{"gene":"ZNF121","run_date":"2026-06-11T09:02:07","timeline":{"discoveries":[{"year":1993,"finding":"ZNF121 (D19S204) was identified as a novel zinc finger protein containing 9 zinc finger motifs, cloned from a human brain cDNA library, and mapped to chromosome 19p by hybrid cell line mapping panels.","method":"cDNA library screening, open reading frame analysis, chromosomal mapping with hybrid cell lines","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct molecular cloning and chromosomal mapping with multiple orthogonal methods (library screen, sequence analysis, hybrid cell mapping), single lab","pmids":["8468057"],"is_preprint":false},{"year":2016,"finding":"ZNF121 physically interacts with MYC oncoprotein via their N-terminal regions, and overexpression of ZNF121 increases MYC expression while knockdown of ZNF121 decreases MYC expression and its target genes (EGR1, CDC2, nucleolin), causing G1 cell cycle arrest and altered expression of cyclin D1, p14, and p21 in epithelial cell lines.","method":"Co-immunoprecipitation, domain-mapping interaction assays, siRNA knockdown, overexpression, Western blot, cell proliferation assays, cell cycle analysis","journal":"Journal of genetics and genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction demonstrated, multiple cell lines, loss-of-function with defined cellular phenotype, single lab with multiple orthogonal methods","pmids":["27988300"],"is_preprint":false},{"year":2018,"finding":"ZNF121 physically interacts with both ZBRK1 (a BRCA1-interacting KRAB domain protein) and BRCA1, demonstrated by yeast two-hybrid assay and other approaches; ZNF121 suppresses expression of ANG1 and HMGA2 (common downstream targets of ZBRK1 and BRCA1) and also regulates expression of BRCA1 and ZBRK1 themselves in mammary epithelial cells.","method":"Yeast two-hybrid assay, co-immunoprecipitation, gene expression assays (knockdown/overexpression)","journal":"FEBS open bio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus additional binding assays, functional target gene regulation confirmed, single lab with two orthogonal methods","pmids":["30524945"],"is_preprint":false}],"current_model":"ZNF121 is a KRAB-domain zinc finger transcription factor that physically interacts with MYC (via N-terminal regions) to mutually regulate each other's expression and promote cell proliferation via MYC target genes, and also associates with the BRCA1/ZBRK1 repressor complex to suppress downstream targets ANG1 and HMGA2 in mammary epithelial cells."},"narrative":{"mechanistic_narrative":"ZNF121 is a zinc finger protein, originally cloned as a novel nine-zinc-finger protein from human brain and mapped to chromosome 19p [PMID:8468057], that acts as a transcriptional regulator coupling cell proliferation to the activity of the MYC oncoprotein and the BRCA1 tumor-suppressor network. ZNF121 physically associates with MYC through their respective N-terminal regions and the two proteins reinforce each other's expression: ZNF121 overexpression raises MYC levels while its depletion lowers MYC and its target genes (EGR1, CDC2, nucleolin), producing G1 cell cycle arrest and altered levels of cyclin D1, p14, and p21 [PMID:27988300]. In mammary epithelial cells ZNF121 also binds the BRCA1-interacting KRAB protein ZBRK1 and BRCA1 itself, and represses the shared ZBRK1/BRCA1 downstream targets ANG1 and HMGA2 while feeding back on BRCA1 and ZBRK1 expression [PMID:30524945]. Beyond these interactions, the DNA-binding specificity and direct genomic targets of ZNF121 have not been characterized in the available corpus.","teleology":[{"year":1993,"claim":"Establishing that ZNF121 exists as a discrete multi-zinc-finger gene gave the field a defined molecular entity and chromosomal locus to study.","evidence":"cDNA library screening and chromosomal mapping with hybrid cell lines from human brain","pmids":["8468057"],"confidence":"Medium","gaps":["No function assigned at cloning beyond presence of zinc finger motifs","DNA-binding targets and specificity not determined","Tissue distribution and regulation unknown"]},{"year":2016,"claim":"Identifying a direct ZNF121-MYC interaction and reciprocal expression dependence connected ZNF121 to proliferative control through the MYC transcriptional program.","evidence":"Co-immunoprecipitation, domain mapping, siRNA knockdown and overexpression with cell cycle analysis in epithelial cell lines","pmids":["27988300"],"confidence":"Medium","gaps":["Whether ZNF121 binds MYC target promoters directly is not shown","Mechanism of reciprocal expression regulation undefined","Single lab; no structural mapping of the interaction interface"]},{"year":2018,"claim":"Demonstrating ZNF121 binding to ZBRK1 and BRCA1 with repression of ANG1 and HMGA2 placed ZNF121 within the BRCA1/ZBRK1 transcriptional repressor network in mammary epithelium.","evidence":"Yeast two-hybrid, co-immunoprecipitation, and knockdown/overexpression gene expression assays in mammary epithelial cells","pmids":["30524945"],"confidence":"Medium","gaps":["Direct promoter occupancy of ANG1/HMGA2 by ZNF121 not demonstrated","Relationship between the MYC and BRCA1/ZBRK1 axes is unresolved","In vivo relevance to mammary biology or tumorigenesis untested"]},{"year":null,"claim":"The intrinsic DNA-binding specificity and the direct genomic target loci of ZNF121 remain unknown, leaving open how it integrates MYC and BRCA1/ZBRK1 signaling at chromatin.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No genome-wide binding (ChIP) data","No defined consensus binding motif","Role of the zinc finger array versus protein-protein interactions in target regulation not separated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,2]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0]}],"localization":[],"pathway":[],"complexes":[],"partners":["MYC","ZBRK1","BRCA1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P58317","full_name":"Zinc finger protein 121","aliases":["Zinc finger protein 20"],"length_aa":390,"mass_kda":44.7,"function":"May be involved in transcriptional regulation","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P58317/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ZNF121","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ZNF121","total_profiled":1310},"omim":[{"mim_id":"194628","title":"ZINC FINGER PROTEIN 121; ZNF121","url":"https://www.omim.org/entry/194628"},{"mim_id":"194551","title":"ZINC FINGER PROTEIN 77; ZNF77","url":"https://www.omim.org/entry/194551"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Centrosome","reliability":"Approved"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ZNF121"},"hgnc":{"alias_symbol":["ZHC32","ZNF20"],"prev_symbol":["D19S204"]},"alphafold":{"accession":"P58317","domains":[{"cath_id":"3.30.160.60","chopping":"144-198","consensus_level":"medium","plddt":89.8638,"start":144,"end":198},{"cath_id":"3.30.160.60","chopping":"311-390","consensus_level":"medium","plddt":94.1854,"start":311,"end":390}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P58317","model_url":"https://alphafold.ebi.ac.uk/files/AF-P58317-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P58317-F1-predicted_aligned_error_v6.png","plddt_mean":67.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ZNF121","jax_strain_url":"https://www.jax.org/strain/search?query=ZNF121"},"sequence":{"accession":"P58317","fasta_url":"https://rest.uniprot.org/uniprotkb/P58317.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P58317/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P58317"}},"corpus_meta":[{"pmid":"29698681","id":"PMC_29698681","title":"Circular RNA hsa_circRNA_103809 promotes lung cancer progression via facilitating ZNF121-dependent MYC expression by sequestering miR-4302.","date":"2018","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/29698681","citation_count":119,"is_preprint":false},{"pmid":"31838046","id":"PMC_31838046","title":"Dual transcriptomic and epigenomic study of reaction severity in peanut-allergic children.","date":"2019","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31838046","citation_count":55,"is_preprint":false},{"pmid":"32620067","id":"PMC_32620067","title":"Exosomes Derived from Human Placental Mesenchymal Stromal Cells Carrying AntagomiR-4450 Alleviate Intervertebral Disc Degeneration Through Upregulation of ZNF121.","date":"2020","source":"Stem cells and development","url":"https://pubmed.ncbi.nlm.nih.gov/32620067","citation_count":48,"is_preprint":false},{"pmid":"27988300","id":"PMC_27988300","title":"Zinc finger factor ZNF121 is a MYC-interacting protein functionally affecting MYC and cell proliferation in epithelial cells.","date":"2016","source":"Journal of genetics and genomics = Yi chuan xue bao","url":"https://pubmed.ncbi.nlm.nih.gov/27988300","citation_count":13,"is_preprint":false},{"pmid":"33274532","id":"PMC_33274532","title":"Constructing a 10-core genes panel for diagnosis of pediatric sepsis.","date":"2020","source":"Journal of clinical laboratory analysis","url":"https://pubmed.ncbi.nlm.nih.gov/33274532","citation_count":13,"is_preprint":false},{"pmid":"30524945","id":"PMC_30524945","title":"ZNF121 interacts with ZBRK1 and BRCA1 to regulate their target genes in mammary epithelial cells.","date":"2018","source":"FEBS open bio","url":"https://pubmed.ncbi.nlm.nih.gov/30524945","citation_count":7,"is_preprint":false},{"pmid":"40241172","id":"PMC_40241172","title":"Colorectal cancer progression to metastasis is associated with dynamic genome-wide biphasic 5-hydroxymethylcytosine accumulation.","date":"2025","source":"BMC biology","url":"https://pubmed.ncbi.nlm.nih.gov/40241172","citation_count":6,"is_preprint":false},{"pmid":"8468057","id":"PMC_8468057","title":"A novel zinc finger cDNA with a polymorphic pentanucleotide repeat (ATTTT)n maps on human chromosome 19p.","date":"1993","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8468057","citation_count":6,"is_preprint":false},{"pmid":"41188932","id":"PMC_41188932","title":"Mutational disruption of transcription factors binding and regulatory networks in a case of unexplained total fertilization failure.","date":"2025","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41188932","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7046,"output_tokens":812,"usd":0.016659,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7275,"output_tokens":1568,"usd":0.037788,"stage2_stop_reason":"end_turn"},"total_usd":0.054447,"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\": 1993,\n      \"finding\": \"ZNF121 (D19S204) was identified as a novel zinc finger protein containing 9 zinc finger motifs, cloned from a human brain cDNA library, and mapped to chromosome 19p by hybrid cell line mapping panels.\",\n      \"method\": \"cDNA library screening, open reading frame analysis, chromosomal mapping with hybrid cell lines\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct molecular cloning and chromosomal mapping with multiple orthogonal methods (library screen, sequence analysis, hybrid cell mapping), single lab\",\n      \"pmids\": [\"8468057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ZNF121 physically interacts with MYC oncoprotein via their N-terminal regions, and overexpression of ZNF121 increases MYC expression while knockdown of ZNF121 decreases MYC expression and its target genes (EGR1, CDC2, nucleolin), causing G1 cell cycle arrest and altered expression of cyclin D1, p14, and p21 in epithelial cell lines.\",\n      \"method\": \"Co-immunoprecipitation, domain-mapping interaction assays, siRNA knockdown, overexpression, Western blot, cell proliferation assays, cell cycle analysis\",\n      \"journal\": \"Journal of genetics and genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction demonstrated, multiple cell lines, loss-of-function with defined cellular phenotype, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"27988300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ZNF121 physically interacts with both ZBRK1 (a BRCA1-interacting KRAB domain protein) and BRCA1, demonstrated by yeast two-hybrid assay and other approaches; ZNF121 suppresses expression of ANG1 and HMGA2 (common downstream targets of ZBRK1 and BRCA1) and also regulates expression of BRCA1 and ZBRK1 themselves in mammary epithelial cells.\",\n      \"method\": \"Yeast two-hybrid assay, co-immunoprecipitation, gene expression assays (knockdown/overexpression)\",\n      \"journal\": \"FEBS open bio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus additional binding assays, functional target gene regulation confirmed, single lab with two orthogonal methods\",\n      \"pmids\": [\"30524945\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ZNF121 is a KRAB-domain zinc finger transcription factor that physically interacts with MYC (via N-terminal regions) to mutually regulate each other's expression and promote cell proliferation via MYC target genes, and also associates with the BRCA1/ZBRK1 repressor complex to suppress downstream targets ANG1 and HMGA2 in mammary epithelial cells.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ZNF121 is a zinc finger protein, originally cloned as a novel nine-zinc-finger protein from human brain and mapped to chromosome 19p [#0], that acts as a transcriptional regulator coupling cell proliferation to the activity of the MYC oncoprotein and the BRCA1 tumor-suppressor network. ZNF121 physically associates with MYC through their respective N-terminal regions and the two proteins reinforce each other's expression: ZNF121 overexpression raises MYC levels while its depletion lowers MYC and its target genes (EGR1, CDC2, nucleolin), producing G1 cell cycle arrest and altered levels of cyclin D1, p14, and p21 [#1]. In mammary epithelial cells ZNF121 also binds the BRCA1-interacting KRAB protein ZBRK1 and BRCA1 itself, and represses the shared ZBRK1/BRCA1 downstream targets ANG1 and HMGA2 while feeding back on BRCA1 and ZBRK1 expression [#2]. Beyond these interactions, the DNA-binding specificity and direct genomic targets of ZNF121 have not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Establishing that ZNF121 exists as a discrete multi-zinc-finger gene gave the field a defined molecular entity and chromosomal locus to study.\",\n      \"evidence\": \"cDNA library screening and chromosomal mapping with hybrid cell lines from human brain\",\n      \"pmids\": [\"8468057\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No function assigned at cloning beyond presence of zinc finger motifs\",\n        \"DNA-binding targets and specificity not determined\",\n        \"Tissue distribution and regulation unknown\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identifying a direct ZNF121-MYC interaction and reciprocal expression dependence connected ZNF121 to proliferative control through the MYC transcriptional program.\",\n      \"evidence\": \"Co-immunoprecipitation, domain mapping, siRNA knockdown and overexpression with cell cycle analysis in epithelial cell lines\",\n      \"pmids\": [\"27988300\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether ZNF121 binds MYC target promoters directly is not shown\",\n        \"Mechanism of reciprocal expression regulation undefined\",\n        \"Single lab; no structural mapping of the interaction interface\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrating ZNF121 binding to ZBRK1 and BRCA1 with repression of ANG1 and HMGA2 placed ZNF121 within the BRCA1/ZBRK1 transcriptional repressor network in mammary epithelium.\",\n      \"evidence\": \"Yeast two-hybrid, co-immunoprecipitation, and knockdown/overexpression gene expression assays in mammary epithelial cells\",\n      \"pmids\": [\"30524945\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct promoter occupancy of ANG1/HMGA2 by ZNF121 not demonstrated\",\n        \"Relationship between the MYC and BRCA1/ZBRK1 axes is unresolved\",\n        \"In vivo relevance to mammary biology or tumorigenesis untested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The intrinsic DNA-binding specificity and the direct genomic target loci of ZNF121 remain unknown, leaving open how it integrates MYC and BRCA1/ZBRK1 signaling at chromatin.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No genome-wide binding (ChIP) data\",\n        \"No defined consensus binding motif\",\n        \"Role of the zinc finger array versus protein-protein interactions in target regulation not separated\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [\"MYC\", \"ZBRK1\", \"BRCA1\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"faith_supported":3,"faith_total":3,"faith_pct":100.0}}