{"gene":"CHD1","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2005,"finding":"The chromodomain of yeast Chd1 specifically interacts with methylated lysine 4 on histone H3 (H3K4me), and this chromodomain-mediated methyl-binding is required for enhanced acetylation activity of the SLIK complex on methylated substrates both in vitro and in vivo. Chd1 was identified as a component of the SAGA and SLIK histone acetyltransferase complexes.","method":"Co-purification/mass spectrometry, in vitro acetylation assay with methylated substrate, chromodomain binding assays, in vivo functional studies","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (co-purification, in vitro assay, in vivo validation) in a single rigorous study","pmids":["15647753"],"is_preprint":false},{"year":2005,"finding":"Human CHD1 (but not yeast Chd1) directly and selectively binds histone H3 methylated at lysine 4 (H3K4me2/me3) via its tandem chromodomains acting cooperatively; both chromodomains are required for this recognition, with Kd ~5 µM for di- and trimethyl H3K4.","method":"In vitro binding studies, dissociation constant measurements, domain mutagenesis/truncation analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — quantitative in vitro binding with mutagenesis, replicated concept across two papers (15647753 and 16263726)","pmids":["16263726"],"is_preprint":false},{"year":2003,"finding":"Yeast Chd1 functions during transcription elongation: it interacts with Rtf1 (Paf1 complex), and with elongation factors Spt4-Spt5 and Spt16-Pob3 (FACT), and associates with actively transcribed chromatin regions. Deletion of CHD1 suppresses cold-sensitive spt5 mutations also suppressed by Paf1 complex defects.","method":"Two-hybrid screen, co-immunoprecipitation, genetic epistasis (suppressor analysis), chromatin immunoprecipitation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, genetic epistasis, and ChIP all converge on same conclusion","pmids":["12682017"],"is_preprint":false},{"year":2005,"finding":"CHD1 functions as an ATP-dependent chromatin assembly factor that, together with NAP1 chaperone and core histones, assembles regularly spaced nucleosomes by a processive mechanism. CHD1 exists predominantly as a monomer and assembles chromatin with shorter nucleosome repeat length than ACF; unlike ACF, CHD1 cannot assemble chromatin containing histone H1.","method":"In vitro chromatin assembly assay with purified components (CHD1, NAP1, core histones, relaxed DNA), nucleosome spacing analysis","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro with purified components, comparative analysis with ACF, multiple functional readouts","pmids":["15643425"],"is_preprint":false},{"year":2007,"finding":"CHD1 (Drosophila) is required for incorporation of histone variant H3.3 into the male pronucleus during early embryogenesis. CHD1 interacts with HIRA (H3.3 chaperone) in cytoplasmic extracts. Loss of CHD1 abolishes H3.3 incorporation and renders the paternal genome unable to participate in zygotic mitoses, leading to haploid embryos.","method":"Genetic loss-of-function (CHD1 elimination in Drosophila embryos), immunofluorescence for H3.3 incorporation, co-immunoprecipitation of CHD1 with HIRA from cytoplasmic extracts","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined phenotype plus reciprocal Co-IP, replicated in concept by multiple subsequent studies","pmids":["17717186"],"is_preprint":false},{"year":2009,"finding":"Chd1 is required to maintain open/euchromatin in mouse embryonic stem cells. Downregulation of Chd1 leads to accumulation of heterochromatin, loss of pluripotency (inability to give rise to primitive endoderm, propensity for neural differentiation), and reduced efficiency of somatic cell reprogramming. Chd1 associates with promoters of active genes.","method":"RNAi knockdown, chromatin immunoprecipitation, differentiation assays, reprogramming assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal functional assays (ChIP, differentiation, reprogramming) replicated across labs","pmids":["19587682"],"is_preprint":false},{"year":2009,"finding":"CHD1 binds to SSRP1 (a subunit of the FACT complex) both in vivo and in vitro, localizes to centromeres in a CENP-H-containing complex-dependent manner, and is required for deposition of newly synthesized CENP-A into centromeric chromatin. RNAi knockdown of CHD1 decreases centromere-localized CENP-A levels.","method":"Co-immunoprecipitation (in vivo and in vitro), conditional mutant cell lines, RNAi knockdown, immunofluorescence","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and functional RNAi readout, single lab","pmids":["19625449"],"is_preprint":false},{"year":2010,"finding":"The double chromodomain unit of Chd1 blocks DNA binding and activation of the ATPase motor in the absence of nucleosome substrates. An acidic helix joining the chromodomains packs against a DNA-binding surface of the ATPase motor (revealed by crystal structure). Disruption of the chromodomain-ATPase interface prevents discrimination between nucleosomes and naked DNA and reduces reliance on the histone H4 tail for nucleosome sliding.","method":"Crystal structure of Chd1 chromodomain region, site-directed mutagenesis, ATPase and nucleosome sliding assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with mutagenesis and functional assays in one study","pmids":["20832723"],"is_preprint":false},{"year":2011,"finding":"The C-terminal DNA-binding domain of yeast Chd1 contains SANT and SLIDE domains (structural homologs of ISWI DNA-binding domains), is required for nucleosome binding and remodeling, and site-directed mutagenesis of conserved residues identifies those important for DNA binding. SLIDE domains were also identified in CHD6-9 proteins.","method":"Crystal structure of Chd1 DNA-binding domain, site-directed mutagenesis, nucleosome binding and remodeling assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with mutagenesis and functional validation","pmids":["21623345"],"is_preprint":false},{"year":2011,"finding":"The DNA-binding domain of Chd1 is not essential for nucleosome sliding per se but is critical for centering mononucleosomes on short DNA fragments. Replacing the native DNA-binding domain with foreign DNA-binding domains (AraC or engrailed) redirects nucleosome sliding toward their cognate DNA sequences, demonstrating that the DNA-binding domain's affinity for extranucleosomal DNA determines the direction of Chd1-mediated nucleosome sliding.","method":"Domain-swap experiments with chimeric Chd1 constructs, nucleosome sliding assays, FRET-based positioning assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution with chimeric proteins, multiple DNA-binding domain swaps tested, clear mechanistic demonstration","pmids":["21969605"],"is_preprint":false},{"year":2011,"finding":"Crystal structure of Saccharomyces cerevisiae Chd1 DNA-binding domain in complex with DNA shows the SLIDE domain contacts the DNA major groove (in contrast to predicted minor-groove binding), with contacts predominantly on one DNA strand. The bound DNA duplex is straight, consistent with preference for extranucleosomal DNA.","method":"X-ray crystallography","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure at atomic resolution","pmids":["22033927"],"is_preprint":false},{"year":2012,"finding":"Chd1 is required for maintenance of high levels of H2B monoubiquitination (H2BK123ub) genome-wide. Loss of Chd1 causes substantial reduction of H2BK123ub levels and reduced nucleosome occupancy in gene bodies, but does not affect H3K4 or H3K79 trimethylation patterns. This function is conserved from yeast to humans.","method":"Genome-wide ChIP-seq, western blot analysis of histone modifications in chd1Δ yeast and human CHD1-depleted cells","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP and biochemical assays, conserved finding demonstrated in two organisms","pmids":["22549955"],"is_preprint":false},{"year":2012,"finding":"Isw1b and Chd1 act in conjunction to prevent trans-histone exchange over coding regions during transcription elongation. Chd1 is recruited to open reading frames by H3K36 methylation context and maintains chromatin integrity during RNAPII passage.","method":"Genome-wide nucleosome mapping, histone exchange assays, genetic epistasis in S. cerevisiae, in vivo and in vitro H3K36me recruitment assays","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide mapping plus in vitro and in vivo recruitment assays, multiple orthogonal methods","pmids":["22922743"],"is_preprint":false},{"year":2013,"finding":"CHD1 is required for efficient recruitment of androgen receptor (AR) to responsive promoters in prostate cells. Inactivation of CHD1 in vitro prevents formation of ERG rearrangements by impairing AR-dependent transcription. CHD1 regulates expression of AR-responsive tumor suppressor genes including NKX3-1, FOXO1, and PPARγ.","method":"RNAi knockdown, chromatin immunoprecipitation for AR, gene expression analysis, FISH for ERG rearrangements","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and functional assays, single lab","pmids":["23492366"],"is_preprint":false},{"year":2014,"finding":"Chd1 is recruited to promoter-proximal nucleosomes of actively transcribed genes and is responsible for the majority of RNAPII-directed nucleosome turnover at these sites. Expression of a dominant-negative Chd1 increases stalling of RNAPII past the entry site of promoter-proximal nucleosomes. Chd1 evicts nucleosomes downstream of the promoter to overcome the nucleosomal barrier and enable RNAPII promoter escape.","method":"Modified ChIP using micrococcal nuclease digestion, dominant-negative Chd1 expression, RNAPII stalling assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — novel ChIP methodology, dominant-negative functional assay, multiple readouts in one study","pmids":["24737864"],"is_preprint":false},{"year":2016,"finding":"Dimethylation of KDM1A at K114 (K114me2) by EHMT2 creates a binding site for CHD1. Co-crystal structure of CHD1 with KDM1A K114me2 peptide characterizes the recognition mode. Genome-wide analyses reveal chromatin co-localization of KDM1A K114me2, CHD1, and androgen receptor (AR) in prostate tumor cells, linking this assembly to AR-dependent transcription and TMPRSS2-ERG fusion formation.","method":"Co-crystal structure (X-ray crystallography), genome-wide ChIP-seq, in vitro binding assays, functional assays for TMPRSS2-ERG translocation","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — co-crystal structure combined with genome-wide ChIP and functional translocation assays","pmids":["26751641"],"is_preprint":false},{"year":2016,"finding":"CHD1 and ISW1 compete to set nucleosome spacing in vivo on most yeast genes, with CHD1 directing shorter spacing and ISW1 directing longer spacing. CHD1-directed short spacing correlates with eviction of linker histone H1, while ISW1-directed longer spacing allows H1 binding and chromatin condensation.","method":"Genome-wide nucleosome sequencing in single and double deletion strains, linker histone H1 occupancy mapping","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide approach with multiple genetic backgrounds, clear quantitative competition model","pmids":["26861626"],"is_preprint":false},{"year":2016,"finding":"The Chd1 chromatin remodeler requires H2A/H2B on the entry side of the nucleosome for sliding. When presented with hexasomes (lacking one H2A/H2B dimer), Chd1 shifts them unidirectionally rather than bidirectionally. Ubiquitin-conjugated H2B on the entry side stimulates nucleosome sliding by Chd1.","method":"Reconstituted hexasome and asymmetric nucleosome sliding assays, single-molecule imaging, ubiquitinated H2B functional assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution with defined asymmetric substrates, multiple functional readouts","pmids":["28032848"],"is_preprint":false},{"year":2017,"finding":"Cryo-EM structure of yeast Chd1 bound to a nucleosome at 4.8 Å resolution. Chd1 detaches two turns of DNA from the histone octamer. The SANT and SLIDE domains contact detached DNA around SHL -7 of the first DNA gyre. The ATPase motor binds the second DNA gyre at SHL +2 and is anchored to the N-terminal tail of histone H4. The double chromodomain swings toward nucleosomal DNA at SHL +1, causing ATPase closure. The ATPase promotes DNA translocation toward the nucleosome dyad.","method":"Cryo-electron microscopy structure determination","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure with functional validation, seminal structural paper for Chd1 mechanism","pmids":["29019976"],"is_preprint":false},{"year":2017,"finding":"Site-specific cross-linking shows that Chd1 chromodomains and ATPase motor bind to adjacent SHL1 and SHL2 sites on nucleosomal DNA and pack against the DNA-binding domain on exiting DNA. This domain arrangement spans both DNA gyres and bridges both ends of a ~90-bp nucleosomal loop, suggesting a mechanism for nucleosome assembly and spacing.","method":"Site-specific cross-linking, biochemical domain mapping, structural modeling","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — site-specific cross-linking with multiple domain mutants, clear mechanistic model","pmids":["28111016"],"is_preprint":false},{"year":2017,"finding":"Monomeric Chd1 shifts nucleosomal DNA bidirectionally by dynamically alternating between different segments of the nucleosome. Sliding generates unstable remodeling intermediates that spontaneously relax. The DNA-binding domain and chromodomains are two regulatory domains controlling sliding: the chromodomains play a key role in substrate discrimination.","method":"Single-molecule FRET, nucleosome sliding assays with truncation and mutation constructs","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — single-molecule assays with domain mutants, quantitative kinetic analysis","pmids":["28943314"],"is_preprint":false},{"year":2017,"finding":"PTEN stimulates GSK3β-mediated phosphorylation of CHD1 degron domains, promoting CHD1 degradation via the β-TrCP-mediated ubiquitination-proteasome pathway. PTEN deficiency results in CHD1 stabilization, which then engages trimethyl H3K4 to activate the TNF-NF-κB gene network.","method":"Biochemical phosphorylation assays, ubiquitination assays, proteasome inhibitor experiments, CHD1 degron mutagenesis, ChIP for H3K4me3","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal biochemical methods establishing a post-translational regulatory pathway","pmids":["28166537"],"is_preprint":false},{"year":2017,"finding":"CHD1 is required for early DNA double-strand break repair via homologous recombination. CHD1 loss leads to reduced H2AX phosphorylation (γH2AX), impaired CtIP recruitment to DSB sites, reduced H2AX incorporation and poor retention at DSBs. The N-terminal region of CHD1 inhibits its own DNA binding, ATPase, and chromatin assembly/remodeling activities.","method":"CRISPR/Cas9 CHD1 knockout in human cells, γH2AX ChIP, HR repair assays, CtIP recruitment assays, ATPase and chromatin remodeling assays with N-terminal truncation constructs","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — clean human KO cells plus multiple biochemical assays, N-terminal inhibitory domain established by direct functional comparison","pmids":["29529298"],"is_preprint":false},{"year":2017,"finding":"CHD1 promotes the XPC-to-TFIIH handover of nucleosomal UV lesions during global-genome nucleotide excision repair (GG-NER). CHD1 is recruited to UV lesions in a nucleosome/histone context in an XPC-dependent manner. CHD1 depletion slows CPD excision and sensitizes cells to UV-induced cytotoxicity.","method":"Chromatin immunoprecipitation of chromatin fragments, chromatin fractionation, immunofluorescence, CHD1 depletion with UV sensitivity assays","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and fractionation showing recruitment, functional handover assay, single lab","pmids":["29018037"],"is_preprint":false},{"year":2018,"finding":"Cryo-EM structures of yeast Chd1 bound to nucleosomes with ADP-beryllium fluoride (transition state mimic) reveal conserved contacts with single-strand translocases plus unique contacts with both DNA strands. Two turns of linker DNA are prised off the histone octamer upon Chd1 binding, and both the histone H3 tail and ubiquitin conjugated to H2B K120 are reoriented toward the unraveled DNA.","method":"Cryo-electron microscopy structure determination with transition state mimic","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution cryo-EM structure with transition state mimic capturing active state","pmids":["30079888"],"is_preprint":false},{"year":2018,"finding":"The Chd1 ATPase motor stimulates DNA unwrapping from the edge of the nucleosome in a nucleotide-dependent and DNA sequence-sensitive fashion. Different nucleotide analogs (AMP-PNP vs. ADP·BeF3-) produce distinct DNA conformations: AMP-PNP causes in-plane DNA unwrapping, while ADP·BeF3- shows out-of-plane unwrapping. The Chd1 DNA-binding domain is not required for unwrapping.","method":"Stopped-flow binding kinetics, bulk FRET, small-angle X-ray scattering with contrast variation","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple biophysical methods (FRET, SAXS) with nucleotide analogs, rigorous quantitative analysis","pmids":["29850894"],"is_preprint":false},{"year":2019,"finding":"CHD1 occupies prostate-specific enhancers enriched for androgen receptor (AR) and lineage-specific cofactors. Upon CHD1 loss, the AR cistrome is redistributed to an oncogenic pattern, driving tumor formation in the murine prostate. CHD1 constrains AR binding/function to limit tumor progression.","method":"ChIP-seq for CHD1 and AR in human and mouse cells, CHD1 knockout/knockdown with ATAC-seq, in vivo mouse prostate tumor models","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-seq plus in vivo mouse model, multiple orthogonal methods","pmids":["30930119"],"is_preprint":false},{"year":2016,"finding":"CHD1 loss impairs CtIP recruitment to chromatin and subsequent DNA end resection during DSB repair, specifically affecting homologous recombination (HR) but not non-homologous end joining (NHEJ). CHD1 is proposed to open chromatin around DSBs to facilitate HR protein recruitment.","method":"CHD1 siRNA/shRNA depletion, CtIP chromatin recruitment assays, HR and NHEJ repair assays, PARP inhibitor sensitivity tests","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional recruitment assays and repair pathway distinction, single lab","pmids":["27596623"],"is_preprint":false},{"year":2021,"finding":"Biochemical reconstitution shows Chd1 and FACT together facilitate Pol II transcription through a nucleosome when elongation factors Spt4/5 and TFIIS are present. Cryo-EM structures reveal: (1) Pol II transcription exposes the proximal H2A-H2B dimer bound by Spt5, with Chd1 poised to pump DNA toward Pol II via its released inhibitory DNA-binding region; (2) a partially unraveled nucleosome generated by Pol II binds FACT, which excludes Chd1 and Spt5, enabling FACT-histone transfer to upstream DNA.","method":"Biochemical reconstitution of Pol II transcription through nucleosomes, cryo-EM structure determination of transcribing complexes","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution plus two cryo-EM structures capturing sequential mechanistic states","pmids":["33846633"],"is_preprint":false},{"year":2021,"finding":"Chd1 interacts with DNA repair factors including Atm, Parp1, Kap1, and Topoisomerase 2β. In Chd1 KO embryonic stem cells, DNA double-strand breaks accumulate specifically at Chd1-bound Pol II-transcribed genes (particularly longer genes with GC-rich promoters) and rDNA.","method":"Co-immunoprecipitation of Chd1 with repair factors, DSB mapping (BLISS/END-seq) in Chd1 KO ES cells, ChIP-seq","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus genome-wide DSB mapping in KO cells, single lab","pmids":["34381042"],"is_preprint":false},{"year":2021,"finding":"Chd1 is required for FACT spreading from the +1 nucleosome to downstream nucleosomes during transcription. FACT binds the +1 nucleosome as it is partially unwrapped by engaging RNAPII, and spreads to downstream nucleosomes aided by Chd1.","method":"High-resolution genome-wide mapping (MNase-ChIP-seq), single-molecule tracking, mathematical modeling, genetic deletion of Chd1","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (genome-wide mapping, single-molecule, modeling) converging on same mechanism","pmids":["34380014"],"is_preprint":false},{"year":2020,"finding":"CHD1 loss results in global changes in open and closed chromatin (ATAC-seq) with associated transcriptomic changes, establishing transcriptional plasticity that enables antiandrogen resistance through four transcription factors (NR3C1, POU3F2, NR2F1, TBX2).","method":"In vivo shRNA screen, ATAC-seq, RNA-seq, CRISPR-based functional screening","journal":"Cancer cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo screen plus genome-wide chromatin and transcriptome analysis, single lab","pmids":["32220301"],"is_preprint":false},{"year":2020,"finding":"CHD1 regulates IL6 transcription, and IL6 is a key transcriptional target of CHD1 involved in recruitment of myeloid-derived suppressor cells (MDSCs) to reshape the tumor microenvironment in PTEN-deficient prostate cancer. Prostate-specific deletion of Chd1 in PTEN-deficient mouse models delays tumor progression and reduces MDSC recruitment.","method":"Genetically engineered mouse models (Pten and Pten/Smad4 with prostate-specific Chd1 deletion), tumor microenvironment immunophenotyping, IL6 ChIP and expression analysis","journal":"Cancer discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo GEM models plus ChIP for direct transcriptional target, single lab","pmids":["32385075"],"is_preprint":false},{"year":2022,"finding":"Cryo-EM structure of Chd1 bound to a nucleosome in a nucleotide-free state at 2.3 Å resolution reveals that Chd1 stimulates the nucleosome to absorb an additional nucleotide on each DNA strand at two different locations. On the tracking strand within the ATPase binding site, this extra nucleotide induces a local A-form DNA geometry, explaining sequential ratcheting of each strand. A histone-binding motif (ChEx) is identified that can block opposing remodelers and may allow Chd1 to participate in histone reorganization during transcription.","method":"Cryo-electron microscopy at 2.3 Å resolution, structural analysis","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution cryo-EM structure revealing atomic-level mechanism of DNA ratcheting","pmids":["35173352"],"is_preprint":false},{"year":2024,"finding":"Cryo-EM structures of Chd1 bound to a hexasome-nucleosome complex show Chd1 positions its ATPase domain to shift the hexasome away from the nucleosome. In the absence of the inner H2A/H2B dimer, Chd1's DNA-binding domain packs against the ATPase domain (inhibited state). Restoration of the H2A/H2B dimer by FACT triggers DBD rearrangement that displaces the DBD and stimulates Chd1 remodeling, demonstrating FACT-Chd1 cooperation in resolving transcription-induced hexasome-nucleosome complexes.","method":"Cryo-EM structure determination of two states (before and after FACT-mediated H2A/H2B restoration), biochemical reconstitution","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — two cryo-EM structures capturing mechanistic states, supported by biochemical reconstitution","pmids":["39270644"],"is_preprint":false},{"year":2021,"finding":"Chd1 disruption in Drosophila heads results in reduced H3.3 levels, perturbed brain chromatin structure, and global de-repression of transcription, with phenotypic consequences of reduced food intake, metabolic alterations, and shortened lifespan. Strong genetic interaction between Chd1 and H3.3 chaperone HIRA was demonstrated.","method":"Quantitative mass spectrometry for histone variant levels, genetic interaction analysis (double mutants), brain-specific rescue experiments, ChIP","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative MS for H3.3, genetic interaction, rescue experiments; single lab","pmids":["34610319"],"is_preprint":false},{"year":2021,"finding":"Autoinhibitory elements of Chd1 (chromodomains and 'bridge') act together to block nucleosome sliding by preventing initiation of twist defects when the DNA-binding domain is not bound to entry-side DNA. These elements target nucleotide-free and ADP-bound states of the ATPase motor, favoring a partially disengaged ATPase-nucleosome state.","method":"Biochemical nucleosome sliding assays with Chd1 mutants lacking autoinhibitory elements, kinetic analysis, nucleotide-state specific assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple autoinhibitory element mutants tested with kinetic mechanistic dissection","pmids":["33468676"],"is_preprint":false},{"year":1999,"finding":"Both the chromodomain (C) and ATPase/helicase-like domain (H) of CHD1 are essential for its proper association with chromatin. CHD1 interacts with SSRP1 (an HMG box-containing protein/FACT subunit) through an N-terminal segment that does not include the chromodomain.","method":"Transient transfection with wild-type and domain-mutant CHD1 constructs, immunocytochemistry, co-immunoprecipitation","journal":"Chromosoma","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — domain mutagenesis with cellular localization readout, plus Co-IP for SSRP1 interaction; single lab","pmids":["10199952"],"is_preprint":false},{"year":1995,"finding":"CHD1 preferentially binds relatively long A-T tracts in double-stranded DNA via minor-groove interactions. The DNA-binding activity maps to a 229-amino-acid C-terminal segment. CHD1 is a constituent of bulk chromatin extractable with 0.6 M NaCl or EDTA after MNase digestion. CHD1 is released into the cytoplasm when cells enter mitosis and is reincorporated into chromatin during telophase-cytokinesis.","method":"DNA binding assays, deletion mapping, chromatin fractionation, immunocytochemistry across cell cycle stages","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — biochemical DNA binding assays with domain mapping plus cell cycle fractionation; foundational paper, single lab","pmids":["7739555"],"is_preprint":false},{"year":2003,"finding":"CHD1 co-immunoprecipitates with histone deacetylase (HDAC) activity and associates with NCoR (a transcriptional corepressor) in yeast two-hybrid and in vitro pull-down assays. CHD1 also interacts with splicing proteins mKIAA0164, Srp20, and SAF-B by two-hybrid, and CHD1 overexpression affects alternative splicing.","method":"Co-immunoprecipitation (for HDAC), yeast two-hybrid and in vitro pull-down (for NCoR and splicing proteins), alternative splicing assays","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP and two-hybrid data for NCoR/HDAC interaction, limited mechanistic follow-up","pmids":["12890497"],"is_preprint":false},{"year":2011,"finding":"Mediator coactivator complex is required for CHD1 recruitment to preinitiation complexes on chromatin. CHD1 is recruited to naive chromatin but shows enhanced recruitment on H3K4me3 chromatin. CHD1 co-immunoprecipitates with Mediator components from cell extracts, and this interaction is abolished by knockdown of a specific Mediator subunit.","method":"MuDPIT proteomic analysis of purified preinitiation complexes, immunoblot, shRNA depletion, co-immunoprecipitation, genome-wide binding (ChIP-seq in mouse ES cells)","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — proteomic PIC analysis plus reciprocal Co-IP and genome-wide ChIP, multiple orthogonal methods","pmids":["21979373"],"is_preprint":false},{"year":2016,"finding":"CHD1 interacts with the influenza virus polymerase complex. CHD1 downregulation reduces viral polymerase activity, viral RNA transcription, and production of infectious particles. CHD1 associates with RNAPII and undergoes parallel degradation with RNAPII during influenza infection.","method":"Co-immunoprecipitation of CHD1 with viral polymerase, CHD1 knockdown with viral replication assays, co-localization immunofluorescence","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP establishing interaction plus functional knockdown assays, single lab","pmids":["26792750"],"is_preprint":false}],"current_model":"CHD1 is an ATP-dependent chromatin remodeler that assembles and repositions nucleosomes using a bilobal ATPase motor anchored to SHL+2 nucleosomal DNA, regulated by autoinhibitory chromodomains that gate DNA access; human CHD1 binds H3K4me2/3 via cooperative tandem chromodomains to localize to actively transcribed genes where it promotes nucleosome turnover, RNAPII elongation through nucleosomes (in cooperation with FACT and Spt4/5), H2B monoubiquitination maintenance, and replication-independent H3.3 deposition, while also functioning in homologous recombination-mediated DNA double-strand break repair by facilitating chromatin opening for CtIP and HR factor recruitment, and is subject to PTEN/GSK3β-mediated phosphorylation that targets it for β-TrCP/proteasome degradation."},"narrative":{"mechanistic_narrative":"CHD1 is an ATP-dependent chromatin remodeler that assembles, spaces, and repositions nucleosomes to maintain accessible chromatin at actively transcribed genes [PMID:15643425, PMID:19587682, PMID:26861626]. Its catalytic core is a bilobal ATPase motor that engages the nucleosome at SHL+2, anchors to the histone H4 N-terminal tail, and detaches roughly two turns of DNA from the octamer to translocate DNA toward the dyad and drive a strand-by-strand ratcheting mechanism [PMID:29019976, PMID:30079888, PMID:35173352]. Substrate engagement is gated by autoinhibitory elements: tandem chromodomains and a connecting bridge pack against a DNA-binding surface of the ATPase to block remodeling until the C-terminal SANT-SLIDE DNA-binding domain engages extranucleosomal entry-side DNA, which also sets the direction of sliding and centers nucleosomes [PMID:20832723, PMID:21969605, PMID:33468676]. CHD1 requires an intact H2A/H2B dimer on the nucleosome entry side, and entry-side H2B ubiquitination stimulates its sliding activity [PMID:28032848, PMID:39270644]. In humans, cooperative tandem chromodomains directly recognize H3K4me2/3, targeting CHD1 to active promoters [PMID:16263726], while H3K36 methylation and the Mediator complex contribute to recruitment at transcribed regions and preinitiation complexes [PMID:22922743, PMID:21979373]. There, CHD1 drives RNAPII-directed nucleosome turnover and promoter escape, and cooperates with FACT and Spt4/5 to enable polymerase passage through nucleosomes and to spread FACT across gene bodies [PMID:24737864, PMID:33846633, PMID:34380014]. It additionally maintains genome-wide H2B monoubiquitination [PMID:22549955] and, with histone chaperones HIRA and NAP1, supports replication-independent H3.3 deposition required for paternal genome activation and brain chromatin integrity [PMID:15643425, PMID:17717186, PMID:34610319]. CHD1 maintains open euchromatin and pluripotency in embryonic stem cells [PMID:19587682] and promotes homologous-recombination repair of double-strand breaks by opening chromatin to permit CtIP recruitment and end resection [PMID:29529298, PMID:27596623]. CHD1 is post-translationally controlled by PTEN/GSK3β-mediated phosphorylation that targets it for β-TrCP/proteasome degradation, linking its stability to the AR cistrome and tumor-microenvironment programs in prostate cancer [PMID:28166537, PMID:30930119].","teleology":[{"year":1995,"claim":"Established CHD1 as a chromatin-associated, sequence-preferential DNA-binding protein, defining its biochemical substrate before any remodeling role was known.","evidence":"DNA binding assays, deletion mapping, and cell-cycle chromatin fractionation","pmids":["7739555"],"confidence":"Medium","gaps":["No ATPase or remodeling activity assigned","Functional role of A-T tract minor-groove binding unresolved"]},{"year":1999,"claim":"Showed that both chromodomain and ATPase domains are needed for chromatin association and identified SSRP1 (FACT) as an early physical partner, hinting at a transcription-coupled function.","evidence":"Domain-mutant transfection with immunocytochemistry and Co-IP","pmids":["10199952"],"confidence":"Medium","gaps":["Functional consequence of SSRP1 interaction not tested","Single-lab cellular readout"]},{"year":2003,"claim":"Linked yeast Chd1 genetically and physically to the transcription elongation machinery, placing it within the Paf1/Spt4-Spt5/FACT network on active genes.","evidence":"Two-hybrid, Co-IP, genetic suppressor analysis, and ChIP in S. cerevisiae","pmids":["12682017"],"confidence":"High","gaps":["Direct enzymatic contribution to elongation not yet demonstrated","Mechanism of recruitment unresolved"]},{"year":2005,"claim":"Defined CHD1 as an ATP-dependent nucleosome assembly factor and established the chromodomain–methyl-histone reading mode, connecting catalytic activity to chromatin targeting.","evidence":"In vitro chromatin assembly with NAP1/histones; chromodomain binding assays and quantitative H3K4me recognition in yeast and human Chd1","pmids":["15643425","15647753","16263726"],"confidence":"High","gaps":["Human vs yeast difference in H3K4me binding mechanistically unexplained at the time","In vivo assembly role not shown"]},{"year":2007,"claim":"Demonstrated a histone-variant deposition role by showing CHD1 is required for H3.3 incorporation into the paternal pronucleus, with HIRA as a partner.","evidence":"Drosophila loss-of-function, H3.3 immunofluorescence, and CHD1–HIRA Co-IP","pmids":["17717186"],"confidence":"High","gaps":["Whether CHD1 deposits H3.3 directly or supports a chaperone unclear","Generality beyond pronucleus untested"]},{"year":2009,"claim":"Connected CHD1 to maintenance of open euchromatin, pluripotency, and centromeric CENP-A deposition, broadening its role to stem-cell identity and chromosome segregation.","evidence":"RNAi, ChIP, differentiation/reprogramming assays in mouse ESCs; Co-IP and RNAi for SSRP1/CENP-A axis","pmids":["19587682","19625449"],"confidence":"High","gaps":["CENP-A deposition role single-lab (Medium)","Direct vs indirect contribution to heterochromatin accumulation unresolved"]},{"year":2011,"claim":"Resolved the architecture and logic of the C-terminal DNA-binding domain, showing it reads extranucleosomal DNA to direct and center nucleosome sliding, and that chromodomains autoinhibit the motor.","evidence":"Crystal structures of the DNA-binding domain (apo and DNA-bound) and chromodomain region, domain-swap chimeras, sliding/ATPase assays; Mediator-dependent recruitment by proteomics and ChIP","pmids":["20832723","21623345","21969605","22033927","21979373"],"confidence":"High","gaps":["Full motor-on-nucleosome geometry not yet visualized","How autoinhibition is relieved in vivo unclear"]},{"year":2012,"claim":"Established chromatin-integrity functions during elongation: maintaining genome-wide H2B monoubiquitination and preventing trans-histone exchange over coding regions via H3K36me-guided recruitment.","evidence":"Genome-wide ChIP-seq, histone-exchange and recruitment assays, genetic epistasis in yeast and human cells","pmids":["22549955","22922743"],"confidence":"High","gaps":["Mechanistic link between remodeling and H2Bub maintenance not fully resolved","Directness of H3K36me readout unclear"]},{"year":2013,"claim":"Placed CHD1 in androgen-receptor-driven transcription in prostate cells, where it enables AR recruitment and AR-responsive tumor-suppressor expression.","evidence":"RNAi, AR ChIP, expression analysis, and FISH for ERG rearrangements","pmids":["23492366"],"confidence":"Medium","gaps":["Single-lab functional data","Direct vs indirect effect on AR binding not separated"]},{"year":2014,"claim":"Showed CHD1 performs the bulk of RNAPII-directed nucleosome turnover at promoter-proximal sites and is required for polymerase promoter escape past the +1 nucleosome.","evidence":"MNase-based ChIP, dominant-negative Chd1 expression, and RNAPII stalling assays","pmids":["24737864"],"confidence":"High","gaps":["Coordination with other elongation factors not yet mechanistically dissected","In vitro reconstitution lacking at this stage"]},{"year":2016,"claim":"Defined entry-side substrate requirements and nucleosome-spacing competition, showing CHD1 needs H2A/H2B and ubiquitinated H2B on the entry side and competes with ISW1 to set short, H1-depleted spacing; also linked a KDM1A-K114me2 mark to CHD1/AR recruitment.","evidence":"Reconstituted hexasome/asymmetric sliding and single-molecule assays; genome-wide nucleosome mapping in deletion strains; co-crystal of CHD1 with KDM1A peptide plus ChIP-seq","pmids":["28032848","26861626","26751641"],"confidence":"High","gaps":["How H2Bub stimulation is structurally transmitted to the motor not yet shown","Relevance of KDM1A mark beyond prostate cells untested"]},{"year":2016,"claim":"Established a direct role in homologous-recombination DSB repair, with CHD1 required for CtIP recruitment and end resection but not NHEJ.","evidence":"CHD1 depletion, CtIP recruitment and HR/NHEJ repair assays, PARP-inhibitor sensitivity","pmids":["27596623"],"confidence":"Medium","gaps":["Single-lab data","Whether chromatin opening at DSBs is direct not structurally shown"]},{"year":2017,"claim":"Delivered the first nucleosome-bound structures and mechanism: CHD1 detaches linker DNA, engages SHL+2 and the H4 tail, swings its chromodomains to close the ATPase, and pumps DNA toward the dyad, while domain cross-linking and single-molecule work defined bidirectional, regulated sliding.","evidence":"Cryo-EM of Chd1-nucleosome, site-specific cross-linking, single-molecule FRET with domain mutants","pmids":["29019976","28111016","28943314"],"confidence":"High","gaps":["Transition-state geometry not yet captured","Coupling of ATP hydrolysis to DNA step size unresolved"]},{"year":2017,"claim":"Extended CHD1 to additional DNA-repair pathways and defined its post-translational control, showing PTEN/GSK3β-driven β-TrCP degradation, an N-terminal autoinhibitory region, and roles in GG-NER XPC-to-TFIIH handover.","evidence":"Phosphorylation/ubiquitination/degron assays; CRISPR KO with γH2AX ChIP and HR assays; UV-lesion recruitment and excision assays","pmids":["28166537","29529298","29018037"],"confidence":"High","gaps":["NER handover role single-lab (Medium)","Interplay between N-terminal and chromodomain autoinhibition not unified"]},{"year":2018,"claim":"Captured the active/transition-state mechanism, showing nucleotide-dependent DNA unwrapping and reorientation of the H3 tail and H2B-ubiquitin toward unraveled DNA.","evidence":"Cryo-EM with ADP-BeF transition-state mimic; stopped-flow, FRET, and SAXS with nucleotide analogs","pmids":["30079888","29850894"],"confidence":"High","gaps":["Per-base-pair stepping not resolved at this stage","Functional role of unwrapping in vivo inferred"]},{"year":2019,"claim":"Showed CHD1 occupies prostate enhancers and constrains the AR cistrome, with its loss redistributing AR to an oncogenic pattern that drives tumorigenesis in vivo.","evidence":"CHD1/AR ChIP-seq, ATAC-seq in KO cells, and in vivo mouse prostate tumor models","pmids":["30930119"],"confidence":"High","gaps":["Mechanism by which CHD1 limits AR binding not fully defined","Link to degradation pathway not integrated"]},{"year":2020,"claim":"Connected CHD1-dependent chromatin state to cancer phenotypes: transcriptional plasticity driving antiandrogen resistance and IL6-mediated MDSC recruitment in PTEN-deficient tumors.","evidence":"In vivo shRNA screens, ATAC/RNA-seq, and genetically engineered mouse models with IL6 ChIP","pmids":["32220301","32385075"],"confidence":"Medium","gaps":["Single-lab in vivo models","Direct vs network-level effects on resistance TFs not separated"]},{"year":2021,"claim":"Reconstituted and structurally resolved CHD1–FACT cooperation during Pol II transcription, showing sequential handoffs that move nucleosomes past polymerase and spread FACT downstream, and defined a chromodomain/bridge autoinhibitory mechanism.","evidence":"Biochemical reconstitution with Spt4/5 and TFIIS, cryo-EM of transcribing complexes, genome-wide MNase-ChIP and single-molecule tracking, kinetic autoinhibition assays; Co-IP/DSB mapping linking Chd1 to repair factors at transcribed genes","pmids":["33846633","34380014","33468676","34381042","34610319"],"confidence":"High","gaps":["Co-IP with ATM/PARP1/KAP1/TOP2B single-lab (Medium)","How autoinhibition is coordinated with FACT-driven activation in vivo not fully resolved"]},{"year":2022,"claim":"Achieved atomic-resolution mechanism, showing CHD1 forces the nucleosome to absorb an extra nucleotide per strand to ratchet DNA, and identified a ChEx histone-binding motif relevant to histone reorganization.","evidence":"2.3 Å cryo-EM of nucleotide-free Chd1-nucleosome","pmids":["35173352"],"confidence":"High","gaps":["Functional role of ChEx motif in transcription not directly tested","Sequence dependence of ratcheting in vivo unknown"]},{"year":2024,"claim":"Defined the structural basis of FACT-dependent activation, showing the entry-side H2A/H2B dimer controls a DBD-ATPase autoinhibitory switch that FACT releases to resolve transcription-induced hexasome-nucleosome complexes.","evidence":"Two-state cryo-EM (before/after FACT-mediated dimer restoration) with biochemical reconstitution","pmids":["39270644"],"confidence":"High","gaps":["In vivo prevalence of hexasome intermediates not quantified","Generality across other remodelers untested"]},{"year":null,"claim":"How CHD1's distinct activities — promoter remodeling, H2Bub/H3.3 maintenance, HR/NER repair, and AR-cistrome constraint — are selectively deployed and coordinated within a single cell context remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking PTEN/GSK3β degradation control to specific chromatin functions","Determinants of pathway choice (transcription vs repair) unknown","Human in-cell structural states of the FACT/Spt5 cooperation not directly visualized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[3,18,25,33]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[9,10,38]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[1,15,33]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3,17,36]}],"localization":[{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[2,5,14,38]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,37,38]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[29]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,14,28,40]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[3,5,11,16]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[22,23,27]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[21,26,31,32]}],"complexes":["SAGA/SLIK histone acetyltransferase complex"],"partners":["SSRP1","HIRA","SPT16","SPT5","RTF1","CTIP","MEDIATOR","KDM1A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O14646","full_name":"ATP-dependent chromatin remodeler CHD1","aliases":["Chromo domain-containing protein 1","CHD-1"],"length_aa":1710,"mass_kda":196.7,"function":"ATP-dependent chromatin-remodeling factor which functions as substrate recognition component of the transcription regulatory histone acetylation (HAT) complex SAGA. Regulates polymerase II transcription. Also required for efficient transcription by RNA polymerase I, and more specifically the polymerase I transcription termination step. Regulates negatively DNA replication. Not only involved in transcription-related chromatin-remodeling, but also required to maintain a specific chromatin configuration across the genome. Is also associated with histone deacetylase (HDAC) activity (By similarity). Required for the bridging of SNF2, the FACT complex, the PAF complex as well as the U2 snRNP complex to H3K4me3. Functions to modulate the efficiency of pre-mRNA splicing in part through physical bridging of spliceosomal components to H3K4me3 (PubMed:18042460, PubMed:28866611). Required for maintaining open chromatin and pluripotency in embryonic stem cells (By similarity)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/O14646/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CHD1","classification":"Not Classified","n_dependent_lines":135,"n_total_lines":1208,"dependency_fraction":0.11175496688741722},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SSRP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CHD1","total_profiled":1310},"omim":[{"mim_id":"617682","title":"PILAROWSKI-BJORNSSON SYNDROME; PILBOS","url":"https://www.omim.org/entry/617682"},{"mim_id":"616114","title":"CHROMODOMAIN HELICASE DNA-BINDING PROTEIN 6; CHD6","url":"https://www.omim.org/entry/616114"},{"mim_id":"613919","title":"KINESIN FAMILY MEMBER 6; KIF6","url":"https://www.omim.org/entry/613919"},{"mim_id":"613733","title":"MENIN 1; MEN1","url":"https://www.omim.org/entry/613733"},{"mim_id":"610506","title":"PAF1 HOMOLOG, PAF1/RNA POLYMERASE II COMPLEX COMPONENT; PAF1","url":"https://www.omim.org/entry/610506"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nucleoli fibrillar center","reliability":"Additional"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CHD1"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"O14646","domains":[{"cath_id":"2.40.50.40","chopping":"275-366","consensus_level":"high","plddt":82.2828,"start":275,"end":366},{"cath_id":"2.40.50.40","chopping":"388-446","consensus_level":"medium","plddt":84.562,"start":388,"end":446},{"cath_id":"3.40.50.10810","chopping":"448-702","consensus_level":"high","plddt":81.639,"start":448,"end":702},{"cath_id":"3.40.50.300","chopping":"710-720_769-944_989-1006","consensus_level":"high","plddt":78.682,"start":710,"end":1006},{"cath_id":"1.10.10.60","chopping":"1129-1184_1200-1321","consensus_level":"medium","plddt":83.6251,"start":1129,"end":1321},{"cath_id":"1.20.1280","chopping":"1412-1510","consensus_level":"high","plddt":81.269,"start":1412,"end":1510}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O14646","model_url":"https://alphafold.ebi.ac.uk/files/AF-O14646-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O14646-F1-predicted_aligned_error_v6.png","plddt_mean":62.09},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CHD1","jax_strain_url":"https://www.jax.org/strain/search?query=CHD1"},"sequence":{"accession":"O14646","fasta_url":"https://rest.uniprot.org/uniprotkb/O14646.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O14646/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O14646"}},"corpus_meta":[{"pmid":"19587682","id":"PMC_19587682","title":"Chd1 regulates open chromatin and pluripotency of embryonic stem cells.","date":"2009","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/19587682","citation_count":398,"is_preprint":false},{"pmid":"15647753","id":"PMC_15647753","title":"Chd1 chromodomain links histone H3 methylation with SAGA- and SLIK-dependent acetylation.","date":"2005","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/15647753","citation_count":394,"is_preprint":false},{"pmid":"16263726","id":"PMC_16263726","title":"Human but not yeast CHD1 binds directly and selectively to histone H3 methylated at lysine 4 via its tandem chromodomains.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16263726","citation_count":304,"is_preprint":false},{"pmid":"12682017","id":"PMC_12682017","title":"Chromatin remodeling protein Chd1 interacts with transcription elongation factors and localizes to transcribed genes.","date":"2003","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/12682017","citation_count":285,"is_preprint":false},{"pmid":"22922743","id":"PMC_22922743","title":"Chromatin remodelers Isw1 and Chd1 maintain chromatin structure during transcription by preventing histone exchange.","date":"2012","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/22922743","citation_count":243,"is_preprint":false},{"pmid":"15643425","id":"PMC_15643425","title":"Distinct activities of CHD1 and ACF in ATP-dependent chromatin assembly.","date":"2005","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15643425","citation_count":233,"is_preprint":false},{"pmid":"29019976","id":"PMC_29019976","title":"Nucleosome-Chd1 structure and implications for chromatin remodelling.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/29019976","citation_count":209,"is_preprint":false},{"pmid":"17717186","id":"PMC_17717186","title":"CHD1 motor protein is required for deposition of histone variant H3.3 into chromatin in vivo.","date":"2007","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/17717186","citation_count":207,"is_preprint":false},{"pmid":"23492366","id":"PMC_23492366","title":"CHD1 is a 5q21 tumor suppressor required for ERG rearrangement in prostate cancer.","date":"2013","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/23492366","citation_count":191,"is_preprint":false},{"pmid":"28166537","id":"PMC_28166537","title":"Synthetic essentiality of chromatin remodelling factor CHD1 in PTEN-deficient cancer.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/28166537","citation_count":182,"is_preprint":false},{"pmid":"20832723","id":"PMC_20832723","title":"The chromodomains of the Chd1 chromatin remodeler regulate DNA access to the ATPase motor.","date":"2010","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/20832723","citation_count":179,"is_preprint":false},{"pmid":"16606615","id":"PMC_16606615","title":"Analysis of nucleosome repositioning by yeast ISWI and Chd1 chromatin remodeling complexes.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16606615","citation_count":159,"is_preprint":false},{"pmid":"32220301","id":"PMC_32220301","title":"Loss of CHD1 Promotes Heterogeneous Mechanisms of Resistance to AR-Targeted Therapy via Chromatin Dysregulation.","date":"2020","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/32220301","citation_count":139,"is_preprint":false},{"pmid":"30068710","id":"PMC_30068710","title":"SPOP-Mutated/CHD1-Deleted Lethal Prostate Cancer and Abiraterone Sensitivity.","date":"2018","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/30068710","citation_count":120,"is_preprint":false},{"pmid":"7739555","id":"PMC_7739555","title":"DNA-binding and chromatin localization properties of CHD1.","date":"1995","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/7739555","citation_count":119,"is_preprint":false},{"pmid":"26861626","id":"PMC_26861626","title":"The ISW1 and CHD1 ATP-dependent chromatin remodelers compete to set nucleosome spacing in vivo.","date":"2016","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/26861626","citation_count":114,"is_preprint":false},{"pmid":"19625449","id":"PMC_19625449","title":"CENP-H-containing complex facilitates centromere deposition of CENP-A in cooperation with FACT and CHD1.","date":"2009","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/19625449","citation_count":113,"is_preprint":false},{"pmid":"33846633","id":"PMC_33846633","title":"Structural basis of nucleosome transcription mediated by Chd1 and FACT.","date":"2021","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/33846633","citation_count":112,"is_preprint":false},{"pmid":"8692958","id":"PMC_8692958","title":"CHD1 is concentrated in interbands and puffed regions of Drosophila polytene chromosomes.","date":"1996","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/8692958","citation_count":108,"is_preprint":false},{"pmid":"24737864","id":"PMC_24737864","title":"The nucleosomal barrier to promoter escape by RNA polymerase II is overcome by the chromatin remodeler Chd1.","date":"2014","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/24737864","citation_count":105,"is_preprint":false},{"pmid":"21623345","id":"PMC_21623345","title":"The DNA-binding domain of the Chd1 chromatin-remodelling enzyme contains SANT and SLIDE domains.","date":"2011","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/21623345","citation_count":102,"is_preprint":false},{"pmid":"28383660","id":"PMC_28383660","title":"CHD1 loss sensitizes prostate cancer to DNA damaging therapy by promoting error-prone double-strand break repair.","date":"2017","source":"Annals of oncology : official journal of the European Society for Medical Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/28383660","citation_count":98,"is_preprint":false},{"pmid":"21969605","id":"PMC_21969605","title":"Extranucleosomal DNA binding directs nucleosome sliding by Chd1.","date":"2011","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/21969605","citation_count":98,"is_preprint":false},{"pmid":"10199952","id":"PMC_10199952","title":"CHD1 interacts with SSRP1 and depends on both its chromodomain and its ATPase/helicase-like domain for proper association with chromatin.","date":"1999","source":"Chromosoma","url":"https://pubmed.ncbi.nlm.nih.gov/10199952","citation_count":97,"is_preprint":false},{"pmid":"24735615","id":"PMC_24735615","title":"Identification of miR-26 as a key mediator of estrogen stimulated cell proliferation by targeting CHD1, GREB1 and KPNA2.","date":"2014","source":"Breast cancer research : BCR","url":"https://pubmed.ncbi.nlm.nih.gov/24735615","citation_count":96,"is_preprint":false},{"pmid":"32385075","id":"PMC_32385075","title":"Chromatin Regulator CHD1 Remodels the Immunosuppressive Tumor Microenvironment in PTEN-Deficient Prostate Cancer.","date":"2020","source":"Cancer discovery","url":"https://pubmed.ncbi.nlm.nih.gov/32385075","citation_count":90,"is_preprint":false},{"pmid":"27596623","id":"PMC_27596623","title":"Loss of CHD1 causes DNA repair defects and enhances prostate cancer therapeutic responsiveness.","date":"2016","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/27596623","citation_count":88,"is_preprint":false},{"pmid":"22179824","id":"PMC_22179824","title":"Recurrent deletion of CHD1 in prostate cancer with relevance to cell invasiveness.","date":"2011","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/22179824","citation_count":87,"is_preprint":false},{"pmid":"30930119","id":"PMC_30930119","title":"CHD1 Loss Alters AR Binding at Lineage-Specific Enhancers and Modulates Distinct Transcriptional Programs to Drive Prostate Tumorigenesis.","date":"2019","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/30930119","citation_count":84,"is_preprint":false},{"pmid":"21811413","id":"PMC_21811413","title":"CHD1 remodels chromatin and influences transient DNA methylation at the clock gene frequency.","date":"2011","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21811413","citation_count":78,"is_preprint":false},{"pmid":"28032848","id":"PMC_28032848","title":"The Chd1 chromatin remodeler shifts hexasomes unidirectionally.","date":"2016","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/28032848","citation_count":77,"is_preprint":false},{"pmid":"23032292","id":"PMC_23032292","title":"Chd1 chromatin remodelers maintain nucleosome organization and repress cryptic transcription.","date":"2012","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/23032292","citation_count":77,"is_preprint":false},{"pmid":"25770290","id":"PMC_25770290","title":"Coordinate loss of MAP3K7 and CHD1 promotes aggressive prostate cancer.","date":"2015","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/25770290","citation_count":76,"is_preprint":false},{"pmid":"21979373","id":"PMC_21979373","title":"Mediator coordinates PIC assembly with recruitment of CHD1.","date":"2011","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/21979373","citation_count":76,"is_preprint":false},{"pmid":"22139082","id":"PMC_22139082","title":"Identification of novel CHD1-associated collaborative alterations of genomic structure and functional assessment of CHD1 in prostate cancer.","date":"2011","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/22139082","citation_count":75,"is_preprint":false},{"pmid":"25480920","id":"PMC_25480920","title":"Chd1 is essential for the high transcriptional output and rapid growth of the mouse epiblast.","date":"2014","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/25480920","citation_count":72,"is_preprint":false},{"pmid":"23103765","id":"PMC_23103765","title":"CHD1 remodelers regulate nucleosome spacing in vitro and align nucleosomal arrays over gene coding regions in S. pombe.","date":"2012","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/23103765","citation_count":72,"is_preprint":false},{"pmid":"26751641","id":"PMC_26751641","title":"Assembly of methylated KDM1A and CHD1 drives androgen receptor-dependent transcription and translocation.","date":"2016","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/26751641","citation_count":69,"is_preprint":false},{"pmid":"30079888","id":"PMC_30079888","title":"Structure of the chromatin remodelling enzyme Chd1 bound to a ubiquitinylated nucleosome.","date":"2018","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/30079888","citation_count":65,"is_preprint":false},{"pmid":"28111016","id":"PMC_28111016","title":"Interdomain Communication of the Chd1 Chromatin Remodeler across the DNA Gyres of the Nucleosome.","date":"2017","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/28111016","citation_count":61,"is_preprint":false},{"pmid":"19948887","id":"PMC_19948887","title":"Histone H3K4 and K36 methylation, Chd1 and Rpd3S oppose the functions of Saccharomyces cerevisiae Spt4-Spt5 in transcription.","date":"2009","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19948887","citation_count":61,"is_preprint":false},{"pmid":"34380014","id":"PMC_34380014","title":"FACT is recruited to the +1 nucleosome of transcribed genes and spreads in a Chd1-dependent manner.","date":"2021","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/34380014","citation_count":59,"is_preprint":false},{"pmid":"22549955","id":"PMC_22549955","title":"Codependency of H2B monoubiquitination and nucleosome reassembly on Chd1.","date":"2012","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/22549955","citation_count":55,"is_preprint":false},{"pmid":"30683752","id":"PMC_30683752","title":"Contrasting roles of the RSC and ISW1/CHD1 chromatin remodelers in RNA polymerase II elongation and termination.","date":"2019","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/30683752","citation_count":53,"is_preprint":false},{"pmid":"22807688","id":"PMC_22807688","title":"A key role for Chd1 in histone H3 dynamics at the 3' ends of long genes in yeast.","date":"2012","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22807688","citation_count":52,"is_preprint":false},{"pmid":"9332370","id":"PMC_9332370","title":"A CHD1 gene is Z chromosome linked in the chicken Gallus domesticus.","date":"1997","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/9332370","citation_count":51,"is_preprint":false},{"pmid":"25621013","id":"PMC_25621013","title":"Transcription-coupled recruitment of human CHD1 and CHD2 influences chromatin accessibility and histone H3 and H3.3 occupancy at active chromatin regions.","date":"2015","source":"Epigenetics & chromatin","url":"https://pubmed.ncbi.nlm.nih.gov/25621013","citation_count":50,"is_preprint":false},{"pmid":"28943314","id":"PMC_28943314","title":"The Chd1 Chromatin Remodeler Shifts Nucleosomal DNA Bidirectionally as a Monomer.","date":"2017","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/28943314","citation_count":49,"is_preprint":false},{"pmid":"12890497","id":"PMC_12890497","title":"CHD1 associates with NCoR and histone deacetylase as well as with RNA splicing proteins.","date":"2003","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/12890497","citation_count":47,"is_preprint":false},{"pmid":"28866611","id":"PMC_28866611","title":"Missense variants in the chromatin remodeler CHD1 are associated with neurodevelopmental disability.","date":"2017","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28866611","citation_count":47,"is_preprint":false},{"pmid":"10924484","id":"PMC_10924484","title":"Molecular evolution of the avian CHD1 genes on the Z and W sex chromosomes.","date":"2000","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10924484","citation_count":47,"is_preprint":false},{"pmid":"28332978","id":"PMC_28332978","title":"Structural reorganization of the chromatin remodeling enzyme Chd1 upon engagement with nucleosomes.","date":"2017","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/28332978","citation_count":46,"is_preprint":false},{"pmid":"28189426","id":"PMC_28189426","title":"The Sequence of Nucleosomal DNA Modulates Sliding by the Chd1 Chromatin Remodeler.","date":"2017","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/28189426","citation_count":41,"is_preprint":false},{"pmid":"18245327","id":"PMC_18245327","title":"A role for Chd1 and Set2 in negatively regulating DNA replication in Saccharomyces cerevisiae.","date":"2008","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18245327","citation_count":39,"is_preprint":false},{"pmid":"35173352","id":"PMC_35173352","title":"Nucleosome recognition and DNA distortion by the Chd1 remodeler in a nucleotide-free state.","date":"2022","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/35173352","citation_count":38,"is_preprint":false},{"pmid":"25581843","id":"PMC_25581843","title":"Chromodomain, Helicase and DNA-binding CHD1 protein, CHR5, are involved in establishing active chromatin state of seed maturation genes.","date":"2015","source":"Plant biotechnology journal","url":"https://pubmed.ncbi.nlm.nih.gov/25581843","citation_count":38,"is_preprint":false},{"pmid":"25831528","id":"PMC_25831528","title":"Emergence of hematopoietic stem and progenitor cells involves a Chd1-dependent increase in total nascent transcription.","date":"2015","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/25831528","citation_count":38,"is_preprint":false},{"pmid":"22039057","id":"PMC_22039057","title":"Identification of residues in chromodomain helicase DNA-binding protein 1 (Chd1) required for coupling ATP hydrolysis to nucleosome sliding.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22039057","citation_count":37,"is_preprint":false},{"pmid":"21177652","id":"PMC_21177652","title":"The chromodomains of CHD1 are critical for enzymatic activity but less important for chromatin localization.","date":"2010","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/21177652","citation_count":37,"is_preprint":false},{"pmid":"31667976","id":"PMC_31667976","title":"MATN1-AS1 promotes glioma progression by functioning as ceRNA of miR-200b/c/429 to regulate CHD1 expression.","date":"2019","source":"Cell proliferation","url":"https://pubmed.ncbi.nlm.nih.gov/31667976","citation_count":36,"is_preprint":false},{"pmid":"28460001","id":"PMC_28460001","title":"The ATP-dependent chromatin remodeler Chd1 is recruited by transcription elongation factors and maintains H3K4me3/H3K36me3 domains at actively transcribed and spliced genes.","date":"2017","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/28460001","citation_count":35,"is_preprint":false},{"pmid":"22033927","id":"PMC_22033927","title":"Crystal structure of the chromodomain helicase DNA-binding protein 1 (Chd1) DNA-binding domain in complex with DNA.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22033927","citation_count":34,"is_preprint":false},{"pmid":"23275572","id":"PMC_23275572","title":"Decoupling nucleosome recognition from DNA binding dramatically alters the properties of the Chd1 chromatin remodeler.","date":"2012","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/23275572","citation_count":34,"is_preprint":false},{"pmid":"17620414","id":"PMC_17620414","title":"Chd1 and yFACT act in opposition in regulating transcription.","date":"2007","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17620414","citation_count":33,"is_preprint":false},{"pmid":"26792750","id":"PMC_26792750","title":"Influenza Virus and Chromatin: Role of the CHD1 Chromatin Remodeler in the Virus Life Cycle.","date":"2016","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/26792750","citation_count":32,"is_preprint":false},{"pmid":"29529298","id":"PMC_29529298","title":"Human CHD1 is required for early DNA-damage signaling and is uniquely regulated by its N terminus.","date":"2018","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/29529298","citation_count":31,"is_preprint":false},{"pmid":"26092847","id":"PMC_26092847","title":"CHD1 acts via the Hmgpi pathway to regulate mouse early embryogenesis.","date":"2015","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/26092847","citation_count":30,"is_preprint":false},{"pmid":"18202396","id":"PMC_18202396","title":"Investigations of CHD1 function in transcription and development of Drosophila melanogaster.","date":"2008","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18202396","citation_count":30,"is_preprint":false},{"pmid":"36776288","id":"PMC_36776288","title":"CHD1, a multifaceted epigenetic remodeler in prostate cancer.","date":"2023","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36776288","citation_count":28,"is_preprint":false},{"pmid":"28475736","id":"PMC_28475736","title":"CHD1 regulates cell fate determination by activation of differentiation-induced genes.","date":"2017","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/28475736","citation_count":28,"is_preprint":false},{"pmid":"27174939","id":"PMC_27174939","title":"The Chd1 chromatin remodeler can sense both entry and exit sides of the nucleosome.","date":"2016","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/27174939","citation_count":27,"is_preprint":false},{"pmid":"17098252","id":"PMC_17098252","title":"Structural polymorphism of chromodomains in Chd1.","date":"2006","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17098252","citation_count":27,"is_preprint":false},{"pmid":"16468993","id":"PMC_16468993","title":"The ISWI and CHD1 chromatin remodelling activities influence ADH2 expression and chromatin organization.","date":"2006","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/16468993","citation_count":25,"is_preprint":false},{"pmid":"25395991","id":"PMC_25395991","title":"Chd1 co-localizes with early transcription elongation factors independently of H3K36 methylation and releases stalled RNA polymerase II at introns.","date":"2014","source":"Epigenetics & chromatin","url":"https://pubmed.ncbi.nlm.nih.gov/25395991","citation_count":25,"is_preprint":false},{"pmid":"25620209","id":"PMC_25620209","title":"Embryonic stem cell differentiation requires full length Chd1.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/25620209","citation_count":22,"is_preprint":false},{"pmid":"34381042","id":"PMC_34381042","title":"Chd1 protects genome integrity at promoters to sustain hypertranscription in embryonic stem cells.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/34381042","citation_count":22,"is_preprint":false},{"pmid":"26993344","id":"PMC_26993344","title":"Sequence-targeted nucleosome sliding in vivo by a hybrid Chd1 chromatin remodeler.","date":"2016","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/26993344","citation_count":22,"is_preprint":false},{"pmid":"33468676","id":"PMC_33468676","title":"Autoinhibitory elements of the Chd1 remodeler block initiation of twist defects by destabilizing the ATPase motor on the nucleosome.","date":"2021","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/33468676","citation_count":22,"is_preprint":false},{"pmid":"29850894","id":"PMC_29850894","title":"The ATPase motor of the Chd1 chromatin remodeler stimulates DNA unwrapping from the nucleosome.","date":"2018","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/29850894","citation_count":21,"is_preprint":false},{"pmid":"29018037","id":"PMC_29018037","title":"Chromatin remodeler CHD1 promotes XPC-to-TFIIH handover of nucleosomal UV lesions in nucleotide excision repair.","date":"2017","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/29018037","citation_count":21,"is_preprint":false},{"pmid":"31222142","id":"PMC_31222142","title":"The chromatin remodeler Chd1 regulates cohesin in budding yeast and humans.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31222142","citation_count":20,"is_preprint":false},{"pmid":"33846123","id":"PMC_33846123","title":"MAP3K7 Loss Drives Enhanced Androgen Signaling and Independently Confers Risk of Recurrence in Prostate Cancer with Joint Loss of CHD1.","date":"2021","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/33846123","citation_count":19,"is_preprint":false},{"pmid":"24126763","id":"PMC_24126763","title":"Nucleosome sliding by Chd1 does not require rigid coupling between DNA-binding and ATPase domains.","date":"2013","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/24126763","citation_count":19,"is_preprint":false},{"pmid":"39270644","id":"PMC_39270644","title":"Resolution of transcription-induced hexasome-nucleosome complexes by Chd1 and FACT.","date":"2024","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/39270644","citation_count":18,"is_preprint":false},{"pmid":"20211173","id":"PMC_20211173","title":"Chd1 remodelers maintain open chromatin and regulate the epigenetics of differentiation.","date":"2010","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/20211173","citation_count":18,"is_preprint":false},{"pmid":"27170440","id":"PMC_27170440","title":"CHD1 Regulates Deposition of Histone Variant H3.3 During Bovine Early Embryonic Development.","date":"2016","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/27170440","citation_count":17,"is_preprint":false},{"pmid":"30728766","id":"PMC_30728766","title":"Role for Chromatin Remodeling Factor Chd1 in Learning and Memory.","date":"2019","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/30728766","citation_count":17,"is_preprint":false},{"pmid":"20396651","id":"PMC_20396651","title":"CenH3/CID incorporation is not dependent on the chromatin assembly factor CHD1 in Drosophila.","date":"2010","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/20396651","citation_count":17,"is_preprint":false},{"pmid":"26175451","id":"PMC_26175451","title":"Comparative Genomics Reveals Chd1 as a Determinant of Nucleosome Spacing in Vivo.","date":"2015","source":"G3 (Bethesda, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/26175451","citation_count":17,"is_preprint":false},{"pmid":"19360591","id":"PMC_19360591","title":"Sexing a wider range of avian species based on two CHD1 introns with a unified reaction condition.","date":"2007","source":"Zoo biology","url":"https://pubmed.ncbi.nlm.nih.gov/19360591","citation_count":17,"is_preprint":false},{"pmid":"37738162","id":"PMC_37738162","title":"Bi-directional nucleosome sliding by the Chd1 chromatin remodeler integrates intrinsic sequence-dependent and ATP-dependent nucleosome positioning.","date":"2023","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/37738162","citation_count":16,"is_preprint":false},{"pmid":"34610319","id":"PMC_34610319","title":"CHD1 controls H3.3 incorporation in adult brain chromatin to maintain metabolic homeostasis and normal lifespan.","date":"2021","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/34610319","citation_count":16,"is_preprint":false},{"pmid":"33116862","id":"PMC_33116862","title":"Knockdown of circ-TTBK2 Inhibits Glioma Progression by Regulating miR-1283 and CHD1.","date":"2020","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/33116862","citation_count":16,"is_preprint":false},{"pmid":"27591891","id":"PMC_27591891","title":"The Chromatin Remodelling Protein CHD1 Contains a Previously Unrecognised C-Terminal Helical Domain.","date":"2016","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/27591891","citation_count":14,"is_preprint":false},{"pmid":"30656528","id":"PMC_30656528","title":"Prostatic adenocarcinoma CNS parenchymal and dural metastases: alterations in ERG, CHD1 and MAP3K7 expression.","date":"2019","source":"Journal of neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/30656528","citation_count":13,"is_preprint":false},{"pmid":"34533858","id":"PMC_34533858","title":"SPOP and CHD1 alterations in prostate cancer: Relationship with PTEN loss, tumor grade, perineural infiltration, and PSA recurrence.","date":"2021","source":"The Prostate","url":"https://pubmed.ncbi.nlm.nih.gov/34533858","citation_count":12,"is_preprint":false},{"pmid":"32529027","id":"PMC_32529027","title":"MAP3K7 and CHD1 Are Novel Mediators of Resistance to Oncolytic Vesicular Stomatitis Virus in Prostate Cancer Cells.","date":"2020","source":"Molecular therapy oncolytics","url":"https://pubmed.ncbi.nlm.nih.gov/32529027","citation_count":12,"is_preprint":false},{"pmid":"22912810","id":"PMC_22912810","title":"CHD1 contributes to intestinal resistance against infection by P. aeruginosa in Drosophila melanogaster.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22912810","citation_count":12,"is_preprint":false},{"pmid":"25175909","id":"PMC_25175909","title":"ERG and CHD1 heterogeneity in prostate cancer: use of confocal microscopy in assessment of microscopic foci.","date":"2014","source":"The Prostate","url":"https://pubmed.ncbi.nlm.nih.gov/25175909","citation_count":12,"is_preprint":false},{"pmid":"27093431","id":"PMC_27093431","title":"Impact of the Chromatin Remodeling Factor CHD1 on Gut Microbiome Composition of Drosophila melanogaster.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27093431","citation_count":11,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":44633,"output_tokens":10075,"usd":0.142512,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":20679,"output_tokens":6379,"usd":0.131435,"stage2_stop_reason":"end_turn"},"total_usd":0.273947,"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\": 2005,\n      \"finding\": \"The chromodomain of yeast Chd1 specifically interacts with methylated lysine 4 on histone H3 (H3K4me), and this chromodomain-mediated methyl-binding is required for enhanced acetylation activity of the SLIK complex on methylated substrates both in vitro and in vivo. Chd1 was identified as a component of the SAGA and SLIK histone acetyltransferase complexes.\",\n      \"method\": \"Co-purification/mass spectrometry, in vitro acetylation assay with methylated substrate, chromodomain binding assays, in vivo functional studies\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (co-purification, in vitro assay, in vivo validation) in a single rigorous study\",\n      \"pmids\": [\"15647753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Human CHD1 (but not yeast Chd1) directly and selectively binds histone H3 methylated at lysine 4 (H3K4me2/me3) via its tandem chromodomains acting cooperatively; both chromodomains are required for this recognition, with Kd ~5 µM for di- and trimethyl H3K4.\",\n      \"method\": \"In vitro binding studies, dissociation constant measurements, domain mutagenesis/truncation analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — quantitative in vitro binding with mutagenesis, replicated concept across two papers (15647753 and 16263726)\",\n      \"pmids\": [\"16263726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Yeast Chd1 functions during transcription elongation: it interacts with Rtf1 (Paf1 complex), and with elongation factors Spt4-Spt5 and Spt16-Pob3 (FACT), and associates with actively transcribed chromatin regions. Deletion of CHD1 suppresses cold-sensitive spt5 mutations also suppressed by Paf1 complex defects.\",\n      \"method\": \"Two-hybrid screen, co-immunoprecipitation, genetic epistasis (suppressor analysis), chromatin immunoprecipitation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, genetic epistasis, and ChIP all converge on same conclusion\",\n      \"pmids\": [\"12682017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CHD1 functions as an ATP-dependent chromatin assembly factor that, together with NAP1 chaperone and core histones, assembles regularly spaced nucleosomes by a processive mechanism. CHD1 exists predominantly as a monomer and assembles chromatin with shorter nucleosome repeat length than ACF; unlike ACF, CHD1 cannot assemble chromatin containing histone H1.\",\n      \"method\": \"In vitro chromatin assembly assay with purified components (CHD1, NAP1, core histones, relaxed DNA), nucleosome spacing analysis\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro with purified components, comparative analysis with ACF, multiple functional readouts\",\n      \"pmids\": [\"15643425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CHD1 (Drosophila) is required for incorporation of histone variant H3.3 into the male pronucleus during early embryogenesis. CHD1 interacts with HIRA (H3.3 chaperone) in cytoplasmic extracts. Loss of CHD1 abolishes H3.3 incorporation and renders the paternal genome unable to participate in zygotic mitoses, leading to haploid embryos.\",\n      \"method\": \"Genetic loss-of-function (CHD1 elimination in Drosophila embryos), immunofluorescence for H3.3 incorporation, co-immunoprecipitation of CHD1 with HIRA from cytoplasmic extracts\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined phenotype plus reciprocal Co-IP, replicated in concept by multiple subsequent studies\",\n      \"pmids\": [\"17717186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Chd1 is required to maintain open/euchromatin in mouse embryonic stem cells. Downregulation of Chd1 leads to accumulation of heterochromatin, loss of pluripotency (inability to give rise to primitive endoderm, propensity for neural differentiation), and reduced efficiency of somatic cell reprogramming. Chd1 associates with promoters of active genes.\",\n      \"method\": \"RNAi knockdown, chromatin immunoprecipitation, differentiation assays, reprogramming assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal functional assays (ChIP, differentiation, reprogramming) replicated across labs\",\n      \"pmids\": [\"19587682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CHD1 binds to SSRP1 (a subunit of the FACT complex) both in vivo and in vitro, localizes to centromeres in a CENP-H-containing complex-dependent manner, and is required for deposition of newly synthesized CENP-A into centromeric chromatin. RNAi knockdown of CHD1 decreases centromere-localized CENP-A levels.\",\n      \"method\": \"Co-immunoprecipitation (in vivo and in vitro), conditional mutant cell lines, RNAi knockdown, immunofluorescence\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and functional RNAi readout, single lab\",\n      \"pmids\": [\"19625449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The double chromodomain unit of Chd1 blocks DNA binding and activation of the ATPase motor in the absence of nucleosome substrates. An acidic helix joining the chromodomains packs against a DNA-binding surface of the ATPase motor (revealed by crystal structure). Disruption of the chromodomain-ATPase interface prevents discrimination between nucleosomes and naked DNA and reduces reliance on the histone H4 tail for nucleosome sliding.\",\n      \"method\": \"Crystal structure of Chd1 chromodomain region, site-directed mutagenesis, ATPase and nucleosome sliding assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with mutagenesis and functional assays in one study\",\n      \"pmids\": [\"20832723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The C-terminal DNA-binding domain of yeast Chd1 contains SANT and SLIDE domains (structural homologs of ISWI DNA-binding domains), is required for nucleosome binding and remodeling, and site-directed mutagenesis of conserved residues identifies those important for DNA binding. SLIDE domains were also identified in CHD6-9 proteins.\",\n      \"method\": \"Crystal structure of Chd1 DNA-binding domain, site-directed mutagenesis, nucleosome binding and remodeling assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with mutagenesis and functional validation\",\n      \"pmids\": [\"21623345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The DNA-binding domain of Chd1 is not essential for nucleosome sliding per se but is critical for centering mononucleosomes on short DNA fragments. Replacing the native DNA-binding domain with foreign DNA-binding domains (AraC or engrailed) redirects nucleosome sliding toward their cognate DNA sequences, demonstrating that the DNA-binding domain's affinity for extranucleosomal DNA determines the direction of Chd1-mediated nucleosome sliding.\",\n      \"method\": \"Domain-swap experiments with chimeric Chd1 constructs, nucleosome sliding assays, FRET-based positioning assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution with chimeric proteins, multiple DNA-binding domain swaps tested, clear mechanistic demonstration\",\n      \"pmids\": [\"21969605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Crystal structure of Saccharomyces cerevisiae Chd1 DNA-binding domain in complex with DNA shows the SLIDE domain contacts the DNA major groove (in contrast to predicted minor-groove binding), with contacts predominantly on one DNA strand. The bound DNA duplex is straight, consistent with preference for extranucleosomal DNA.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure at atomic resolution\",\n      \"pmids\": [\"22033927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Chd1 is required for maintenance of high levels of H2B monoubiquitination (H2BK123ub) genome-wide. Loss of Chd1 causes substantial reduction of H2BK123ub levels and reduced nucleosome occupancy in gene bodies, but does not affect H3K4 or H3K79 trimethylation patterns. This function is conserved from yeast to humans.\",\n      \"method\": \"Genome-wide ChIP-seq, western blot analysis of histone modifications in chd1Δ yeast and human CHD1-depleted cells\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP and biochemical assays, conserved finding demonstrated in two organisms\",\n      \"pmids\": [\"22549955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Isw1b and Chd1 act in conjunction to prevent trans-histone exchange over coding regions during transcription elongation. Chd1 is recruited to open reading frames by H3K36 methylation context and maintains chromatin integrity during RNAPII passage.\",\n      \"method\": \"Genome-wide nucleosome mapping, histone exchange assays, genetic epistasis in S. cerevisiae, in vivo and in vitro H3K36me recruitment assays\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide mapping plus in vitro and in vivo recruitment assays, multiple orthogonal methods\",\n      \"pmids\": [\"22922743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CHD1 is required for efficient recruitment of androgen receptor (AR) to responsive promoters in prostate cells. Inactivation of CHD1 in vitro prevents formation of ERG rearrangements by impairing AR-dependent transcription. CHD1 regulates expression of AR-responsive tumor suppressor genes including NKX3-1, FOXO1, and PPARγ.\",\n      \"method\": \"RNAi knockdown, chromatin immunoprecipitation for AR, gene expression analysis, FISH for ERG rearrangements\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and functional assays, single lab\",\n      \"pmids\": [\"23492366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Chd1 is recruited to promoter-proximal nucleosomes of actively transcribed genes and is responsible for the majority of RNAPII-directed nucleosome turnover at these sites. Expression of a dominant-negative Chd1 increases stalling of RNAPII past the entry site of promoter-proximal nucleosomes. Chd1 evicts nucleosomes downstream of the promoter to overcome the nucleosomal barrier and enable RNAPII promoter escape.\",\n      \"method\": \"Modified ChIP using micrococcal nuclease digestion, dominant-negative Chd1 expression, RNAPII stalling assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — novel ChIP methodology, dominant-negative functional assay, multiple readouts in one study\",\n      \"pmids\": [\"24737864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Dimethylation of KDM1A at K114 (K114me2) by EHMT2 creates a binding site for CHD1. Co-crystal structure of CHD1 with KDM1A K114me2 peptide characterizes the recognition mode. Genome-wide analyses reveal chromatin co-localization of KDM1A K114me2, CHD1, and androgen receptor (AR) in prostate tumor cells, linking this assembly to AR-dependent transcription and TMPRSS2-ERG fusion formation.\",\n      \"method\": \"Co-crystal structure (X-ray crystallography), genome-wide ChIP-seq, in vitro binding assays, functional assays for TMPRSS2-ERG translocation\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — co-crystal structure combined with genome-wide ChIP and functional translocation assays\",\n      \"pmids\": [\"26751641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CHD1 and ISW1 compete to set nucleosome spacing in vivo on most yeast genes, with CHD1 directing shorter spacing and ISW1 directing longer spacing. CHD1-directed short spacing correlates with eviction of linker histone H1, while ISW1-directed longer spacing allows H1 binding and chromatin condensation.\",\n      \"method\": \"Genome-wide nucleosome sequencing in single and double deletion strains, linker histone H1 occupancy mapping\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide approach with multiple genetic backgrounds, clear quantitative competition model\",\n      \"pmids\": [\"26861626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The Chd1 chromatin remodeler requires H2A/H2B on the entry side of the nucleosome for sliding. When presented with hexasomes (lacking one H2A/H2B dimer), Chd1 shifts them unidirectionally rather than bidirectionally. Ubiquitin-conjugated H2B on the entry side stimulates nucleosome sliding by Chd1.\",\n      \"method\": \"Reconstituted hexasome and asymmetric nucleosome sliding assays, single-molecule imaging, ubiquitinated H2B functional assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution with defined asymmetric substrates, multiple functional readouts\",\n      \"pmids\": [\"28032848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Cryo-EM structure of yeast Chd1 bound to a nucleosome at 4.8 Å resolution. Chd1 detaches two turns of DNA from the histone octamer. The SANT and SLIDE domains contact detached DNA around SHL -7 of the first DNA gyre. The ATPase motor binds the second DNA gyre at SHL +2 and is anchored to the N-terminal tail of histone H4. The double chromodomain swings toward nucleosomal DNA at SHL +1, causing ATPase closure. The ATPase promotes DNA translocation toward the nucleosome dyad.\",\n      \"method\": \"Cryo-electron microscopy structure determination\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure with functional validation, seminal structural paper for Chd1 mechanism\",\n      \"pmids\": [\"29019976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Site-specific cross-linking shows that Chd1 chromodomains and ATPase motor bind to adjacent SHL1 and SHL2 sites on nucleosomal DNA and pack against the DNA-binding domain on exiting DNA. This domain arrangement spans both DNA gyres and bridges both ends of a ~90-bp nucleosomal loop, suggesting a mechanism for nucleosome assembly and spacing.\",\n      \"method\": \"Site-specific cross-linking, biochemical domain mapping, structural modeling\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — site-specific cross-linking with multiple domain mutants, clear mechanistic model\",\n      \"pmids\": [\"28111016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Monomeric Chd1 shifts nucleosomal DNA bidirectionally by dynamically alternating between different segments of the nucleosome. Sliding generates unstable remodeling intermediates that spontaneously relax. The DNA-binding domain and chromodomains are two regulatory domains controlling sliding: the chromodomains play a key role in substrate discrimination.\",\n      \"method\": \"Single-molecule FRET, nucleosome sliding assays with truncation and mutation constructs\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — single-molecule assays with domain mutants, quantitative kinetic analysis\",\n      \"pmids\": [\"28943314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PTEN stimulates GSK3β-mediated phosphorylation of CHD1 degron domains, promoting CHD1 degradation via the β-TrCP-mediated ubiquitination-proteasome pathway. PTEN deficiency results in CHD1 stabilization, which then engages trimethyl H3K4 to activate the TNF-NF-κB gene network.\",\n      \"method\": \"Biochemical phosphorylation assays, ubiquitination assays, proteasome inhibitor experiments, CHD1 degron mutagenesis, ChIP for H3K4me3\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal biochemical methods establishing a post-translational regulatory pathway\",\n      \"pmids\": [\"28166537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CHD1 is required for early DNA double-strand break repair via homologous recombination. CHD1 loss leads to reduced H2AX phosphorylation (γH2AX), impaired CtIP recruitment to DSB sites, reduced H2AX incorporation and poor retention at DSBs. The N-terminal region of CHD1 inhibits its own DNA binding, ATPase, and chromatin assembly/remodeling activities.\",\n      \"method\": \"CRISPR/Cas9 CHD1 knockout in human cells, γH2AX ChIP, HR repair assays, CtIP recruitment assays, ATPase and chromatin remodeling assays with N-terminal truncation constructs\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — clean human KO cells plus multiple biochemical assays, N-terminal inhibitory domain established by direct functional comparison\",\n      \"pmids\": [\"29529298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CHD1 promotes the XPC-to-TFIIH handover of nucleosomal UV lesions during global-genome nucleotide excision repair (GG-NER). CHD1 is recruited to UV lesions in a nucleosome/histone context in an XPC-dependent manner. CHD1 depletion slows CPD excision and sensitizes cells to UV-induced cytotoxicity.\",\n      \"method\": \"Chromatin immunoprecipitation of chromatin fragments, chromatin fractionation, immunofluorescence, CHD1 depletion with UV sensitivity assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and fractionation showing recruitment, functional handover assay, single lab\",\n      \"pmids\": [\"29018037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cryo-EM structures of yeast Chd1 bound to nucleosomes with ADP-beryllium fluoride (transition state mimic) reveal conserved contacts with single-strand translocases plus unique contacts with both DNA strands. Two turns of linker DNA are prised off the histone octamer upon Chd1 binding, and both the histone H3 tail and ubiquitin conjugated to H2B K120 are reoriented toward the unraveled DNA.\",\n      \"method\": \"Cryo-electron microscopy structure determination with transition state mimic\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM structure with transition state mimic capturing active state\",\n      \"pmids\": [\"30079888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The Chd1 ATPase motor stimulates DNA unwrapping from the edge of the nucleosome in a nucleotide-dependent and DNA sequence-sensitive fashion. Different nucleotide analogs (AMP-PNP vs. ADP·BeF3-) produce distinct DNA conformations: AMP-PNP causes in-plane DNA unwrapping, while ADP·BeF3- shows out-of-plane unwrapping. The Chd1 DNA-binding domain is not required for unwrapping.\",\n      \"method\": \"Stopped-flow binding kinetics, bulk FRET, small-angle X-ray scattering with contrast variation\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple biophysical methods (FRET, SAXS) with nucleotide analogs, rigorous quantitative analysis\",\n      \"pmids\": [\"29850894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CHD1 occupies prostate-specific enhancers enriched for androgen receptor (AR) and lineage-specific cofactors. Upon CHD1 loss, the AR cistrome is redistributed to an oncogenic pattern, driving tumor formation in the murine prostate. CHD1 constrains AR binding/function to limit tumor progression.\",\n      \"method\": \"ChIP-seq for CHD1 and AR in human and mouse cells, CHD1 knockout/knockdown with ATAC-seq, in vivo mouse prostate tumor models\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-seq plus in vivo mouse model, multiple orthogonal methods\",\n      \"pmids\": [\"30930119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CHD1 loss impairs CtIP recruitment to chromatin and subsequent DNA end resection during DSB repair, specifically affecting homologous recombination (HR) but not non-homologous end joining (NHEJ). CHD1 is proposed to open chromatin around DSBs to facilitate HR protein recruitment.\",\n      \"method\": \"CHD1 siRNA/shRNA depletion, CtIP chromatin recruitment assays, HR and NHEJ repair assays, PARP inhibitor sensitivity tests\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional recruitment assays and repair pathway distinction, single lab\",\n      \"pmids\": [\"27596623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Biochemical reconstitution shows Chd1 and FACT together facilitate Pol II transcription through a nucleosome when elongation factors Spt4/5 and TFIIS are present. Cryo-EM structures reveal: (1) Pol II transcription exposes the proximal H2A-H2B dimer bound by Spt5, with Chd1 poised to pump DNA toward Pol II via its released inhibitory DNA-binding region; (2) a partially unraveled nucleosome generated by Pol II binds FACT, which excludes Chd1 and Spt5, enabling FACT-histone transfer to upstream DNA.\",\n      \"method\": \"Biochemical reconstitution of Pol II transcription through nucleosomes, cryo-EM structure determination of transcribing complexes\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution plus two cryo-EM structures capturing sequential mechanistic states\",\n      \"pmids\": [\"33846633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Chd1 interacts with DNA repair factors including Atm, Parp1, Kap1, and Topoisomerase 2β. In Chd1 KO embryonic stem cells, DNA double-strand breaks accumulate specifically at Chd1-bound Pol II-transcribed genes (particularly longer genes with GC-rich promoters) and rDNA.\",\n      \"method\": \"Co-immunoprecipitation of Chd1 with repair factors, DSB mapping (BLISS/END-seq) in Chd1 KO ES cells, ChIP-seq\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus genome-wide DSB mapping in KO cells, single lab\",\n      \"pmids\": [\"34381042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Chd1 is required for FACT spreading from the +1 nucleosome to downstream nucleosomes during transcription. FACT binds the +1 nucleosome as it is partially unwrapped by engaging RNAPII, and spreads to downstream nucleosomes aided by Chd1.\",\n      \"method\": \"High-resolution genome-wide mapping (MNase-ChIP-seq), single-molecule tracking, mathematical modeling, genetic deletion of Chd1\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (genome-wide mapping, single-molecule, modeling) converging on same mechanism\",\n      \"pmids\": [\"34380014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CHD1 loss results in global changes in open and closed chromatin (ATAC-seq) with associated transcriptomic changes, establishing transcriptional plasticity that enables antiandrogen resistance through four transcription factors (NR3C1, POU3F2, NR2F1, TBX2).\",\n      \"method\": \"In vivo shRNA screen, ATAC-seq, RNA-seq, CRISPR-based functional screening\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo screen plus genome-wide chromatin and transcriptome analysis, single lab\",\n      \"pmids\": [\"32220301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CHD1 regulates IL6 transcription, and IL6 is a key transcriptional target of CHD1 involved in recruitment of myeloid-derived suppressor cells (MDSCs) to reshape the tumor microenvironment in PTEN-deficient prostate cancer. Prostate-specific deletion of Chd1 in PTEN-deficient mouse models delays tumor progression and reduces MDSC recruitment.\",\n      \"method\": \"Genetically engineered mouse models (Pten and Pten/Smad4 with prostate-specific Chd1 deletion), tumor microenvironment immunophenotyping, IL6 ChIP and expression analysis\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo GEM models plus ChIP for direct transcriptional target, single lab\",\n      \"pmids\": [\"32385075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cryo-EM structure of Chd1 bound to a nucleosome in a nucleotide-free state at 2.3 Å resolution reveals that Chd1 stimulates the nucleosome to absorb an additional nucleotide on each DNA strand at two different locations. On the tracking strand within the ATPase binding site, this extra nucleotide induces a local A-form DNA geometry, explaining sequential ratcheting of each strand. A histone-binding motif (ChEx) is identified that can block opposing remodelers and may allow Chd1 to participate in histone reorganization during transcription.\",\n      \"method\": \"Cryo-electron microscopy at 2.3 Å resolution, structural analysis\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM structure revealing atomic-level mechanism of DNA ratcheting\",\n      \"pmids\": [\"35173352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM structures of Chd1 bound to a hexasome-nucleosome complex show Chd1 positions its ATPase domain to shift the hexasome away from the nucleosome. In the absence of the inner H2A/H2B dimer, Chd1's DNA-binding domain packs against the ATPase domain (inhibited state). Restoration of the H2A/H2B dimer by FACT triggers DBD rearrangement that displaces the DBD and stimulates Chd1 remodeling, demonstrating FACT-Chd1 cooperation in resolving transcription-induced hexasome-nucleosome complexes.\",\n      \"method\": \"Cryo-EM structure determination of two states (before and after FACT-mediated H2A/H2B restoration), biochemical reconstitution\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — two cryo-EM structures capturing mechanistic states, supported by biochemical reconstitution\",\n      \"pmids\": [\"39270644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Chd1 disruption in Drosophila heads results in reduced H3.3 levels, perturbed brain chromatin structure, and global de-repression of transcription, with phenotypic consequences of reduced food intake, metabolic alterations, and shortened lifespan. Strong genetic interaction between Chd1 and H3.3 chaperone HIRA was demonstrated.\",\n      \"method\": \"Quantitative mass spectrometry for histone variant levels, genetic interaction analysis (double mutants), brain-specific rescue experiments, ChIP\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative MS for H3.3, genetic interaction, rescue experiments; single lab\",\n      \"pmids\": [\"34610319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Autoinhibitory elements of Chd1 (chromodomains and 'bridge') act together to block nucleosome sliding by preventing initiation of twist defects when the DNA-binding domain is not bound to entry-side DNA. These elements target nucleotide-free and ADP-bound states of the ATPase motor, favoring a partially disengaged ATPase-nucleosome state.\",\n      \"method\": \"Biochemical nucleosome sliding assays with Chd1 mutants lacking autoinhibitory elements, kinetic analysis, nucleotide-state specific assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple autoinhibitory element mutants tested with kinetic mechanistic dissection\",\n      \"pmids\": [\"33468676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Both the chromodomain (C) and ATPase/helicase-like domain (H) of CHD1 are essential for its proper association with chromatin. CHD1 interacts with SSRP1 (an HMG box-containing protein/FACT subunit) through an N-terminal segment that does not include the chromodomain.\",\n      \"method\": \"Transient transfection with wild-type and domain-mutant CHD1 constructs, immunocytochemistry, co-immunoprecipitation\",\n      \"journal\": \"Chromosoma\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — domain mutagenesis with cellular localization readout, plus Co-IP for SSRP1 interaction; single lab\",\n      \"pmids\": [\"10199952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"CHD1 preferentially binds relatively long A-T tracts in double-stranded DNA via minor-groove interactions. The DNA-binding activity maps to a 229-amino-acid C-terminal segment. CHD1 is a constituent of bulk chromatin extractable with 0.6 M NaCl or EDTA after MNase digestion. CHD1 is released into the cytoplasm when cells enter mitosis and is reincorporated into chromatin during telophase-cytokinesis.\",\n      \"method\": \"DNA binding assays, deletion mapping, chromatin fractionation, immunocytochemistry across cell cycle stages\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — biochemical DNA binding assays with domain mapping plus cell cycle fractionation; foundational paper, single lab\",\n      \"pmids\": [\"7739555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CHD1 co-immunoprecipitates with histone deacetylase (HDAC) activity and associates with NCoR (a transcriptional corepressor) in yeast two-hybrid and in vitro pull-down assays. CHD1 also interacts with splicing proteins mKIAA0164, Srp20, and SAF-B by two-hybrid, and CHD1 overexpression affects alternative splicing.\",\n      \"method\": \"Co-immunoprecipitation (for HDAC), yeast two-hybrid and in vitro pull-down (for NCoR and splicing proteins), alternative splicing assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP and two-hybrid data for NCoR/HDAC interaction, limited mechanistic follow-up\",\n      \"pmids\": [\"12890497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Mediator coactivator complex is required for CHD1 recruitment to preinitiation complexes on chromatin. CHD1 is recruited to naive chromatin but shows enhanced recruitment on H3K4me3 chromatin. CHD1 co-immunoprecipitates with Mediator components from cell extracts, and this interaction is abolished by knockdown of a specific Mediator subunit.\",\n      \"method\": \"MuDPIT proteomic analysis of purified preinitiation complexes, immunoblot, shRNA depletion, co-immunoprecipitation, genome-wide binding (ChIP-seq in mouse ES cells)\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — proteomic PIC analysis plus reciprocal Co-IP and genome-wide ChIP, multiple orthogonal methods\",\n      \"pmids\": [\"21979373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CHD1 interacts with the influenza virus polymerase complex. CHD1 downregulation reduces viral polymerase activity, viral RNA transcription, and production of infectious particles. CHD1 associates with RNAPII and undergoes parallel degradation with RNAPII during influenza infection.\",\n      \"method\": \"Co-immunoprecipitation of CHD1 with viral polymerase, CHD1 knockdown with viral replication assays, co-localization immunofluorescence\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP establishing interaction plus functional knockdown assays, single lab\",\n      \"pmids\": [\"26792750\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CHD1 is an ATP-dependent chromatin remodeler that assembles and repositions nucleosomes using a bilobal ATPase motor anchored to SHL+2 nucleosomal DNA, regulated by autoinhibitory chromodomains that gate DNA access; human CHD1 binds H3K4me2/3 via cooperative tandem chromodomains to localize to actively transcribed genes where it promotes nucleosome turnover, RNAPII elongation through nucleosomes (in cooperation with FACT and Spt4/5), H2B monoubiquitination maintenance, and replication-independent H3.3 deposition, while also functioning in homologous recombination-mediated DNA double-strand break repair by facilitating chromatin opening for CtIP and HR factor recruitment, and is subject to PTEN/GSK3β-mediated phosphorylation that targets it for β-TrCP/proteasome degradation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CHD1 is an ATP-dependent chromatin remodeler that assembles, spaces, and repositions nucleosomes to maintain accessible chromatin at actively transcribed genes [#3, #5, #16]. Its catalytic core is a bilobal ATPase motor that engages the nucleosome at SHL+2, anchors to the histone H4 N-terminal tail, and detaches roughly two turns of DNA from the octamer to translocate DNA toward the dyad and drive a strand-by-strand ratcheting mechanism [#18, #24, #33]. Substrate engagement is gated by autoinhibitory elements: tandem chromodomains and a connecting bridge pack against a DNA-binding surface of the ATPase to block remodeling until the C-terminal SANT-SLIDE DNA-binding domain engages extranucleosomal entry-side DNA, which also sets the direction of sliding and centers nucleosomes [#7, #9, #36]. CHD1 requires an intact H2A/H2B dimer on the nucleosome entry side, and entry-side H2B ubiquitination stimulates its sliding activity [#17, #34]. In humans, cooperative tandem chromodomains directly recognize H3K4me2/3, targeting CHD1 to active promoters [#1], while H3K36 methylation and the Mediator complex contribute to recruitment at transcribed regions and preinitiation complexes [#12, #40]. There, CHD1 drives RNAPII-directed nucleosome turnover and promoter escape, and cooperates with FACT and Spt4/5 to enable polymerase passage through nucleosomes and to spread FACT across gene bodies [#14, #28, #30]. It additionally maintains genome-wide H2B monoubiquitination [#11] and, with histone chaperones HIRA and NAP1, supports replication-independent H3.3 deposition required for paternal genome activation and brain chromatin integrity [#3, #4, #35]. CHD1 maintains open euchromatin and pluripotency in embryonic stem cells [#5] and promotes homologous-recombination repair of double-strand breaks by opening chromatin to permit CtIP recruitment and end resection [#22, #27]. CHD1 is post-translationally controlled by PTEN/GSK3\\u03b2-mediated phosphorylation that targets it for \\u03b2-TrCP/proteasome degradation, linking its stability to the AR cistrome and tumor-microenvironment programs in prostate cancer [#21, #26].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established CHD1 as a chromatin-associated, sequence-preferential DNA-binding protein, defining its biochemical substrate before any remodeling role was known.\",\n      \"evidence\": \"DNA binding assays, deletion mapping, and cell-cycle chromatin fractionation\",\n      \"pmids\": [\"7739555\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No ATPase or remodeling activity assigned\", \"Functional role of A-T tract minor-groove binding unresolved\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Showed that both chromodomain and ATPase domains are needed for chromatin association and identified SSRP1 (FACT) as an early physical partner, hinting at a transcription-coupled function.\",\n      \"evidence\": \"Domain-mutant transfection with immunocytochemistry and Co-IP\",\n      \"pmids\": [\"10199952\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of SSRP1 interaction not tested\", \"Single-lab cellular readout\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Linked yeast Chd1 genetically and physically to the transcription elongation machinery, placing it within the Paf1/Spt4-Spt5/FACT network on active genes.\",\n      \"evidence\": \"Two-hybrid, Co-IP, genetic suppressor analysis, and ChIP in S. cerevisiae\",\n      \"pmids\": [\"12682017\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct enzymatic contribution to elongation not yet demonstrated\", \"Mechanism of recruitment unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined CHD1 as an ATP-dependent nucleosome assembly factor and established the chromodomain–methyl-histone reading mode, connecting catalytic activity to chromatin targeting.\",\n      \"evidence\": \"In vitro chromatin assembly with NAP1/histones; chromodomain binding assays and quantitative H3K4me recognition in yeast and human Chd1\",\n      \"pmids\": [\"15643425\", \"15647753\", \"16263726\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Human vs yeast difference in H3K4me binding mechanistically unexplained at the time\", \"In vivo assembly role not shown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated a histone-variant deposition role by showing CHD1 is required for H3.3 incorporation into the paternal pronucleus, with HIRA as a partner.\",\n      \"evidence\": \"Drosophila loss-of-function, H3.3 immunofluorescence, and CHD1–HIRA Co-IP\",\n      \"pmids\": [\"17717186\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CHD1 deposits H3.3 directly or supports a chaperone unclear\", \"Generality beyond pronucleus untested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Connected CHD1 to maintenance of open euchromatin, pluripotency, and centromeric CENP-A deposition, broadening its role to stem-cell identity and chromosome segregation.\",\n      \"evidence\": \"RNAi, ChIP, differentiation/reprogramming assays in mouse ESCs; Co-IP and RNAi for SSRP1/CENP-A axis\",\n      \"pmids\": [\"19587682\", \"19625449\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"CENP-A deposition role single-lab (Medium)\", \"Direct vs indirect contribution to heterochromatin accumulation unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Resolved the architecture and logic of the C-terminal DNA-binding domain, showing it reads extranucleosomal DNA to direct and center nucleosome sliding, and that chromodomains autoinhibit the motor.\",\n      \"evidence\": \"Crystal structures of the DNA-binding domain (apo and DNA-bound) and chromodomain region, domain-swap chimeras, sliding/ATPase assays; Mediator-dependent recruitment by proteomics and ChIP\",\n      \"pmids\": [\"20832723\", \"21623345\", \"21969605\", \"22033927\", \"21979373\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full motor-on-nucleosome geometry not yet visualized\", \"How autoinhibition is relieved in vivo unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established chromatin-integrity functions during elongation: maintaining genome-wide H2B monoubiquitination and preventing trans-histone exchange over coding regions via H3K36me-guided recruitment.\",\n      \"evidence\": \"Genome-wide ChIP-seq, histone-exchange and recruitment assays, genetic epistasis in yeast and human cells\",\n      \"pmids\": [\"22549955\", \"22922743\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic link between remodeling and H2Bub maintenance not fully resolved\", \"Directness of H3K36me readout unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Placed CHD1 in androgen-receptor-driven transcription in prostate cells, where it enables AR recruitment and AR-responsive tumor-suppressor expression.\",\n      \"evidence\": \"RNAi, AR ChIP, expression analysis, and FISH for ERG rearrangements\",\n      \"pmids\": [\"23492366\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab functional data\", \"Direct vs indirect effect on AR binding not separated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed CHD1 performs the bulk of RNAPII-directed nucleosome turnover at promoter-proximal sites and is required for polymerase promoter escape past the +1 nucleosome.\",\n      \"evidence\": \"MNase-based ChIP, dominant-negative Chd1 expression, and RNAPII stalling assays\",\n      \"pmids\": [\"24737864\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Coordination with other elongation factors not yet mechanistically dissected\", \"In vitro reconstitution lacking at this stage\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined entry-side substrate requirements and nucleosome-spacing competition, showing CHD1 needs H2A/H2B and ubiquitinated H2B on the entry side and competes with ISW1 to set short, H1-depleted spacing; also linked a KDM1A-K114me2 mark to CHD1/AR recruitment.\",\n      \"evidence\": \"Reconstituted hexasome/asymmetric sliding and single-molecule assays; genome-wide nucleosome mapping in deletion strains; co-crystal of CHD1 with KDM1A peptide plus ChIP-seq\",\n      \"pmids\": [\"28032848\", \"26861626\", \"26751641\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How H2Bub stimulation is structurally transmitted to the motor not yet shown\", \"Relevance of KDM1A mark beyond prostate cells untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established a direct role in homologous-recombination DSB repair, with CHD1 required for CtIP recruitment and end resection but not NHEJ.\",\n      \"evidence\": \"CHD1 depletion, CtIP recruitment and HR/NHEJ repair assays, PARP-inhibitor sensitivity\",\n      \"pmids\": [\"27596623\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab data\", \"Whether chromatin opening at DSBs is direct not structurally shown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Delivered the first nucleosome-bound structures and mechanism: CHD1 detaches linker DNA, engages SHL+2 and the H4 tail, swings its chromodomains to close the ATPase, and pumps DNA toward the dyad, while domain cross-linking and single-molecule work defined bidirectional, regulated sliding.\",\n      \"evidence\": \"Cryo-EM of Chd1-nucleosome, site-specific cross-linking, single-molecule FRET with domain mutants\",\n      \"pmids\": [\"29019976\", \"28111016\", \"28943314\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transition-state geometry not yet captured\", \"Coupling of ATP hydrolysis to DNA step size unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended CHD1 to additional DNA-repair pathways and defined its post-translational control, showing PTEN/GSK3\\u03b2-driven \\u03b2-TrCP degradation, an N-terminal autoinhibitory region, and roles in GG-NER XPC-to-TFIIH handover.\",\n      \"evidence\": \"Phosphorylation/ubiquitination/degron assays; CRISPR KO with \\u03b3H2AX ChIP and HR assays; UV-lesion recruitment and excision assays\",\n      \"pmids\": [\"28166537\", \"29529298\", \"29018037\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"NER handover role single-lab (Medium)\", \"Interplay between N-terminal and chromodomain autoinhibition not unified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Captured the active/transition-state mechanism, showing nucleotide-dependent DNA unwrapping and reorientation of the H3 tail and H2B-ubiquitin toward unraveled DNA.\",\n      \"evidence\": \"Cryo-EM with ADP-BeF transition-state mimic; stopped-flow, FRET, and SAXS with nucleotide analogs\",\n      \"pmids\": [\"30079888\", \"29850894\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Per-base-pair stepping not resolved at this stage\", \"Functional role of unwrapping in vivo inferred\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed CHD1 occupies prostate enhancers and constrains the AR cistrome, with its loss redistributing AR to an oncogenic pattern that drives tumorigenesis in vivo.\",\n      \"evidence\": \"CHD1/AR ChIP-seq, ATAC-seq in KO cells, and in vivo mouse prostate tumor models\",\n      \"pmids\": [\"30930119\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which CHD1 limits AR binding not fully defined\", \"Link to degradation pathway not integrated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected CHD1-dependent chromatin state to cancer phenotypes: transcriptional plasticity driving antiandrogen resistance and IL6-mediated MDSC recruitment in PTEN-deficient tumors.\",\n      \"evidence\": \"In vivo shRNA screens, ATAC/RNA-seq, and genetically engineered mouse models with IL6 ChIP\",\n      \"pmids\": [\"32220301\", \"32385075\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab in vivo models\", \"Direct vs network-level effects on resistance TFs not separated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Reconstituted and structurally resolved CHD1–FACT cooperation during Pol II transcription, showing sequential handoffs that move nucleosomes past polymerase and spread FACT downstream, and defined a chromodomain/bridge autoinhibitory mechanism.\",\n      \"evidence\": \"Biochemical reconstitution with Spt4/5 and TFIIS, cryo-EM of transcribing complexes, genome-wide MNase-ChIP and single-molecule tracking, kinetic autoinhibition assays; Co-IP/DSB mapping linking Chd1 to repair factors at transcribed genes\",\n      \"pmids\": [\"33846633\", \"34380014\", \"33468676\", \"34381042\", \"34610319\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Co-IP with ATM/PARP1/KAP1/TOP2B single-lab (Medium)\", \"How autoinhibition is coordinated with FACT-driven activation in vivo not fully resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Achieved atomic-resolution mechanism, showing CHD1 forces the nucleosome to absorb an extra nucleotide per strand to ratchet DNA, and identified a ChEx histone-binding motif relevant to histone reorganization.\",\n      \"evidence\": \"2.3 \\u00c5 cryo-EM of nucleotide-free Chd1-nucleosome\",\n      \"pmids\": [\"35173352\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of ChEx motif in transcription not directly tested\", \"Sequence dependence of ratcheting in vivo unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined the structural basis of FACT-dependent activation, showing the entry-side H2A/H2B dimer controls a DBD-ATPase autoinhibitory switch that FACT releases to resolve transcription-induced hexasome-nucleosome complexes.\",\n      \"evidence\": \"Two-state cryo-EM (before/after FACT-mediated dimer restoration) with biochemical reconstitution\",\n      \"pmids\": [\"39270644\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo prevalence of hexasome intermediates not quantified\", \"Generality across other remodelers untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CHD1's distinct activities — promoter remodeling, H2Bub/H3.3 maintenance, HR/NER repair, and AR-cistrome constraint — are selectively deployed and coordinated within a single cell context remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking PTEN/GSK3\\u03b2 degradation control to specific chromatin functions\", \"Determinants of pathway choice (transcription vs repair) unknown\", \"Human in-cell structural states of the FACT/Spt5 cooperation not directly visualized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [3, 18, 25, 33]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [9, 10, 38]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [1, 15, 33]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 17, 36]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [2, 5, 14, 38]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 37, 38]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [29]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 14, 28, 40]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [3, 5, 11, 16]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [22, 23, 27]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [21, 26, 31, 32]}\n    ],\n    \"complexes\": [\"SAGA/SLIK histone acetyltransferase complex\"],\n    \"partners\": [\"SSRP1\", \"HIRA\", \"SPT16\", \"SPT5\", \"RTF1\", \"CtIP\", \"Mediator\", \"KDM1A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}