{"gene":"ZNF711","run_date":"2026-06-11T09:02:07","timeline":{"discoveries":[{"year":2010,"finding":"ZNF711 physically interacts with the histone demethylase PHF8 (another XLMR protein), and ZNF711 binds to a subset of PHF8 target genes, including the XLMR gene JARID1C, functionally linking these two proteins at transcription initiation sites.","method":"Co-immunoprecipitation, ChIP, co-localization studies","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and ChIP demonstrating physical interaction and co-occupancy of target gene promoters; single lab but multiple orthogonal methods","pmids":["20346720"],"is_preprint":false},{"year":2021,"finding":"ZNF711 recruits the histone demethylase JHDM2A to the SLC31A1 promoter, reducing H3K9me2 levels and activating SLC31A1 transcription, thereby enhancing cisplatin uptake in ovarian cancer cells.","method":"Co-IP, ChIP assay, CAPTURE approach, luciferase reporter assay","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, ChIP, luciferase reporter) from a single lab establishing the ZNF711–JHDM2A–SLC31A1 axis","pmids":["34521054"],"is_preprint":false},{"year":2024,"finding":"The seventh zinc finger domain (Z7) of ZNF711, previously considered non-functional due to an H23F substitution, adopts a stable ββα-fold upon Zn2+ binding with a tridentate metal-binding site (C3, C6, H19). H26 does not participate in metal binding; the F23H mutation creates a tetradentate site. The WT Z7 domain is catalytically active, hydrolyzing 4-nitrophenyl acetate.","method":"NMR structure determination, site-directed mutagenesis, pH titration, in vitro enzymatic assay","journal":"Protein science : a publication of the Protein Society","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structure with mutagenesis and in vitro catalytic assay; confirmed in both preprint and peer-reviewed publication","pmids":["39180464","38645208"],"is_preprint":false},{"year":2024,"finding":"MAFF binds the ZNF711 promoter (together with its binding partner BATF3) and represses ZNF711 transcription; knockdown of MAFF or BATF3 increases ZNF711 expression and carboplatin sensitivity in ovarian cancer cells.","method":"Dual luciferase assay, ChIP-PCR, co-immunoprecipitation, immunofluorescence colocalization","journal":"Chemico-biological interactions","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods (luciferase, ChIP-PCR, Co-IP) from a single lab establishing transcriptional regulation of ZNF711 by MAFF/BATF3 complex","pmids":["38908812"],"is_preprint":false},{"year":2025,"finding":"In mouse embryonic stem cell differentiation, loss of Zfp711 (mouse ortholog of ZNF711) increases blood progenitors and erythroid cells but decreases endothelial cells, with a shift from Hoxa+ to Hoxb+ mesoderm. Zfp711 binds the Atf3 promoter, indicating hierarchical regulation of hematopoietic transcription factors.","method":"Knockout in differentiating mouse ESCs, single-cell RNA sequencing, flow cytometry, chromatin binding (promoter binding)","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined cellular phenotype and direct promoter binding evidence; single lab","pmids":["41200855"],"is_preprint":false},{"year":2026,"finding":"The Znf711–Phf8 complex operates as a transcriptional rheostat in neutrophil development through a repressive mechanism: Znf711 promotes neutrophil maturation in a DNA-binding-independent manner by sequestering Phf8; upon Znf711 loss, Phf8 is recruited by Gfi1a to the c/ebpα promoter where SUMOylated Phf8 acts as a corepressor. C/ebpα in turn directly activates znf711 expression, forming a positive feedback loop.","method":"Loss-of-function experiments, ChIP, co-immunoprecipitation, transcriptional reporter assays","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods (ChIP, Co-IP, loss-of-function with defined phenotype) from a single lab delineating a feedback mechanism","pmids":["41709745"],"is_preprint":false},{"year":2026,"finding":"ZNF711 directly binds the AR (androgen receptor) promoter to transcriptionally upregulate AR expression, forms a complex with BMI1 and AR, and suppresses CpG methylation at the promoters of AR and downstream target genes (KLK3, TMPRSS2), thereby potentiating AR transcriptional activity and promoting enzalutamide resistance in prostate cancer.","method":"ChIP, co-immunoprecipitation, chromatin occupancy assays, knockdown with in vitro/in vivo functional readouts","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ChIP, Co-IP, methylation analysis, in vivo rescue) from a single lab","pmids":["41656388"],"is_preprint":false}],"current_model":"ZNF711 is an X-chromosomal zinc finger transcription factor that interacts with the histone demethylase PHF8 (and its mouse ortholog Phf8) to regulate gene expression at target promoters; depending on context it can act as a transcriptional activator (recruiting JHDM2A to demethylate H3K9me2 and activate SLC31A1, or binding the AR promoter to upregulate AR alongside a BMI1 complex that suppresses CpG methylation) or, unexpectedly, as a repressor of PHF8 activity by sequestering it away from target promoters during neutrophil differentiation; its seventh zinc finger domain adopts a tridentate metal-binding ββα-fold with intrinsic esterase activity; and its transcription is repressed by a MAFF–BATF3 complex that binds its promoter."},"narrative":{"mechanistic_narrative":"ZNF711 is an X-chromosomal zinc finger transcription factor that controls gene expression by partnering with histone-modifying enzymes at target promoters [PMID:20346720]. Its defining biochemical partnership is a physical interaction with the histone demethylase PHF8, with which it co-occupies a subset of target promoters, including the X-linked intellectual disability gene JARID1C, linking the two proteins at transcription initiation sites [PMID:20346720]. ZNF711 acts as a context-dependent regulator: it functions as an activator by recruiting the H3K9me2 demethylase JHDM2A to the SLC31A1 promoter to drive its transcription [PMID:34521054] and by binding the AR promoter to upregulate AR while forming a complex with BMI1 and AR that suppresses CpG methylation at AR and its downstream targets KLK3 and TMPRSS2 [PMID:41656388]; conversely, during neutrophil maturation it acts in a DNA-binding-independent, repressive mode by sequestering PHF8 away from target promoters [PMID:41709745]. ZNF711 expression is itself transcriptionally constrained by a MAFF–BATF3 complex that binds its promoter [PMID:38908812], and it participates in developmental transcriptional hierarchies, binding the Atf3 promoter and shaping mesoderm and hematopoietic lineage choice in differentiating mouse cells [PMID:41200855]. Structurally, its seventh zinc finger adopts a tridentate metal-binding ββα-fold with intrinsic esterase activity toward 4-nitrophenyl acetate [PMID:39180464, PMID:38645208].","teleology":[{"year":2010,"claim":"Established ZNF711 as a chromatin-associated factor by physically tethering it to the histone demethylase PHF8 at shared target promoters, placing both XLMR proteins on a common transcriptional axis.","evidence":"Reciprocal co-immunoprecipitation, ChIP, and co-localization in human cells","pmids":["20346720"],"confidence":"High","gaps":["Did not define how ZNF711 selects target genes or whether its zinc fingers bind specific DNA sequences","Functional consequence on PHF8 demethylase activity at promoters not resolved"]},{"year":2021,"claim":"Showed ZNF711 can act as a transcriptional activator by recruiting a second demethylase, JHDM2A, to erase repressive H3K9me2 and activate a defined target, linking it to cisplatin uptake.","evidence":"Co-IP, ChIP, CAPTURE, and luciferase reporter assays in ovarian cancer cells","pmids":["34521054"],"confidence":"Medium","gaps":["Single lab and single target gene (SLC31A1)","Whether JHDM2A recruitment generalizes beyond this promoter is unknown"]},{"year":2024,"claim":"Determined that the previously dismissed seventh zinc finger folds into a stable ββα domain with a tridentate metal site and possesses intrinsic esterase activity, revealing an unexpected catalytic property of the protein.","evidence":"NMR structure determination, site-directed mutagenesis, pH titration, and in vitro hydrolysis assay (preprint and peer-reviewed)","pmids":["39180464","38645208"],"confidence":"High","gaps":["Physiological substrate and in vivo relevance of the esterase activity unknown","Whether Z7 catalysis contributes to transcriptional function not addressed"]},{"year":2024,"claim":"Identified an upstream control point for ZNF711 itself, showing its promoter is repressed by a MAFF–BATF3 complex that modulates chemosensitivity.","evidence":"Dual luciferase, ChIP-PCR, Co-IP, and immunofluorescence in ovarian cancer cells","pmids":["38908812"],"confidence":"Medium","gaps":["Single lab","Signals that govern MAFF–BATF3 occupancy of the ZNF711 promoter not defined"]},{"year":2025,"claim":"Placed Zfp711 within a developmental transcriptional hierarchy, demonstrating its loss reshapes mesoderm identity and hematopoietic lineage output and that it binds the Atf3 promoter.","evidence":"Gene knockout in differentiating mouse ESCs with scRNA-seq, flow cytometry, and chromatin binding","pmids":["41200855"],"confidence":"Medium","gaps":["Direct regulatory targets beyond Atf3 not enumerated","Whether the phenotype depends on the PHF8 partnership unknown"]},{"year":2026,"claim":"Revealed a repressive, DNA-binding-independent mode in which Znf711 sequesters Phf8 to promote neutrophil maturation, embedded in a C/ebpα feedback loop, contrasting with its activator roles.","evidence":"Loss-of-function experiments, ChIP, Co-IP, and reporter assays in neutrophil development","pmids":["41709745"],"confidence":"Medium","gaps":["Single lab","Molecular basis for the switch between sequestration and promoter recruitment of PHF8 not resolved"]},{"year":2026,"claim":"Demonstrated an activator role in prostate cancer where ZNF711 binds the AR promoter, complexes with BMI1 and AR, and suppresses CpG methylation to potentiate AR signaling and drug resistance.","evidence":"ChIP, Co-IP, chromatin occupancy, methylation analysis, and in vitro/in vivo functional readouts","pmids":["41656388"],"confidence":"Medium","gaps":["Single lab","Mechanism by which ZNF711 suppresses CpG methylation not defined"]},{"year":null,"claim":"How ZNF711 toggles between activating (JHDM2A/BMI1 recruitment) and repressive (PHF8 sequestration) outputs, and what genomic features dictate its target selection, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model linking context to activator versus repressor behavior","Genome-wide DNA-binding specificity not mapped","Role of the esterase-active Z7 domain in transcriptional function unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,5,6]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[4,6]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,6]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,5]}],"complexes":[],"partners":["PHF8","JHDM2A","BMI1","AR","MAFF","BATF3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y462","full_name":"Zinc finger protein 711","aliases":["Zinc finger protein 6"],"length_aa":761,"mass_kda":86.2,"function":"Transcription regulator required for brain development (PubMed:20346720). Probably acts as a transcription factor that binds to the promoter of target genes and recruits PHF8 histone demethylase, leading to activated expression of genes involved in neuron development, such as KDM5C (PubMed:20346720, PubMed:31691806). May compete with transcription factor ARX for activation of expression of KDM5C (PubMed:31691806)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9Y462/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ZNF711","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ZNF711","total_profiled":1310},"omim":[{"mim_id":"314990","title":"ZINC FINGER PROTEIN 711; ZNF711","url":"https://www.omim.org/entry/314990"},{"mim_id":"300803","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED 97; XLID97","url":"https://www.omim.org/entry/300803"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"testis","ntpm":34.9}],"url":"https://www.proteinatlas.org/search/ZNF711"},"hgnc":{"alias_symbol":["CMPX1","ZNF4","ZNF5","dJ75N13.1","Zfp711","MRX97"],"prev_symbol":["ZNF6","MRX65"]},"alphafold":{"accession":"Q9Y462","domains":[{"cath_id":"-","chopping":"378-432","consensus_level":"medium","plddt":73.1485,"start":378,"end":432},{"cath_id":"3.30.160.60","chopping":"703-761","consensus_level":"medium","plddt":77.0237,"start":703,"end":761}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y462","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y462-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y462-F1-predicted_aligned_error_v6.png","plddt_mean":54.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ZNF711","jax_strain_url":"https://www.jax.org/strain/search?query=ZNF711"},"sequence":{"accession":"Q9Y462","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y462.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y462/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y462"}},"corpus_meta":[{"pmid":"20346720","id":"PMC_20346720","title":"A functional link between the histone demethylase PHF8 and the transcription factor ZNF711 in X-linked mental retardation.","date":"2010","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/20346720","citation_count":177,"is_preprint":false},{"pmid":"21095585","id":"PMC_21095585","title":"Ubiquitin binding to A20 ZnF4 is required for modulation of NF-κB signaling.","date":"2010","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/21095585","citation_count":172,"is_preprint":false},{"pmid":"34521054","id":"PMC_34521054","title":"ZNF711 down-regulation promotes CISPLATIN resistance in epithelial ovarian cancer via interacting with JHDM2A and suppressing SLC31A1 expression.","date":"2021","source":"EBioMedicine","url":"https://pubmed.ncbi.nlm.nih.gov/34521054","citation_count":62,"is_preprint":false},{"pmid":"27993705","id":"PMC_27993705","title":"Mutations in two large pedigrees highlight the role of ZNF711 in X-linked intellectual disability.","date":"2016","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/27993705","citation_count":26,"is_preprint":false},{"pmid":"36288691","id":"PMC_36288691","title":"Crystal structures and functional analysis of the ZnF5-WWE1-WWE2 region of PARP13/ZAP define a distinctive mode of engaging poly(ADP-ribose).","date":"2022","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/36288691","citation_count":19,"is_preprint":false},{"pmid":"35626703","id":"PMC_35626703","title":"The Plasmodium falciparum CCCH Zinc Finger Protein ZNF4 Plays an Important Role in Gametocyte Exflagellation through the Regulation of Male Enriched Transcripts.","date":"2022","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/35626703","citation_count":19,"is_preprint":false},{"pmid":"21384559","id":"PMC_21384559","title":"Fine mapping of Xq11.1-q21.33 and mutation screening of RPS6KA6, ZNF711, ACSL4, DLG3, and IL1RAPL2 for autism spectrum disorders (ASD).","date":"2011","source":"Autism research : official journal of the International Society for Autism Research","url":"https://pubmed.ncbi.nlm.nih.gov/21384559","citation_count":14,"is_preprint":false},{"pmid":"34992252","id":"PMC_34992252","title":"Clinical findings and a DNA methylation signature in kindreds with alterations in ZNF711.","date":"2022","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/34992252","citation_count":12,"is_preprint":false},{"pmid":"32753895","id":"PMC_32753895","title":"Clinical Significance of ZNF711 in Human Breast Cancer.","date":"2020","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/32753895","citation_count":8,"is_preprint":false},{"pmid":"38908812","id":"PMC_38908812","title":"MAFF mediates PEITC-induced enhancement of sensitivity to carboplatin in ovarian cancer cell lines via activating ZNF711 transcription in vivo and invitro.","date":"2024","source":"Chemico-biological interactions","url":"https://pubmed.ncbi.nlm.nih.gov/38908812","citation_count":4,"is_preprint":false},{"pmid":"39180464","id":"PMC_39180464","title":"Formerly degenerate seventh zinc finger domain from transcription factor ZNF711 rehabilitated by experimental NMR structure.","date":"2024","source":"Protein science : a publication of the Protein Society","url":"https://pubmed.ncbi.nlm.nih.gov/39180464","citation_count":4,"is_preprint":false},{"pmid":"41200855","id":"PMC_41200855","title":"Distinct roles of Atf3, Zfp711 and Bcl6b in early embryonic hematopoietic and endothelial lineage specification.","date":"2025","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/41200855","citation_count":1,"is_preprint":false},{"pmid":"39852778","id":"PMC_39852778","title":"Electroencephalographic and Epilepsy Findings in ZNF711 Variants: A Case Series of Two Siblings.","date":"2025","source":"Neurology international","url":"https://pubmed.ncbi.nlm.nih.gov/39852778","citation_count":1,"is_preprint":false},{"pmid":"41656388","id":"PMC_41656388","title":"ZNF711 promotes enzalutamide resistance through transcriptional and epigenetic modification of the androgen receptor signaling pathway.","date":"2026","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/41656388","citation_count":0,"is_preprint":false},{"pmid":"38645208","id":"PMC_38645208","title":"Formerly degenerate seventh zinc finger domain from transcription factor ZNF711 rehabilitated by experimental NMR structure.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/38645208","citation_count":0,"is_preprint":false},{"pmid":"41709745","id":"PMC_41709745","title":"The Znf711-Phf8 complex functions as a transcriptional rheostat essential for neutrophil development.","date":"2026","source":"Haematologica","url":"https://pubmed.ncbi.nlm.nih.gov/41709745","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.03.17.643620","title":"A Population Model Reveals Surprising Role of Stochastic Cell Division in Epigenetic Memory Systems","date":"2025-03-20","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.17.643620","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9901,"output_tokens":1887,"usd":0.029004,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8791,"output_tokens":2655,"usd":0.055165,"stage2_stop_reason":"end_turn"},"total_usd":0.084169,"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\": 2010,\n      \"finding\": \"ZNF711 physically interacts with the histone demethylase PHF8 (another XLMR protein), and ZNF711 binds to a subset of PHF8 target genes, including the XLMR gene JARID1C, functionally linking these two proteins at transcription initiation sites.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, co-localization studies\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and ChIP demonstrating physical interaction and co-occupancy of target gene promoters; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"20346720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ZNF711 recruits the histone demethylase JHDM2A to the SLC31A1 promoter, reducing H3K9me2 levels and activating SLC31A1 transcription, thereby enhancing cisplatin uptake in ovarian cancer cells.\",\n      \"method\": \"Co-IP, ChIP assay, CAPTURE approach, luciferase reporter assay\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, ChIP, luciferase reporter) from a single lab establishing the ZNF711–JHDM2A–SLC31A1 axis\",\n      \"pmids\": [\"34521054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The seventh zinc finger domain (Z7) of ZNF711, previously considered non-functional due to an H23F substitution, adopts a stable ββα-fold upon Zn2+ binding with a tridentate metal-binding site (C3, C6, H19). H26 does not participate in metal binding; the F23H mutation creates a tetradentate site. The WT Z7 domain is catalytically active, hydrolyzing 4-nitrophenyl acetate.\",\n      \"method\": \"NMR structure determination, site-directed mutagenesis, pH titration, in vitro enzymatic assay\",\n      \"journal\": \"Protein science : a publication of the Protein Society\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structure with mutagenesis and in vitro catalytic assay; confirmed in both preprint and peer-reviewed publication\",\n      \"pmids\": [\"39180464\", \"38645208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MAFF binds the ZNF711 promoter (together with its binding partner BATF3) and represses ZNF711 transcription; knockdown of MAFF or BATF3 increases ZNF711 expression and carboplatin sensitivity in ovarian cancer cells.\",\n      \"method\": \"Dual luciferase assay, ChIP-PCR, co-immunoprecipitation, immunofluorescence colocalization\",\n      \"journal\": \"Chemico-biological interactions\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods (luciferase, ChIP-PCR, Co-IP) from a single lab establishing transcriptional regulation of ZNF711 by MAFF/BATF3 complex\",\n      \"pmids\": [\"38908812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In mouse embryonic stem cell differentiation, loss of Zfp711 (mouse ortholog of ZNF711) increases blood progenitors and erythroid cells but decreases endothelial cells, with a shift from Hoxa+ to Hoxb+ mesoderm. Zfp711 binds the Atf3 promoter, indicating hierarchical regulation of hematopoietic transcription factors.\",\n      \"method\": \"Knockout in differentiating mouse ESCs, single-cell RNA sequencing, flow cytometry, chromatin binding (promoter binding)\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined cellular phenotype and direct promoter binding evidence; single lab\",\n      \"pmids\": [\"41200855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"The Znf711–Phf8 complex operates as a transcriptional rheostat in neutrophil development through a repressive mechanism: Znf711 promotes neutrophil maturation in a DNA-binding-independent manner by sequestering Phf8; upon Znf711 loss, Phf8 is recruited by Gfi1a to the c/ebpα promoter where SUMOylated Phf8 acts as a corepressor. C/ebpα in turn directly activates znf711 expression, forming a positive feedback loop.\",\n      \"method\": \"Loss-of-function experiments, ChIP, co-immunoprecipitation, transcriptional reporter assays\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods (ChIP, Co-IP, loss-of-function with defined phenotype) from a single lab delineating a feedback mechanism\",\n      \"pmids\": [\"41709745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ZNF711 directly binds the AR (androgen receptor) promoter to transcriptionally upregulate AR expression, forms a complex with BMI1 and AR, and suppresses CpG methylation at the promoters of AR and downstream target genes (KLK3, TMPRSS2), thereby potentiating AR transcriptional activity and promoting enzalutamide resistance in prostate cancer.\",\n      \"method\": \"ChIP, co-immunoprecipitation, chromatin occupancy assays, knockdown with in vitro/in vivo functional readouts\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ChIP, Co-IP, methylation analysis, in vivo rescue) from a single lab\",\n      \"pmids\": [\"41656388\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ZNF711 is an X-chromosomal zinc finger transcription factor that interacts with the histone demethylase PHF8 (and its mouse ortholog Phf8) to regulate gene expression at target promoters; depending on context it can act as a transcriptional activator (recruiting JHDM2A to demethylate H3K9me2 and activate SLC31A1, or binding the AR promoter to upregulate AR alongside a BMI1 complex that suppresses CpG methylation) or, unexpectedly, as a repressor of PHF8 activity by sequestering it away from target promoters during neutrophil differentiation; its seventh zinc finger domain adopts a tridentate metal-binding ββα-fold with intrinsic esterase activity; and its transcription is repressed by a MAFF–BATF3 complex that binds its promoter.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ZNF711 is an X-chromosomal zinc finger transcription factor that controls gene expression by partnering with histone-modifying enzymes at target promoters [#0]. Its defining biochemical partnership is a physical interaction with the histone demethylase PHF8, with which it co-occupies a subset of target promoters, including the X-linked intellectual disability gene JARID1C, linking the two proteins at transcription initiation sites [#0]. ZNF711 acts as a context-dependent regulator: it functions as an activator by recruiting the H3K9me2 demethylase JHDM2A to the SLC31A1 promoter to drive its transcription [#1] and by binding the AR promoter to upregulate AR while forming a complex with BMI1 and AR that suppresses CpG methylation at AR and its downstream targets KLK3 and TMPRSS2 [#6]; conversely, during neutrophil maturation it acts in a DNA-binding-independent, repressive mode by sequestering PHF8 away from target promoters [#5]. ZNF711 expression is itself transcriptionally constrained by a MAFF–BATF3 complex that binds its promoter [#3], and it participates in developmental transcriptional hierarchies, binding the Atf3 promoter and shaping mesoderm and hematopoietic lineage choice in differentiating mouse cells [#4]. Structurally, its seventh zinc finger adopts a tridentate metal-binding ββα-fold with intrinsic esterase activity toward 4-nitrophenyl acetate [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established ZNF711 as a chromatin-associated factor by physically tethering it to the histone demethylase PHF8 at shared target promoters, placing both XLMR proteins on a common transcriptional axis.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, ChIP, and co-localization in human cells\",\n      \"pmids\": [\"20346720\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define how ZNF711 selects target genes or whether its zinc fingers bind specific DNA sequences\", \"Functional consequence on PHF8 demethylase activity at promoters not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed ZNF711 can act as a transcriptional activator by recruiting a second demethylase, JHDM2A, to erase repressive H3K9me2 and activate a defined target, linking it to cisplatin uptake.\",\n      \"evidence\": \"Co-IP, ChIP, CAPTURE, and luciferase reporter assays in ovarian cancer cells\",\n      \"pmids\": [\"34521054\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab and single target gene (SLC31A1)\", \"Whether JHDM2A recruitment generalizes beyond this promoter is unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Determined that the previously dismissed seventh zinc finger folds into a stable ββα domain with a tridentate metal site and possesses intrinsic esterase activity, revealing an unexpected catalytic property of the protein.\",\n      \"evidence\": \"NMR structure determination, site-directed mutagenesis, pH titration, and in vitro hydrolysis assay (preprint and peer-reviewed)\",\n      \"pmids\": [\"39180464\", \"38645208\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological substrate and in vivo relevance of the esterase activity unknown\", \"Whether Z7 catalysis contributes to transcriptional function not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified an upstream control point for ZNF711 itself, showing its promoter is repressed by a MAFF–BATF3 complex that modulates chemosensitivity.\",\n      \"evidence\": \"Dual luciferase, ChIP-PCR, Co-IP, and immunofluorescence in ovarian cancer cells\",\n      \"pmids\": [\"38908812\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Signals that govern MAFF–BATF3 occupancy of the ZNF711 promoter not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed Zfp711 within a developmental transcriptional hierarchy, demonstrating its loss reshapes mesoderm identity and hematopoietic lineage output and that it binds the Atf3 promoter.\",\n      \"evidence\": \"Gene knockout in differentiating mouse ESCs with scRNA-seq, flow cytometry, and chromatin binding\",\n      \"pmids\": [\"41200855\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct regulatory targets beyond Atf3 not enumerated\", \"Whether the phenotype depends on the PHF8 partnership unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Revealed a repressive, DNA-binding-independent mode in which Znf711 sequesters Phf8 to promote neutrophil maturation, embedded in a C/ebpα feedback loop, contrasting with its activator roles.\",\n      \"evidence\": \"Loss-of-function experiments, ChIP, Co-IP, and reporter assays in neutrophil development\",\n      \"pmids\": [\"41709745\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Molecular basis for the switch between sequestration and promoter recruitment of PHF8 not resolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated an activator role in prostate cancer where ZNF711 binds the AR promoter, complexes with BMI1 and AR, and suppresses CpG methylation to potentiate AR signaling and drug resistance.\",\n      \"evidence\": \"ChIP, Co-IP, chromatin occupancy, methylation analysis, and in vitro/in vivo functional readouts\",\n      \"pmids\": [\"41656388\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanism by which ZNF711 suppresses CpG methylation not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ZNF711 toggles between activating (JHDM2A/BMI1 recruitment) and repressive (PHF8 sequestration) outputs, and what genomic features dictate its target selection, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model linking context to activator versus repressor behavior\", \"Genome-wide DNA-binding specificity not mapped\", \"Role of the esterase-active Z7 domain in transcriptional function unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 5, 6]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [4, 6]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 6]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PHF8\", \"JHDM2A\", \"BMI1\", \"AR\", \"MAFF\", \"BATF3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":5,"faith_pct":80.0}}