{"gene":"ZNF644","run_date":"2026-04-28T23:00:24","timeline":{"discoveries":[{"year":2015,"finding":"ZNF644 is a core subunit of the G9a/GLP histone methyltransferase complex; it interacts with the transcription activation domain of G9a, targets G9a to chromatin via its zinc finger motifs that recognize consensus DNA sequences, and mediates G9a/GLP complex-dependent H3K9 mono- and dimethylation and gene repression.","method":"Unbiased protein affinity purification, Co-IP, zinc finger DNA-binding assays, chromatin recruitment assays, H3K9 methylation assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP and affinity purification with multiple orthogonal functional readouts (chromatin targeting, H3K9 methylation, gene repression) in a single rigorous study","pmids":["25789554"],"is_preprint":false},{"year":2011,"finding":"ZNF644 is expressed in human retinal and retinal pigment epithelium (RPE) cells, and missense mutations in ZNF644 co-segregate with autosomal dominant high myopia in affected families, implicating ZNF644 as a transcription factor regulating genes involved in eye development.","method":"Exome sequencing, Sanger sequencing validation, expression analysis in human retinal/RPE tissue","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 3 — genetic co-segregation and expression localization, no direct functional reconstitution of mutant mechanism","pmids":["21695231"],"is_preprint":false},{"year":2018,"finding":"miR-362 directly targets the 3'UTR of ZNF644 to suppress its expression in porcine immature Sertoli cells; knockdown of ZNF644 arrests cells in G1/G2 phases, inhibits proliferation, and promotes apoptosis, establishing ZNF644 as a regulator of Sertoli cell cycle progression and survival.","method":"Dual luciferase reporter assay, qRT-PCR, siRNA knockdown, flow cytometry, CCK8/EdU proliferation assays, Annexin V apoptosis assay","journal":"Yi chuan = Hereditas","confidence":"Medium","confidence_rationale":"Tier 2–3 — dual luciferase confirms direct miR-362/ZNF644 interaction; KD phenotype characterized by multiple orthogonal methods, but single lab and porcine model","pmids":["30021720"],"is_preprint":false}],"current_model":"ZNF644 functions as a core subunit of the G9a/GLP histone H3K9 methyltransferase complex, using its zinc finger motifs to bind specific DNA sequences and recruit G9a/GLP to chromatin for H3K9 methylation and transcriptional repression; it is also expressed in retinal tissue where mutations associate with high myopia, and it regulates cell cycle progression in Sertoli cells downstream of miR-362."},"narrative":{"teleology":[{"year":2011,"claim":"Exome sequencing in myopia families revealed that ZNF644 harbors missense mutations co-segregating with autosomal dominant high myopia, establishing it as a candidate disease gene expressed in retinal tissue but leaving its molecular function undefined.","evidence":"Exome sequencing with Sanger validation and expression analysis in human retinal/RPE cells","pmids":["21695231"],"confidence":"Medium","gaps":["No functional reconstitution showing how specific mutations alter ZNF644 activity","Molecular targets and binding partners of ZNF644 in the retina remain unknown","Co-segregation data without independent replication in additional cohorts"]},{"year":2015,"claim":"Biochemical characterization resolved ZNF644's molecular function: it is a DNA-binding subunit of the G9a/GLP complex that targets this histone methyltransferase to specific genomic loci for H3K9 methylation and gene repression, answering how G9a/GLP achieves locus-specific chromatin modification.","evidence":"Unbiased protein affinity purification, reciprocal Co-IP, zinc finger DNA-binding assays, chromatin recruitment assays, and H3K9 methylation readouts","pmids":["25789554"],"confidence":"High","gaps":["Structural basis of ZNF644–G9a interaction not determined","Whether myopia-associated mutations disrupt G9a recruitment or DNA binding is untested","Genome-wide map of ZNF644-directed G9a/GLP target loci not established"]},{"year":2018,"claim":"Functional studies showed that ZNF644 is required for cell cycle progression and survival in Sertoli cells and is post-transcriptionally regulated by miR-362, extending its role beyond chromatin regulation to proliferation control.","evidence":"Dual luciferase reporter assay confirming miR-362 targeting of ZNF644 3′UTR; siRNA knockdown with flow cytometry, proliferation, and apoptosis assays in porcine immature Sertoli cells","pmids":["30021720"],"confidence":"Medium","gaps":["Single-lab study in a porcine model; not independently confirmed in other species","Whether ZNF644's pro-proliferative role depends on its G9a/GLP-targeting function is unknown","Downstream transcriptional targets mediating cell cycle effects not identified"]},{"year":null,"claim":"It remains unknown how myopia-associated ZNF644 mutations alter G9a/GLP chromatin targeting, what the full set of ZNF644-directed target genes is in retinal tissue, and whether ZNF644's role in cell cycle control operates through H3K9 methylation.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structure of ZNF644 or ZNF644–G9a complex available","ChIP-seq for ZNF644 in retinal cells not performed","Mechanistic link between ZNF644 mutations and myopia pathogenesis not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0]}],"complexes":["G9a/GLP H3K9 methyltransferase complex"],"partners":["G9A","GLP"],"other_free_text":[]},"mechanistic_narrative":"ZNF644 is a core subunit of the G9a/GLP histone H3K9 methyltransferase complex, where it uses its zinc finger motifs to recognize specific DNA sequences and recruit G9a/GLP to chromatin, thereby mediating H3K9 mono- and dimethylation and transcriptional repression [PMID:25789554]. Missense mutations in ZNF644 co-segregate with autosomal dominant high myopia in affected families, consistent with its expression in retinal and retinal pigment epithelium cells [PMID:21695231]. ZNF644 also promotes cell cycle progression and survival, as its knockdown arrests cells in G1/G2 phases and induces apoptosis [PMID:30021720]."},"prefetch_data":{"uniprot":{"accession":"Q9H582","full_name":"Zinc finger protein 644","aliases":["Zinc finger motif enhancer-binding protein 2","Zep-2"],"length_aa":1327,"mass_kda":149.6,"function":"May be involved in transcriptional regulation","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9H582/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ZNF644","classification":"Not Classified","n_dependent_lines":33,"n_total_lines":1208,"dependency_fraction":0.027317880794701987},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"NOL10","stoichiometry":10.0},{"gene":"CBX1","stoichiometry":0.2},{"gene":"CSNK2B","stoichiometry":0.2},{"gene":"H2AFZ","stoichiometry":0.2},{"gene":"HDAC2","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"HMGA1","stoichiometry":0.2},{"gene":"SSRP1","stoichiometry":0.2},{"gene":"TRIM28","stoichiometry":0.2},{"gene":"YY1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ZNF644","total_profiled":1310},"omim":[{"mim_id":"619715","title":"WIZ ZINC FINGER PROTEIN; WIZ","url":"https://www.omim.org/entry/619715"},{"mim_id":"615431","title":"MYOPIA 23, AUTOSOMAL RECESSIVE; MYP23","url":"https://www.omim.org/entry/615431"},{"mim_id":"614167","title":"MYOPIA 21, AUTOSOMAL DOMINANT; MYP21","url":"https://www.omim.org/entry/614167"},{"mim_id":"614159","title":"ZINC FINGER PROTEIN 644; ZNF644","url":"https://www.omim.org/entry/614159"},{"mim_id":"607001","title":"EUCHROMATIC HISTONE METHYLTRANSFERASE 1; EHMT1","url":"https://www.omim.org/entry/607001"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Vesicles","reliability":"Uncertain"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ZNF644"},"hgnc":{"alias_symbol":["KIAA1221","BM-005","MGC60165","MGC70410"],"prev_symbol":[]},"alphafold":{"accession":"Q9H582","domains":[{"cath_id":"3.30.160","chopping":"489-552","consensus_level":"medium","plddt":76.1142,"start":489,"end":552},{"cath_id":"-","chopping":"1038-1085","consensus_level":"medium","plddt":82.6496,"start":1038,"end":1085},{"cath_id":"-","chopping":"1263-1287","consensus_level":"medium","plddt":88.6532,"start":1263,"end":1287}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H582","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H582-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H582-F1-predicted_aligned_error_v6.png","plddt_mean":45.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ZNF644","jax_strain_url":"https://www.jax.org/strain/search?query=ZNF644"},"sequence":{"accession":"Q9H582","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H582.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H582/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H582"}},"corpus_meta":[{"pmid":"21695231","id":"PMC_21695231","title":"Exome sequencing identifies ZNF644 mutations in high myopia.","date":"2011","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21695231","citation_count":160,"is_preprint":false},{"pmid":"25525168","id":"PMC_25525168","title":"Detection of mutations in LRPAP1, CTSH, LEPREL1, ZNF644, SLC39A5, and SCO2 in 298 families with early-onset high myopia by exome sequencing.","date":"2014","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/25525168","citation_count":93,"is_preprint":false},{"pmid":"25789554","id":"PMC_25789554","title":"The zinc finger proteins ZNF644 and WIZ regulate the G9a/GLP complex for gene repression.","date":"2015","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/25789554","citation_count":52,"is_preprint":false},{"pmid":"22539872","id":"PMC_22539872","title":"Study of a US cohort supports the role of ZNF644 and high-grade myopia susceptibility.","date":"2012","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/22539872","citation_count":28,"is_preprint":false},{"pmid":"24991186","id":"PMC_24991186","title":"New ZNF644 mutations identified in patients with high myopia.","date":"2014","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/24991186","citation_count":13,"is_preprint":false},{"pmid":"36052886","id":"PMC_36052886","title":"Downregulation of circ-ZNF644 alleviates LPS-induced HK2 cell injury via miR-335-5p/HIPK1 axis.","date":"2022","source":"Environmental toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/36052886","citation_count":9,"is_preprint":false},{"pmid":"35002215","id":"PMC_35002215","title":"Mutational screening of AGRN, SLC39A5, SCO2, P4HA2, BSG, ZNF644, and CPSF1 in a Chinese cohort of 103 patients with nonsyndromic high myopia.","date":"2021","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/35002215","citation_count":7,"is_preprint":false},{"pmid":"25142846","id":"PMC_25142846","title":"[Association of ZNF644, GRM6 and CTNND2 genes polymorphisms with high myopia].","date":"2014","source":"Zhonghua yi xue za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/25142846","citation_count":4,"is_preprint":false},{"pmid":"30021720","id":"PMC_30021720","title":"[miR-362 regulates the proliferation and apoptosis of porcine immature Sertoli cells through targeting the ZNF644 gene].","date":"2018","source":"Yi chuan = Hereditas","url":"https://pubmed.ncbi.nlm.nih.gov/30021720","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6787,"output_tokens":839,"usd":0.016473},"stage2":{"model":"claude-opus-4-6","input_tokens":4022,"output_tokens":1289,"usd":0.078503},"total_usd":0.094976,"stage1_batch_id":"msgbatch_01BparvgRZ9S2LMidvaoo86K","stage2_batch_id":"msgbatch_01NkBfv9SVZWthhS7j6mU6G3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"ZNF644 is a core subunit of the G9a/GLP histone methyltransferase complex; it interacts with the transcription activation domain of G9a, targets G9a to chromatin via its zinc finger motifs that recognize consensus DNA sequences, and mediates G9a/GLP complex-dependent H3K9 mono- and dimethylation and gene repression.\",\n      \"method\": \"Unbiased protein affinity purification, Co-IP, zinc finger DNA-binding assays, chromatin recruitment assays, H3K9 methylation assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP and affinity purification with multiple orthogonal functional readouts (chromatin targeting, H3K9 methylation, gene repression) in a single rigorous study\",\n      \"pmids\": [\"25789554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ZNF644 is expressed in human retinal and retinal pigment epithelium (RPE) cells, and missense mutations in ZNF644 co-segregate with autosomal dominant high myopia in affected families, implicating ZNF644 as a transcription factor regulating genes involved in eye development.\",\n      \"method\": \"Exome sequencing, Sanger sequencing validation, expression analysis in human retinal/RPE tissue\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — genetic co-segregation and expression localization, no direct functional reconstitution of mutant mechanism\",\n      \"pmids\": [\"21695231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"miR-362 directly targets the 3'UTR of ZNF644 to suppress its expression in porcine immature Sertoli cells; knockdown of ZNF644 arrests cells in G1/G2 phases, inhibits proliferation, and promotes apoptosis, establishing ZNF644 as a regulator of Sertoli cell cycle progression and survival.\",\n      \"method\": \"Dual luciferase reporter assay, qRT-PCR, siRNA knockdown, flow cytometry, CCK8/EdU proliferation assays, Annexin V apoptosis assay\",\n      \"journal\": \"Yi chuan = Hereditas\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — dual luciferase confirms direct miR-362/ZNF644 interaction; KD phenotype characterized by multiple orthogonal methods, but single lab and porcine model\",\n      \"pmids\": [\"30021720\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ZNF644 functions as a core subunit of the G9a/GLP histone H3K9 methyltransferase complex, using its zinc finger motifs to bind specific DNA sequences and recruit G9a/GLP to chromatin for H3K9 methylation and transcriptional repression; it is also expressed in retinal tissue where mutations associate with high myopia, and it regulates cell cycle progression in Sertoli cells downstream of miR-362.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ZNF644 is a core subunit of the G9a/GLP histone H3K9 methyltransferase complex, where it uses its zinc finger motifs to recognize specific DNA sequences and recruit G9a/GLP to chromatin, thereby mediating H3K9 mono- and dimethylation and transcriptional repression [PMID:25789554]. Missense mutations in ZNF644 co-segregate with autosomal dominant high myopia in affected families, consistent with its expression in retinal and retinal pigment epithelium cells [PMID:21695231]. ZNF644 also promotes cell cycle progression and survival, as its knockdown arrests cells in G1/G2 phases and induces apoptosis [PMID:30021720].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Exome sequencing in myopia families revealed that ZNF644 harbors missense mutations co-segregating with autosomal dominant high myopia, establishing it as a candidate disease gene expressed in retinal tissue but leaving its molecular function undefined.\",\n      \"evidence\": \"Exome sequencing with Sanger validation and expression analysis in human retinal/RPE cells\",\n      \"pmids\": [\"21695231\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No functional reconstitution showing how specific mutations alter ZNF644 activity\",\n        \"Molecular targets and binding partners of ZNF644 in the retina remain unknown\",\n        \"Co-segregation data without independent replication in additional cohorts\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Biochemical characterization resolved ZNF644's molecular function: it is a DNA-binding subunit of the G9a/GLP complex that targets this histone methyltransferase to specific genomic loci for H3K9 methylation and gene repression, answering how G9a/GLP achieves locus-specific chromatin modification.\",\n      \"evidence\": \"Unbiased protein affinity purification, reciprocal Co-IP, zinc finger DNA-binding assays, chromatin recruitment assays, and H3K9 methylation readouts\",\n      \"pmids\": [\"25789554\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of ZNF644–G9a interaction not determined\",\n        \"Whether myopia-associated mutations disrupt G9a recruitment or DNA binding is untested\",\n        \"Genome-wide map of ZNF644-directed G9a/GLP target loci not established\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Functional studies showed that ZNF644 is required for cell cycle progression and survival in Sertoli cells and is post-transcriptionally regulated by miR-362, extending its role beyond chromatin regulation to proliferation control.\",\n      \"evidence\": \"Dual luciferase reporter assay confirming miR-362 targeting of ZNF644 3′UTR; siRNA knockdown with flow cytometry, proliferation, and apoptosis assays in porcine immature Sertoli cells\",\n      \"pmids\": [\"30021720\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study in a porcine model; not independently confirmed in other species\",\n        \"Whether ZNF644's pro-proliferative role depends on its G9a/GLP-targeting function is unknown\",\n        \"Downstream transcriptional targets mediating cell cycle effects not identified\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how myopia-associated ZNF644 mutations alter G9a/GLP chromatin targeting, what the full set of ZNF644-directed target genes is in retinal tissue, and whether ZNF644's role in cell cycle control operates through H3K9 methylation.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structure of ZNF644 or ZNF644–G9a complex available\",\n        \"ChIP-seq for ZNF644 in retinal cells not performed\",\n        \"Mechanistic link between ZNF644 mutations and myopia pathogenesis not established\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\n      \"G9a/GLP H3K9 methyltransferase complex\"\n    ],\n    \"partners\": [\n      \"G9a\",\n      \"GLP\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}