{"gene":"ZNF449","run_date":"2026-06-11T09:02:07","timeline":{"discoveries":[{"year":2006,"finding":"ZNF449 protein localizes to the nucleus when overexpressed in cultured cells, consistent with a role as a transcription factor. The protein contains a SCAN domain at the N-terminus and seven C2H2 zinc-finger motifs at the C-terminus.","method":"Subcellular localization by overexpression in cultured cells; domain architecture by sequence analysis of isolated cDNA","journal":"Molecular biology reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single overexpression localization experiment with no functional consequence demonstrated","pmids":["16636917"],"is_preprint":false},{"year":2014,"finding":"ZNF449 (and mouse Zfp449) transactivates enhancers/promoters of SOX6, SOX9, and COL2A1, identified initially by yeast one-hybrid screening using the 46-bp core enhancer of SOX6 (CES6) as bait. Overexpression of ZNF449 in human mesenchymal stem cells enhanced SOX9 and SOX6 expression specifically at the initial stage of chondrogenic differentiation.","method":"Yeast one-hybrid assay (binding to CES6 enhancer), transactivation reporter assays, overexpression in human mesenchymal stem cells during chondrogenic differentiation","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple orthogonal methods (yeast one-hybrid, transactivation assay, cell overexpression), single lab","pmids":["25546433"],"is_preprint":false},{"year":2014,"finding":"Zfp449 (mouse ortholog of ZNF449) protein is abundantly expressed in periarticular chondrocytes of limb cartilage in mouse embryos and decreases with differentiation, and is also detected in articular cartilage of adult mice; however, Zfp449 knockout mice show no obvious abnormality in skeletal development or articular cartilage homeostasis.","method":"Immunohistochemistry/protein detection in mouse tissues; Zfp449 knockout mouse generation and phenotypic analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout mouse with defined phenotypic readout (negative result for skeletal abnormality), single lab","pmids":["25546433"],"is_preprint":false},{"year":2025,"finding":"ZNF449 physically interacts with PTOV1 and the PTOV1/ZNF449 complex synergistically promotes transcription of MYC, thereby accelerating colorectal cancer (CRC) development in vitro and in vivo. Disruption of this interaction using a TAT-PTOV1(125-283 aa) peptide inhibits CRC development in a xenograft mouse model.","method":"Co-immunoprecipitation (Co-IP), GST pull-down, transcriptional reporter/qRT-PCR for MYC, in vitro proliferation/colony/invasion assays, mouse xenograft model","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and GST pull-down establish physical interaction; functional consequence (MYC transcription, in vivo tumor growth) demonstrated by multiple methods in single lab","pmids":["40133702"],"is_preprint":false}],"current_model":"ZNF449 is a nuclear SCAN-domain C2H2 zinc-finger transcription factor that binds the SOX6 core enhancer and transactivates SOX6, SOX9, and COL2A1 promoters/enhancers during early chondrogenesis, and also physically interacts with PTOV1 to synergistically drive MYC transcription and promote colorectal cancer progression."},"narrative":{"mechanistic_narrative":"ZNF449 is a nuclear SCAN-domain C2H2 zinc-finger transcription factor that regulates gene expression in both developmental and oncogenic contexts [PMID:16636917, PMID:25546433]. During early chondrogenesis it binds the 46-bp core enhancer of SOX6 (CES6) and transactivates the SOX6, SOX9, and COL2A1 promoters/enhancers; its overexpression in human mesenchymal stem cells enhances SOX6 and SOX9 expression specifically at the initial stage of chondrogenic differentiation, and the mouse ortholog Zfp449 is enriched in periarticular chondrocytes, although Zfp449-knockout mice show no overt skeletal or articular cartilage phenotype [PMID:25546433]. In colorectal cancer, ZNF449 physically interacts with PTOV1 to form a complex that synergistically drives MYC transcription and accelerates tumor growth, an activity that can be blocked by a peptide disrupting the PTOV1–ZNF449 interaction in xenografts [PMID:40133702]. Beyond these contexts, the direct DNA-binding specificity and the regulatory logic linking ZNF449's developmental and oncogenic roles have not been characterized in the available corpus.","teleology":[{"year":2006,"claim":"Established the basic identity of ZNF449 as a candidate transcription factor by defining its domain architecture and nuclear residence.","evidence":"Overexpression-based subcellular localization and sequence analysis of isolated cDNA in cultured cells","pmids":["16636917"],"confidence":"Low","gaps":["Localization shown only by overexpression, not endogenous protein","No DNA-binding target or functional consequence demonstrated","Roles of the SCAN domain and individual zinc fingers not tested"]},{"year":2014,"claim":"Identified ZNF449 as a sequence-specific transactivator of chondrogenic genes, linking it to a defined enhancer and a differentiation program.","evidence":"Yeast one-hybrid against the SOX6 CES6 enhancer, transactivation reporter assays, and overexpression in human mesenchymal stem cells during chondrogenic differentiation","pmids":["25546433"],"confidence":"Medium","gaps":["Direct binding shown in yeast, not validated by ChIP at endogenous loci","Single lab; in vivo requirement not established"]},{"year":2014,"claim":"Tested whether the chondrogenic transactivator function is required in vivo, revealing dispensability of the gene for skeletal development.","evidence":"Immunohistochemical detection of Zfp449 in mouse limb cartilage and phenotypic analysis of Zfp449-knockout mice","pmids":["25546433"],"confidence":"Medium","gaps":["Negative skeletal phenotype may reflect genetic redundancy not addressed","No conditional or compound knockout tested","Discrepancy between expression pattern and loss-of-function phenotype unexplained"]},{"year":2025,"claim":"Defined an oncogenic role for ZNF449 through a physical partnership with PTOV1 that drives MYC transcription, establishing a druggable interaction in colorectal cancer.","evidence":"Reciprocal Co-IP, GST pull-down, MYC reporter/qRT-PCR, proliferation/colony/invasion assays, and a xenograft model with a TAT-PTOV1(125-283) disrupting peptide","pmids":["40133702"],"confidence":"Medium","gaps":["Whether ZNF449 binds the MYC promoter directly versus via PTOV1 not resolved","Single lab; interaction interface mapped only functionally via peptide","Link between chondrogenic and oncogenic functions unexplored"]},{"year":null,"claim":"The intrinsic DNA-binding specificity of ZNF449 and the mechanism reconciling its enhancer-binding developmental role with its PTOV1-dependent oncogenic role remain undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No genome-wide binding map (ChIP-seq) reported","Contribution of individual zinc fingers and the SCAN domain to each function untested","No structural model of the ZNF449–PTOV1 complex"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,3]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[1]}],"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":[1,3]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,2]}],"complexes":["PTOV1–ZNF449 complex"],"partners":["PTOV1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6P9G9","full_name":"Zinc finger protein 449","aliases":["Zinc finger and SCAN domain-containing protein 19"],"length_aa":518,"mass_kda":59.9,"function":"May be involved in transcriptional regulation","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q6P9G9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ZNF449","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/ZNF449","total_profiled":1310},"omim":[{"mim_id":"300627","title":"ZINC FINGER PROTEIN 449; ZNF449","url":"https://www.omim.org/entry/300627"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ZNF449"},"hgnc":{"alias_symbol":["ZSCAN19","FLJ23614"],"prev_symbol":[]},"alphafold":{"accession":"Q6P9G9","domains":[{"cath_id":"1.10.4020.10","chopping":"2-15_25-103","consensus_level":"medium","plddt":70.5432,"start":2,"end":103},{"cath_id":"3.30.160.60","chopping":"324-431","consensus_level":"medium","plddt":81.6538,"start":324,"end":431}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6P9G9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6P9G9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6P9G9-F1-predicted_aligned_error_v6.png","plddt_mean":61.97},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ZNF449","jax_strain_url":"https://www.jax.org/strain/search?query=ZNF449"},"sequence":{"accession":"Q6P9G9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6P9G9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6P9G9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6P9G9"}},"corpus_meta":[{"pmid":"38982123","id":"PMC_38982123","title":"Sex-specific survival gene mutations are discovered as clinical predictors of clear cell renal cell carcinoma.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/38982123","citation_count":7,"is_preprint":false},{"pmid":"25546433","id":"PMC_25546433","title":"Identification of SCAN domain zinc-finger gene ZNF449 as a novel factor of chondrogenesis.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25546433","citation_count":5,"is_preprint":false},{"pmid":"16636917","id":"PMC_16636917","title":"Identification and characterization of the human SCAN domain zinc-finger gene ZNF449.","date":"2006","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/16636917","citation_count":3,"is_preprint":false},{"pmid":"40133702","id":"PMC_40133702","title":"PTOV1 interacts with ZNF449 to promote colorectal cancer development.","date":"2025","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/40133702","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4192,"output_tokens":1068,"usd":0.014298,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7608,"output_tokens":1918,"usd":0.042995,"stage2_stop_reason":"end_turn"},"total_usd":0.057293,"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\": 2006,\n      \"finding\": \"ZNF449 protein localizes to the nucleus when overexpressed in cultured cells, consistent with a role as a transcription factor. The protein contains a SCAN domain at the N-terminus and seven C2H2 zinc-finger motifs at the C-terminus.\",\n      \"method\": \"Subcellular localization by overexpression in cultured cells; domain architecture by sequence analysis of isolated cDNA\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single overexpression localization experiment with no functional consequence demonstrated\",\n      \"pmids\": [\"16636917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ZNF449 (and mouse Zfp449) transactivates enhancers/promoters of SOX6, SOX9, and COL2A1, identified initially by yeast one-hybrid screening using the 46-bp core enhancer of SOX6 (CES6) as bait. Overexpression of ZNF449 in human mesenchymal stem cells enhanced SOX9 and SOX6 expression specifically at the initial stage of chondrogenic differentiation.\",\n      \"method\": \"Yeast one-hybrid assay (binding to CES6 enhancer), transactivation reporter assays, overexpression in human mesenchymal stem cells during chondrogenic differentiation\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple orthogonal methods (yeast one-hybrid, transactivation assay, cell overexpression), single lab\",\n      \"pmids\": [\"25546433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Zfp449 (mouse ortholog of ZNF449) protein is abundantly expressed in periarticular chondrocytes of limb cartilage in mouse embryos and decreases with differentiation, and is also detected in articular cartilage of adult mice; however, Zfp449 knockout mice show no obvious abnormality in skeletal development or articular cartilage homeostasis.\",\n      \"method\": \"Immunohistochemistry/protein detection in mouse tissues; Zfp449 knockout mouse generation and phenotypic analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout mouse with defined phenotypic readout (negative result for skeletal abnormality), single lab\",\n      \"pmids\": [\"25546433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZNF449 physically interacts with PTOV1 and the PTOV1/ZNF449 complex synergistically promotes transcription of MYC, thereby accelerating colorectal cancer (CRC) development in vitro and in vivo. Disruption of this interaction using a TAT-PTOV1(125-283 aa) peptide inhibits CRC development in a xenograft mouse model.\",\n      \"method\": \"Co-immunoprecipitation (Co-IP), GST pull-down, transcriptional reporter/qRT-PCR for MYC, in vitro proliferation/colony/invasion assays, mouse xenograft model\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and GST pull-down establish physical interaction; functional consequence (MYC transcription, in vivo tumor growth) demonstrated by multiple methods in single lab\",\n      \"pmids\": [\"40133702\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ZNF449 is a nuclear SCAN-domain C2H2 zinc-finger transcription factor that binds the SOX6 core enhancer and transactivates SOX6, SOX9, and COL2A1 promoters/enhancers during early chondrogenesis, and also physically interacts with PTOV1 to synergistically drive MYC transcription and promote colorectal cancer progression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ZNF449 is a nuclear SCAN-domain C2H2 zinc-finger transcription factor that regulates gene expression in both developmental and oncogenic contexts [#0, #1]. During early chondrogenesis it binds the 46-bp core enhancer of SOX6 (CES6) and transactivates the SOX6, SOX9, and COL2A1 promoters/enhancers; its overexpression in human mesenchymal stem cells enhances SOX6 and SOX9 expression specifically at the initial stage of chondrogenic differentiation, and the mouse ortholog Zfp449 is enriched in periarticular chondrocytes, although Zfp449-knockout mice show no overt skeletal or articular cartilage phenotype [#1, #2]. In colorectal cancer, ZNF449 physically interacts with PTOV1 to form a complex that synergistically drives MYC transcription and accelerates tumor growth, an activity that can be blocked by a peptide disrupting the PTOV1–ZNF449 interaction in xenografts [#3]. Beyond these contexts, the direct DNA-binding specificity and the regulatory logic linking ZNF449's developmental and oncogenic roles have not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established the basic identity of ZNF449 as a candidate transcription factor by defining its domain architecture and nuclear residence.\",\n      \"evidence\": \"Overexpression-based subcellular localization and sequence analysis of isolated cDNA in cultured cells\",\n      \"pmids\": [\"16636917\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Localization shown only by overexpression, not endogenous protein\",\n        \"No DNA-binding target or functional consequence demonstrated\",\n        \"Roles of the SCAN domain and individual zinc fingers not tested\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified ZNF449 as a sequence-specific transactivator of chondrogenic genes, linking it to a defined enhancer and a differentiation program.\",\n      \"evidence\": \"Yeast one-hybrid against the SOX6 CES6 enhancer, transactivation reporter assays, and overexpression in human mesenchymal stem cells during chondrogenic differentiation\",\n      \"pmids\": [\"25546433\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct binding shown in yeast, not validated by ChIP at endogenous loci\",\n        \"Single lab; in vivo requirement not established\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Tested whether the chondrogenic transactivator function is required in vivo, revealing dispensability of the gene for skeletal development.\",\n      \"evidence\": \"Immunohistochemical detection of Zfp449 in mouse limb cartilage and phenotypic analysis of Zfp449-knockout mice\",\n      \"pmids\": [\"25546433\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Negative skeletal phenotype may reflect genetic redundancy not addressed\",\n        \"No conditional or compound knockout tested\",\n        \"Discrepancy between expression pattern and loss-of-function phenotype unexplained\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined an oncogenic role for ZNF449 through a physical partnership with PTOV1 that drives MYC transcription, establishing a druggable interaction in colorectal cancer.\",\n      \"evidence\": \"Reciprocal Co-IP, GST pull-down, MYC reporter/qRT-PCR, proliferation/colony/invasion assays, and a xenograft model with a TAT-PTOV1(125-283) disrupting peptide\",\n      \"pmids\": [\"40133702\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether ZNF449 binds the MYC promoter directly versus via PTOV1 not resolved\",\n        \"Single lab; interaction interface mapped only functionally via peptide\",\n        \"Link between chondrogenic and oncogenic functions unexplored\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The intrinsic DNA-binding specificity of ZNF449 and the mechanism reconciling its enhancer-binding developmental role with its PTOV1-dependent oncogenic role remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No genome-wide binding map (ChIP-seq) reported\",\n        \"Contribution of individual zinc fingers and the SCAN domain to each function untested\",\n        \"No structural model of the ZNF449–PTOV1 complex\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [\"PTOV1\\u2013ZNF449 complex\"],\n    \"partners\": [\"PTOV1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":3,"faith_total":3,"faith_pct":100.0}}