{"gene":"ZNF827","run_date":"2026-06-11T09:02:07","timeline":{"discoveries":[{"year":2014,"finding":"Nuclear receptors bound to ALT telomeres recruit ZNF827, which in turn recruits the NuRD (nucleosome remodeling and histone deacetylation) complex via binding to an N-terminal RRK motif within ZNF827. This NuRD-ZNF827 recruitment results in decreased shelterin binding, hypoacetylation of telomeric chromatin, enhanced telomere-telomere interactions, and recruitment of HR proteins, and is critically important for ALT cell viability and proliferation.","method":"Co-immunoprecipitation, domain mapping (N-terminal RRK motif), chromatin immunoprecipitation, telomere-specific assays, loss-of-function (siRNA knockdown) with viability/proliferation readout","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, domain mapping, multiple orthogonal methods (ChIP, telomere interaction assays, loss-of-function phenotype), replicated in subsequent studies","pmids":["25150861"],"is_preprint":false},{"year":2018,"finding":"The NuRD subunit RBBP4 binds to the N-terminal 14 amino acids of ZNF827 through a negatively charged channel via electrostatic interactions. Disruption of the specific RBBP4 residues required for this interaction prevents RBBP4 binding to both ZNF827 and telomeres, but is insufficient to decrease ALT activity.","method":"Crystal structure of RBBP4 bound to ZNF827 N-terminal peptide; mutagenesis of RBBP4 binding residues; telomere recruitment assays","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with mutagenesis validation in a single lab, two orthogonal methods (structure + functional mutagenesis + telomere recruitment assay)","pmids":["30045876"],"is_preprint":false},{"year":2015,"finding":"NuRD-ZNF827 protein-protein interactions provide a platform for the telomeric recruitment of homologous recombination (HR) proteins as part of the ALT mechanism, enabling strand exchange and template-driven DNA synthesis.","method":"Review/synthesis drawing on experimental data from prior studies; protein-protein interaction and HR recruitment assays described","journal":"Nature structural & molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic synthesis supported by prior experimental data, but this paper is a review/perspective rather than primary experimental report","pmids":["26581522"],"is_preprint":false},{"year":2022,"finding":"ZNF827 is strongly induced during epithelial-to-mesenchymal transition (EMT) and is required for EMT in brain development and breast cancer metastasis. Mechanistically, ZNF827 recruits HDAC1 for epigenetic modulation of distinct genomic loci, slowing RNA polymerase II progression and altering splicing of genes encoding key EMT regulators in cis, thereby orchestrating large-scale remodeling of the splicing landscape.","method":"Loss-of-function (knockdown/knockout) with molecular and phenotypic readouts; co-immunoprecipitation of ZNF827-HDAC1 complex; RNA Pol II ChIP; splicing analysis; in vivo brain development and breast cancer metastasis models","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, ChIP, splicing analysis, in vivo models, loss-of-function with defined phenotypes) in a single rigorous study","pmids":["35941369"],"is_preprint":false},{"year":2024,"finding":"ZNF827 is a single-stranded DNA (ssDNA) binding protein that associates with RPA through concurrent binding to ssDNA intermediates; these interactions depend on two clusters of C2H2 zinc finger motifs within ZNF827. ZNF827 accumulates at stalled replication forks and DNA damage sites, activates ATR, promotes homologous recombination-mediated DNA repair, and its depletion inhibits replication initiation and sensitizes cancer cells to topotecan.","method":"In vitro ssDNA binding assays; Co-immunoprecipitation with RPA; domain mutagenesis (C2H2 zinc finger cluster mutations); immunofluorescence at stalled forks/damage sites; ATR activation assays; HR repair assays; replication initiation assays; cell viability assays with topotecan","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro reconstitution of ssDNA binding, mutagenesis of zinc finger clusters, multiple orthogonal methods (Co-IP, imaging, kinase activation, functional HR/replication assays) in one rigorous study","pmids":["38472229"],"is_preprint":false},{"year":2020,"finding":"The ZNF827 protein is part of the mRNP complex associated with circZNF827; knockdown of circZNF827 deregulates neuronal gene expression (including upregulation of NGFR), suggesting functional co-evolution of the circRNA and the protein encoded by its linear pre-mRNA host. (Note: this finding pertains to ZNF827 protein participation in an mRNP complex, not to circZNF827 itself.)","method":"RNA immunoprecipitation / mRNP complex identification; circRNA knockdown with gene expression readout","journal":"eLife","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP/RIP experiment identifying ZNF827 protein in mRNP complex; mechanistic role of the protein itself not further resolved in this study","pmids":["33174841"],"is_preprint":false},{"year":2026,"finding":"Knockdown of ZNF827 in human iPSC-derived smooth muscle cells and fibroblasts dysregulates a large number of genes enriched in macroautophagy and insulin signaling pathways, indicating ZNF827 acts as a broad regulator of gene expression in vascular SMCs and fibroblasts. A SCAD-risk intronic variant (rs13128814-A) increases transcriptional activity and preferentially binds NF1 transcription factors, with the variant colocalizing with a ZNF827 eQTL in artery tissues.","method":"siRNA knockdown in iPSC-derived SMCs and fibroblasts with transcriptomic readout; reporter assay for variant transcriptional activity; in silico NF1 binding prediction confirmed by reporter assay","journal":"Clinical science (London, England : 1979)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown with defined transcriptomic phenotype plus reporter assays for variant function, single lab, two orthogonal methods","pmids":["41983892"],"is_preprint":false}],"current_model":"ZNF827 is a C2H2 zinc-finger protein that functions as a multifunctional chromatin and DNA-damage regulator: it binds single-stranded DNA and RPA to activate the ATR-CHK1 pathway and promote homologous recombination at stalled forks; at ALT telomeres it is recruited by nuclear receptors and recruits the NuRD complex (via its N-terminal RRK motif binding to RBBP4) to remodel telomeric chromatin and create a platform for HR-mediated telomere synthesis; and during EMT it recruits HDAC1 to slow RNA polymerase II and reprogram the splicing landscape, acting as a master regulator coupling epigenetic and splicing programs in brain development and cancer metastasis."},"narrative":{"mechanistic_narrative":"ZNF827 is a C2H2 zinc-finger protein that couples chromatin remodeling to genome maintenance and gene-expression programs across telomere biology, DNA replication stress, and cell-state transitions [PMID:25150861, PMID:35941369, PMID:38472229]. At alternative-lengthening-of-telomeres (ALT) telomeres, nuclear-receptor-bound ZNF827 recruits the NuRD chromatin-remodeling and histone-deacetylation complex through an N-terminal RRK motif, driving shelterin displacement, telomeric chromatin hypoacetylation, enhanced telomere-telomere interactions, and assembly of a homologous-recombination platform required for ALT cell viability [PMID:25150861]; the NuRD subunit RBBP4 engages the first 14 residues of ZNF827 through a negatively charged electrostatic channel [PMID:30045876]. In the context of replication stress, ZNF827 binds single-stranded DNA and associates with RPA via two clusters of C2H2 zinc-finger motifs, accumulating at stalled forks and damage sites to activate ATR and promote HR-mediated repair, such that its loss impairs replication initiation and sensitizes cancer cells to topotecan [PMID:38472229]. During epithelial-to-mesenchymal transition, ZNF827 is strongly induced and recruits HDAC1 to slow RNA polymerase II progression and reprogram co-transcriptional splicing of EMT regulators, a function required for brain development and breast cancer metastasis [PMID:35941369]. ZNF827 also acts as a broad transcriptional regulator in vascular smooth muscle cells and fibroblasts, where its depletion dysregulates macroautophagy and insulin-signaling genes [PMID:41983892].","teleology":[{"year":2014,"claim":"Established how ALT telomeres are epigenetically remodeled by identifying ZNF827 as the adaptor that brings the NuRD complex to telomeres downstream of nuclear receptors.","evidence":"Co-IP, N-terminal RRK motif domain mapping, ChIP, telomere-interaction assays, and siRNA loss-of-function with viability readout in ALT cells","pmids":["25150861"],"confidence":"High","gaps":["Did not resolve the atomic basis of the ZNF827-NuRD contact","Mechanism linking chromatin hypoacetylation to HR protein recruitment not fully defined"]},{"year":2015,"claim":"Synthesized how NuRD-ZNF827 interactions provide a physical platform for HR protein recruitment enabling template-driven telomere synthesis in ALT.","evidence":"Review/synthesis of prior protein-protein interaction and HR recruitment data","pmids":["26581522"],"confidence":"Medium","gaps":["Secondary synthesis rather than new primary data","Order of events from chromatin remodeling to strand exchange not directly tested"]},{"year":2018,"claim":"Defined the structural basis of the ZNF827-NuRD interface, showing RBBP4 binds the ZNF827 N-terminal 14 residues through a negatively charged channel.","evidence":"Crystal structure of RBBP4 bound to the ZNF827 N-terminal peptide with mutagenesis of binding residues and telomere recruitment assays","pmids":["30045876"],"confidence":"High","gaps":["Disrupting RBBP4 binding was insufficient to reduce ALT activity, indicating redundant recruitment routes","Contribution of other NuRD subunits to ZNF827 engagement not resolved"]},{"year":2020,"claim":"Placed ZNF827 protein within an mRNP complex linked to neuronal gene expression, hinting at a post-transcriptional/RNA-associated context.","evidence":"RNA immunoprecipitation/mRNP identification and circRNA knockdown with gene-expression readout","pmids":["33174841"],"confidence":"Low","gaps":["Single RIP experiment; mechanistic role of the protein itself not resolved","Direct RNA binding by ZNF827 not demonstrated"]},{"year":2022,"claim":"Revealed a distinct ZNF827 function in cell-state transitions: recruiting HDAC1 to slow RNA Pol II and reprogram splicing of EMT regulators in brain development and metastasis.","evidence":"Loss-of-function with phenotypes, ZNF827-HDAC1 Co-IP, RNA Pol II ChIP, splicing analysis, and in vivo brain development and breast cancer metastasis models","pmids":["35941369"],"confidence":"High","gaps":["Genomic targeting specificity of ZNF827 at EMT loci not defined","Relationship between the telomeric NuRD function and the HDAC1 splicing function unclear"]},{"year":2024,"claim":"Identified ZNF827 as an ssDNA/RPA-binding factor that operates in the replication-stress response, connecting it to ATR signaling and HR repair.","evidence":"In vitro ssDNA binding, RPA Co-IP, C2H2 zinc-finger cluster mutagenesis, damage-site imaging, ATR activation, HR and replication-initiation assays, and topotecan sensitivity","pmids":["38472229"],"confidence":"High","gaps":["How ZNF827 is recruited to forks relative to RPA loading not fully ordered","Whether the same zinc-finger clusters mediate chromatin/telomere functions untested"]},{"year":2026,"claim":"Extended ZNF827 to vascular biology as a broad gene-expression regulator and linked a SCAD-risk variant to its expression.","evidence":"siRNA knockdown in iPSC-derived SMCs/fibroblasts with transcriptomics, plus reporter assays for variant activity and NF1 binding","pmids":["41983892"],"confidence":"Medium","gaps":["Direct ZNF827 targets in SMCs not identified","Causal mechanism connecting the eQTL variant to vascular disease not established"]},{"year":null,"claim":"It remains unknown how ZNF827's distinct activities—NuRD/HDAC1 chromatin recruitment, ssDNA/RPA binding, and splicing/transcriptional control—are functionally integrated or context-switched within a single protein.","evidence":"No unifying study in the available corpus","pmids":[],"confidence":"Low","gaps":["No structural or regulatory model coordinating its multiple functions","DNA sequence specificity of the C2H2 array not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[4]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[3,6]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,3,4]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[4]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,3]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,6]}],"complexes":["NuRD complex","circZNF827 mRNP complex"],"partners":["RBBP4","HDAC1","RPA"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q17R98","full_name":"Zinc finger protein 827","aliases":[],"length_aa":1081,"mass_kda":119.2,"function":"As part of a ribonucleoprotein complex composed at least of HNRNPK, HNRNPL and the circular RNA circZNF827 that nucleates the complex on chromatin, may negatively regulate the transcription of genes involved in neuronal differentiation (PubMed:33174841). Could also recruit the nucleosome remodeling and histone deacetylase/NuRD complex to telomeric regions of chromosomes to regulate chromatin remodeling as part of telomere maintenance (PubMed:25150861)","subcellular_location":"Nucleus; Chromosome, telomere","url":"https://www.uniprot.org/uniprotkb/Q17R98/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ZNF827","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ZNF827","total_profiled":1310},"omim":[{"mim_id":"617962","title":"ZINC FINGER PROTEIN 827; ZNF827","url":"https://www.omim.org/entry/617962"},{"mim_id":"613637","title":"TUBERCULIN SKIN TEST REACTIVITY QUANTITATIVE TRAIT LOCUS","url":"https://www.omim.org/entry/613637"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ZNF827"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q17R98","domains":[{"cath_id":"3.30.160.60","chopping":"375-457","consensus_level":"medium","plddt":72.9061,"start":375,"end":457},{"cath_id":"3.30.160","chopping":"898-952","consensus_level":"medium","plddt":75.6842,"start":898,"end":952},{"cath_id":"3.30.160","chopping":"1019-1069","consensus_level":"medium","plddt":75.1751,"start":1019,"end":1069}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q17R98","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q17R98-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q17R98-F1-predicted_aligned_error_v6.png","plddt_mean":48.59},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ZNF827","jax_strain_url":"https://www.jax.org/strain/search?query=ZNF827"},"sequence":{"accession":"Q17R98","fasta_url":"https://rest.uniprot.org/uniprotkb/Q17R98.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q17R98/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q17R98"}},"corpus_meta":[{"pmid":"22001757","id":"PMC_22001757","title":"Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma.","date":"2011","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22001757","citation_count":456,"is_preprint":false},{"pmid":"26581522","id":"PMC_26581522","title":"Molecular mechanisms of activity and derepression of alternative lengthening of telomeres.","date":"2015","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/26581522","citation_count":155,"is_preprint":false},{"pmid":"25150861","id":"PMC_25150861","title":"NuRD-ZNF827 recruitment to telomeres creates a molecular scaffold for homologous recombination.","date":"2014","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/25150861","citation_count":99,"is_preprint":false},{"pmid":"31673075","id":"PMC_31673075","title":"Prediction and Analysis of Skin Cancer Progression using Genomics Profiles of Patients.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31673075","citation_count":51,"is_preprint":false},{"pmid":"33174841","id":"PMC_33174841","title":"circZNF827 nucleates a transcription inhibitory complex to balance neuronal differentiation.","date":"2020","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/33174841","citation_count":43,"is_preprint":false},{"pmid":"34396283","id":"PMC_34396283","title":"Machine Learning Identifies Clinical and Genetic Factors Associated With Anthracycline Cardiotoxicity in Pediatric Cancer Survivors.","date":"2020","source":"JACC. CardioOncology","url":"https://pubmed.ncbi.nlm.nih.gov/34396283","citation_count":42,"is_preprint":false},{"pmid":"35941369","id":"PMC_35941369","title":"A complex epigenome-splicing crosstalk governs epithelial-to-mesenchymal transition in metastasis and brain development.","date":"2022","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/35941369","citation_count":23,"is_preprint":false},{"pmid":"38472229","id":"PMC_38472229","title":"ZNF827 is a single-stranded DNA binding protein that regulates the ATR-CHK1 DNA damage response pathway.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/38472229","citation_count":15,"is_preprint":false},{"pmid":"30045876","id":"PMC_30045876","title":"Structural and functional characterization of the RBBP4-ZNF827 interaction and its role in NuRD recruitment to telomeres.","date":"2018","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/30045876","citation_count":11,"is_preprint":false},{"pmid":"34387878","id":"PMC_34387878","title":"Genome-wide association of individual vulnerability with alcohol-associated liver disease: A Korean genome and epidemiology study.","date":"2021","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/34387878","citation_count":11,"is_preprint":false},{"pmid":"28399120","id":"PMC_28399120","title":"Sotos syndrome associated with Hirschsprung's disease: a new case and exome-sequencing analysis.","date":"2017","source":"Pediatric research","url":"https://pubmed.ncbi.nlm.nih.gov/28399120","citation_count":1,"is_preprint":false},{"pmid":"41983892","id":"PMC_41983892","title":"ZNF827 pleiotropic cardiovascular risk locus involves regulation by nuclear factor-1.","date":"2026","source":"Clinical science (London, England : 1979)","url":"https://pubmed.ncbi.nlm.nih.gov/41983892","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7267,"output_tokens":2116,"usd":0.02677,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9132,"output_tokens":2828,"usd":0.05818,"stage2_stop_reason":"end_turn"},"total_usd":0.08495,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"Nuclear receptors bound to ALT telomeres recruit ZNF827, which in turn recruits the NuRD (nucleosome remodeling and histone deacetylation) complex via binding to an N-terminal RRK motif within ZNF827. This NuRD-ZNF827 recruitment results in decreased shelterin binding, hypoacetylation of telomeric chromatin, enhanced telomere-telomere interactions, and recruitment of HR proteins, and is critically important for ALT cell viability and proliferation.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping (N-terminal RRK motif), chromatin immunoprecipitation, telomere-specific assays, loss-of-function (siRNA knockdown) with viability/proliferation readout\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, domain mapping, multiple orthogonal methods (ChIP, telomere interaction assays, loss-of-function phenotype), replicated in subsequent studies\",\n      \"pmids\": [\"25150861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The NuRD subunit RBBP4 binds to the N-terminal 14 amino acids of ZNF827 through a negatively charged channel via electrostatic interactions. Disruption of the specific RBBP4 residues required for this interaction prevents RBBP4 binding to both ZNF827 and telomeres, but is insufficient to decrease ALT activity.\",\n      \"method\": \"Crystal structure of RBBP4 bound to ZNF827 N-terminal peptide; mutagenesis of RBBP4 binding residues; telomere recruitment assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with mutagenesis validation in a single lab, two orthogonal methods (structure + functional mutagenesis + telomere recruitment assay)\",\n      \"pmids\": [\"30045876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NuRD-ZNF827 protein-protein interactions provide a platform for the telomeric recruitment of homologous recombination (HR) proteins as part of the ALT mechanism, enabling strand exchange and template-driven DNA synthesis.\",\n      \"method\": \"Review/synthesis drawing on experimental data from prior studies; protein-protein interaction and HR recruitment assays described\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic synthesis supported by prior experimental data, but this paper is a review/perspective rather than primary experimental report\",\n      \"pmids\": [\"26581522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ZNF827 is strongly induced during epithelial-to-mesenchymal transition (EMT) and is required for EMT in brain development and breast cancer metastasis. Mechanistically, ZNF827 recruits HDAC1 for epigenetic modulation of distinct genomic loci, slowing RNA polymerase II progression and altering splicing of genes encoding key EMT regulators in cis, thereby orchestrating large-scale remodeling of the splicing landscape.\",\n      \"method\": \"Loss-of-function (knockdown/knockout) with molecular and phenotypic readouts; co-immunoprecipitation of ZNF827-HDAC1 complex; RNA Pol II ChIP; splicing analysis; in vivo brain development and breast cancer metastasis models\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, ChIP, splicing analysis, in vivo models, loss-of-function with defined phenotypes) in a single rigorous study\",\n      \"pmids\": [\"35941369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZNF827 is a single-stranded DNA (ssDNA) binding protein that associates with RPA through concurrent binding to ssDNA intermediates; these interactions depend on two clusters of C2H2 zinc finger motifs within ZNF827. ZNF827 accumulates at stalled replication forks and DNA damage sites, activates ATR, promotes homologous recombination-mediated DNA repair, and its depletion inhibits replication initiation and sensitizes cancer cells to topotecan.\",\n      \"method\": \"In vitro ssDNA binding assays; Co-immunoprecipitation with RPA; domain mutagenesis (C2H2 zinc finger cluster mutations); immunofluorescence at stalled forks/damage sites; ATR activation assays; HR repair assays; replication initiation assays; cell viability assays with topotecan\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro reconstitution of ssDNA binding, mutagenesis of zinc finger clusters, multiple orthogonal methods (Co-IP, imaging, kinase activation, functional HR/replication assays) in one rigorous study\",\n      \"pmids\": [\"38472229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The ZNF827 protein is part of the mRNP complex associated with circZNF827; knockdown of circZNF827 deregulates neuronal gene expression (including upregulation of NGFR), suggesting functional co-evolution of the circRNA and the protein encoded by its linear pre-mRNA host. (Note: this finding pertains to ZNF827 protein participation in an mRNP complex, not to circZNF827 itself.)\",\n      \"method\": \"RNA immunoprecipitation / mRNP complex identification; circRNA knockdown with gene expression readout\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP/RIP experiment identifying ZNF827 protein in mRNP complex; mechanistic role of the protein itself not further resolved in this study\",\n      \"pmids\": [\"33174841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Knockdown of ZNF827 in human iPSC-derived smooth muscle cells and fibroblasts dysregulates a large number of genes enriched in macroautophagy and insulin signaling pathways, indicating ZNF827 acts as a broad regulator of gene expression in vascular SMCs and fibroblasts. A SCAD-risk intronic variant (rs13128814-A) increases transcriptional activity and preferentially binds NF1 transcription factors, with the variant colocalizing with a ZNF827 eQTL in artery tissues.\",\n      \"method\": \"siRNA knockdown in iPSC-derived SMCs and fibroblasts with transcriptomic readout; reporter assay for variant transcriptional activity; in silico NF1 binding prediction confirmed by reporter assay\",\n      \"journal\": \"Clinical science (London, England : 1979)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown with defined transcriptomic phenotype plus reporter assays for variant function, single lab, two orthogonal methods\",\n      \"pmids\": [\"41983892\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ZNF827 is a C2H2 zinc-finger protein that functions as a multifunctional chromatin and DNA-damage regulator: it binds single-stranded DNA and RPA to activate the ATR-CHK1 pathway and promote homologous recombination at stalled forks; at ALT telomeres it is recruited by nuclear receptors and recruits the NuRD complex (via its N-terminal RRK motif binding to RBBP4) to remodel telomeric chromatin and create a platform for HR-mediated telomere synthesis; and during EMT it recruits HDAC1 to slow RNA polymerase II and reprogram the splicing landscape, acting as a master regulator coupling epigenetic and splicing programs in brain development and cancer metastasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ZNF827 is a C2H2 zinc-finger protein that couples chromatin remodeling to genome maintenance and gene-expression programs across telomere biology, DNA replication stress, and cell-state transitions [#0, #3, #4]. At alternative-lengthening-of-telomeres (ALT) telomeres, nuclear-receptor-bound ZNF827 recruits the NuRD chromatin-remodeling and histone-deacetylation complex through an N-terminal RRK motif, driving shelterin displacement, telomeric chromatin hypoacetylation, enhanced telomere-telomere interactions, and assembly of a homologous-recombination platform required for ALT cell viability [#0]; the NuRD subunit RBBP4 engages the first 14 residues of ZNF827 through a negatively charged electrostatic channel [#1]. In the context of replication stress, ZNF827 binds single-stranded DNA and associates with RPA via two clusters of C2H2 zinc-finger motifs, accumulating at stalled forks and damage sites to activate ATR and promote HR-mediated repair, such that its loss impairs replication initiation and sensitizes cancer cells to topotecan [#4]. During epithelial-to-mesenchymal transition, ZNF827 is strongly induced and recruits HDAC1 to slow RNA polymerase II progression and reprogram co-transcriptional splicing of EMT regulators, a function required for brain development and breast cancer metastasis [#3]. ZNF827 also acts as a broad transcriptional regulator in vascular smooth muscle cells and fibroblasts, where its depletion dysregulates macroautophagy and insulin-signaling genes [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Established how ALT telomeres are epigenetically remodeled by identifying ZNF827 as the adaptor that brings the NuRD complex to telomeres downstream of nuclear receptors.\",\n      \"evidence\": \"Co-IP, N-terminal RRK motif domain mapping, ChIP, telomere-interaction assays, and siRNA loss-of-function with viability readout in ALT cells\",\n      \"pmids\": [\"25150861\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the atomic basis of the ZNF827-NuRD contact\", \"Mechanism linking chromatin hypoacetylation to HR protein recruitment not fully defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Synthesized how NuRD-ZNF827 interactions provide a physical platform for HR protein recruitment enabling template-driven telomere synthesis in ALT.\",\n      \"evidence\": \"Review/synthesis of prior protein-protein interaction and HR recruitment data\",\n      \"pmids\": [\"26581522\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Secondary synthesis rather than new primary data\", \"Order of events from chromatin remodeling to strand exchange not directly tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined the structural basis of the ZNF827-NuRD interface, showing RBBP4 binds the ZNF827 N-terminal 14 residues through a negatively charged channel.\",\n      \"evidence\": \"Crystal structure of RBBP4 bound to the ZNF827 N-terminal peptide with mutagenesis of binding residues and telomere recruitment assays\",\n      \"pmids\": [\"30045876\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Disrupting RBBP4 binding was insufficient to reduce ALT activity, indicating redundant recruitment routes\", \"Contribution of other NuRD subunits to ZNF827 engagement not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed ZNF827 protein within an mRNP complex linked to neuronal gene expression, hinting at a post-transcriptional/RNA-associated context.\",\n      \"evidence\": \"RNA immunoprecipitation/mRNP identification and circRNA knockdown with gene-expression readout\",\n      \"pmids\": [\"33174841\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single RIP experiment; mechanistic role of the protein itself not resolved\", \"Direct RNA binding by ZNF827 not demonstrated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed a distinct ZNF827 function in cell-state transitions: recruiting HDAC1 to slow RNA Pol II and reprogram splicing of EMT regulators in brain development and metastasis.\",\n      \"evidence\": \"Loss-of-function with phenotypes, ZNF827-HDAC1 Co-IP, RNA Pol II ChIP, splicing analysis, and in vivo brain development and breast cancer metastasis models\",\n      \"pmids\": [\"35941369\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genomic targeting specificity of ZNF827 at EMT loci not defined\", \"Relationship between the telomeric NuRD function and the HDAC1 splicing function unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified ZNF827 as an ssDNA/RPA-binding factor that operates in the replication-stress response, connecting it to ATR signaling and HR repair.\",\n      \"evidence\": \"In vitro ssDNA binding, RPA Co-IP, C2H2 zinc-finger cluster mutagenesis, damage-site imaging, ATR activation, HR and replication-initiation assays, and topotecan sensitivity\",\n      \"pmids\": [\"38472229\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ZNF827 is recruited to forks relative to RPA loading not fully ordered\", \"Whether the same zinc-finger clusters mediate chromatin/telomere functions untested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extended ZNF827 to vascular biology as a broad gene-expression regulator and linked a SCAD-risk variant to its expression.\",\n      \"evidence\": \"siRNA knockdown in iPSC-derived SMCs/fibroblasts with transcriptomics, plus reporter assays for variant activity and NF1 binding\",\n      \"pmids\": [\"41983892\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ZNF827 targets in SMCs not identified\", \"Causal mechanism connecting the eQTL variant to vascular disease not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how ZNF827's distinct activities—NuRD/HDAC1 chromatin recruitment, ssDNA/RPA binding, and splicing/transcriptional control—are functionally integrated or context-switched within a single protein.\",\n      \"evidence\": \"No unifying study in the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural or regulatory model coordinating its multiple functions\", \"DNA sequence specificity of the C2H2 array not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 3, 4]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 6]}\n    ],\n    \"complexes\": [\"NuRD complex\", \"circZNF827 mRNP complex\"],\n    \"partners\": [\"RBBP4\", \"HDAC1\", \"RPA\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}