not separated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected CHD8 haploinsufficiency to neurodevelopmental gene regulation in vivo, identifying REST as a partner and Wnt-pathway disruption as a rescuable mechanism in cortical development.\",\n      \"evidence\": \"Chd8 heterozygous mice with RNA-seq and Co-IP; in vivo shRNA with RNA-seq, ChIP-seq, Wnt rescue, behavior\",\n      \"pmids\": [\"27602517\", \"27694995\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not isolate which downstream pathway dominates the autism-relevant phenotype\", \"Direct versus indirect REST regulation unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Resolved CHD8's distinct biochemical remodeling behavior, showing it requires longer linker DNA and slides nucleosomes (unlike disrupting CHD6), differentiating it from paralogs.\",\n      \"evidence\": \"Purified-protein nucleosome binding, sliding, and ATPase assays on reconstituted chromatin\",\n      \"pmids\": [\"28533432\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not connect sliding directionality to in vivo transcriptional outcomes\", \"Single lab biochemistry\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined a successive chromatin-remodeling cascade (CHD8 \\u2192 BRG1/SWI/SNF \\u2192 CHD7) and MLL/KMT2 recruitment that establishes accessible promoters driving oligodendrocyte differentiation and myelination, and showed CHD8 promotes adipogenesis via C/EBP\\u03b2.\",\n      \"evidence\": \"Cell-type-specific conditional KOs, ChIP-seq, ATAC-seq, Co-IP, demethylase inhibitor rescue (myelination); Co-IP and adipocyte-specific KO (adipogenesis)\",\n      \"pmids\": [\"29920279\", \"29768199\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Order and dependency within the remodeling cascade not fully dissected mechanistically\", \"How lineage-specific factors target CHD8 unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established CHD8's central role in genome stability and stem cell survival: it complexes with ATM and restrains an ATM\\u2013p53 apoptotic axis, with p53 deletion rescuing hematopoietic, neural, and embryonic phenotypes; also defined H3K36me3/splicing regulation via SETD2/hnRNPL and a role in Rho-GTPase\\u2013dependent erythroblast cytokinesis.\",\n      \"evidence\": \"Hematopoietic conditional KOs with Co-IP, ATAC-seq, p53 rescue, BM transplantation; ChIP-seq/MS/splicing analysis; ChIP and Rho-GTPase activity assays\",\n      \"pmids\": [\"34292326\", \"33535054\", \"36537238\", \"35830790\", \"36127134\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CHD8 loss mechanistically opens chromatin to trigger ATM remains correlative\", \"Direct versus indirect control of Rho-GTPase and splicing genes not fully separated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined CHD8 as a context-dependent transcriptional activator cooperating with sequence-specific factors (ELK1 at ETS/MAPK targets, SOX factors) and showed dosage-sensitive control of neurodevelopmental trajectories, cell-cycle length, excitatory/inhibitory balance, spermatogenesis/meiosis, astrocyte reactivity, and enteric neural crest development.\",\n      \"evidence\": \"Isogenic human iPSC neurons and organoids with ATAC/RNA/scRNA-seq and ELK1 KD; allelic-series mESCs; cell-type-specific KOs in germ cells and astrocytes; zebrafish chd8 mutant\",\n      \"pmids\": [\"36575212\", \"35385734\", \"36222238\", \"38224953\", \"39154337\", \"36375841\", \"32839322\", \"33826902\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of cell-type-specific CHD8 targeting remain only partly defined\", \"How the same remodeler produces opposite activator/repressor outcomes across contexts is unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how CHD8's single biochemical activity\\u2014nucleosome sliding and H3K4me-reading\\u2014is mechanistically converted into context-specific activation versus repression, and what structural features dictate its partner selection (H1, p53, \\u03b2-catenin, E2F1, ELK1, SWI/SNF, ATM) at any given locus.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model linking remodeling output to transcriptional direction\", \"Rules governing locus- and lineage-specific recruitment unknown\", \"Relative contributions of remodeling versus scaffolding/adaptor functions not partitioned\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 17]},\n      {\"term_id\": \"GO:0006338\", \"supporting_discovery_ids\": [0, 17]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 12, 26]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 17]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [17]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 10, 11]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [0, 7, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 7, 12, 14]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [17, 18, 31]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [12, 34]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 5, 26]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 16, 18, 27, 31]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 22, 23]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [24]}\n    ],\n    \"complexes\": [\n      \"BRD4\\u2013NSD3-short\\u2013CHD8 super-enhancer complex\",\n      \"CHD7\\u2013CHD8\\u2013FAM124B complex\",\n      \"SWI/SNF (BRG1/BRM) associated\",\n      \"CHD8\\u2013p53\\u2013histone H1 / CHD8\\u2013\\u03b2-catenin\\u2013histone H1 complex\"\n    ],\n    \"partners\": [\n      \"CTNNB1\",\n      \"TP53\",\n      \"CHD7\",\n      \"E2F1\",\n      \"ELK1\",\n      \"ATM\",\n      \"REST\",\n      \"CEBPB\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}