{"gene":"ZSCAN20","run_date":"2026-06-11T09:02:07","timeline":{"discoveries":[{"year":2026,"finding":"ZSCAN20 is a transcription factor that selectively governs terminally exhausted CD8+ T cell (TEXterm) differentiation; targeted deletion of ZSCAN20 enhanced tumor control, synergized with immune checkpoint blockade, and reduced expression of inhibitory receptors in human T cells, without interfering with tissue-resident memory T (TRM) cell formation.","method":"In vivo CRISPR screening integrated with single-cell RNA sequencing (in vivo Perturb-seq); targeted genetic deletion with functional readouts (tumor control, inhibitory receptor expression, effector function in human T cells)","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo CRISPR loss-of-function with single-cell transcriptomic readout, replicated in human T cells with orthogonal functional assays; peer-reviewed publication","pmids":["41639465"],"is_preprint":false},{"year":2025,"finding":"ZSCAN20 is a transcription factor that selectively governs terminally exhausted CD8+ T cell (TEXterm) differentiation; its depletion enhanced tumor control, synergized with immune checkpoint blockade, reduced inhibitory receptor expression, and improved effector function in human T cells.","method":"In vivo CRISPR screening with in vivo Perturb-seq; targeted deletion with functional tumor control and human T cell effector assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — same findings as peer-reviewed paper but preprint version; orthogonal methods used but not yet peer-reviewed at time of this entry","pmids":["36711632"],"is_preprint":true}],"current_model":"ZSCAN20 is a transcription factor that selectively drives terminally exhausted CD8+ T cell (TEXterm) differentiation, decoupled from protective tissue-resident memory T cell programming; its loss-of-function reduces inhibitory receptor expression, enhances effector function, and improves anti-tumor immunity, synergizing with immune checkpoint blockade."},"narrative":{"mechanistic_narrative":"ZSCAN20 is a transcription factor that selectively governs the differentiation of terminally exhausted CD8+ T cells (TEXterm), a program it drives in a manner decoupled from protective tissue-resident memory T cell (TRM) formation [PMID:41639465]. Targeted deletion of ZSCAN20 enhances tumor control, reduces expression of inhibitory receptors, and improves effector function in human T cells, with loss synergizing with immune checkpoint blockade [PMID:41639465]. Beyond this transcriptional control of the exhaustion program, no direct target genes, DNA-binding sites, or protein partners have been characterized in the available corpus.","teleology":[{"year":2025,"claim":"Before this work it was unknown which transcription factors selectively control the terminally exhausted CD8+ T cell state versus protective memory programs; an in vivo perturbation screen nominated ZSCAN20 as a selective driver of TEXterm differentiation whose loss improves anti-tumor immunity.","evidence":"In vivo CRISPR screening with in vivo Perturb-seq plus targeted deletion and human T cell effector assays (preprint)","pmids":["36711632"],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed at time of entry","Direct transcriptional targets and DNA-binding sites of ZSCAN20 not defined","Mechanism by which ZSCAN20 distinguishes TEXterm from TRM programming unresolved"]},{"year":2026,"claim":"Peer-reviewed confirmation established that ZSCAN20 deletion enhances tumor control and synergizes with checkpoint blockade while sparing TRM formation, defining it as a selective, druggable node in the exhaustion program.","evidence":"In vivo CRISPR screen integrated with single-cell RNA sequencing and targeted deletion with functional readouts in human T cells","pmids":["41639465"],"confidence":"High","gaps":["No identified ZSCAN20 target genes or cis-regulatory elements","No structural or biochemical characterization of its DNA-binding or zinc-finger/SCAN domains","Cofactors and chromatin context through which it specifies the TEXterm fate are unknown"]},{"year":null,"claim":"How ZSCAN20 mechanistically enforces the terminally exhausted transcriptional program — its direct target genes, binding sites, and protein partners — remains undefined.","evidence":"","pmids":[],"confidence":"High","gaps":["No direct transcriptional targets identified","No partner transcription factors or chromatin regulators mapped","No structural basis for fate selectivity (TEXterm vs TRM)"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0]}],"localization":[],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P17040","full_name":"Zinc finger and SCAN domain-containing protein 20","aliases":["Zinc finger protein 31","Zinc finger protein 360","Zinc finger protein KOX29"],"length_aa":1043,"mass_kda":117.5,"function":"May be involved in transcriptional regulation","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P17040/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ZSCAN20","classification":"Not Classified","n_dependent_lines":11,"n_total_lines":1208,"dependency_fraction":0.009105960264900662},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ZSCAN20","total_profiled":1310},"omim":[{"mim_id":"611315","title":"ZINC FINGER- AND SCAN DOMAIN-CONTAINING PROTEIN 20; ZSCAN20","url":"https://www.omim.org/entry/611315"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ZSCAN20"},"hgnc":{"alias_symbol":["KOX29"],"prev_symbol":["ZNF360","ZNF31"]},"alphafold":{"accession":"P17040","domains":[{"cath_id":"1.10.4020.10","chopping":"48-121","consensus_level":"medium","plddt":80.3022,"start":48,"end":121},{"cath_id":"3.30.160.60","chopping":"712-817","consensus_level":"medium","plddt":80.8105,"start":712,"end":817}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P17040","model_url":"https://alphafold.ebi.ac.uk/files/AF-P17040-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P17040-F1-predicted_aligned_error_v6.png","plddt_mean":55.72},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ZSCAN20","jax_strain_url":"https://www.jax.org/strain/search?query=ZSCAN20"},"sequence":{"accession":"P17040","fasta_url":"https://rest.uniprot.org/uniprotkb/P17040.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P17040/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P17040"}},"corpus_meta":[{"pmid":"38747976","id":"PMC_38747976","title":"Brugada syndrome in Japan and Europe: a genome-wide association study reveals shared genetic architecture and new risk loci.","date":"2024","source":"European heart journal","url":"https://pubmed.ncbi.nlm.nih.gov/38747976","citation_count":15,"is_preprint":false},{"pmid":"32884031","id":"PMC_32884031","title":"Genome-wide association study for circulating fibroblast growth factor 21 and 23.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32884031","citation_count":14,"is_preprint":false},{"pmid":"38515383","id":"PMC_38515383","title":"ZNF263 cooperates with ZNF31 to promote the drug resistance and EMT of pancreatic cancer through transactivating RNF126.","date":"2024","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/38515383","citation_count":9,"is_preprint":false},{"pmid":"41639465","id":"PMC_41639465","title":"Atlas-guided discovery of transcription factors for T cell programming.","date":"2026","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/41639465","citation_count":5,"is_preprint":false},{"pmid":"36711632","id":"PMC_36711632","title":"Atlas-Guided Discovery of Transcription Factors for T Cell Programming.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/36711632","citation_count":4,"is_preprint":false},{"pmid":"40255485","id":"PMC_40255485","title":"Transcriptomic signature can distinguish chronic neutrophilic leukemia from ambiguous neutrophilic leukemias.","date":"2025","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/40255485","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":5746,"output_tokens":574,"usd":0.012924,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6949,"output_tokens":1208,"usd":0.032473,"stage2_stop_reason":"end_turn"},"total_usd":0.045397,"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\": 2026,\n      \"finding\": \"ZSCAN20 is a transcription factor that selectively governs terminally exhausted CD8+ T cell (TEXterm) differentiation; targeted deletion of ZSCAN20 enhanced tumor control, synergized with immune checkpoint blockade, and reduced expression of inhibitory receptors in human T cells, without interfering with tissue-resident memory T (TRM) cell formation.\",\n      \"method\": \"In vivo CRISPR screening integrated with single-cell RNA sequencing (in vivo Perturb-seq); targeted genetic deletion with functional readouts (tumor control, inhibitory receptor expression, effector function in human T cells)\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo CRISPR loss-of-function with single-cell transcriptomic readout, replicated in human T cells with orthogonal functional assays; peer-reviewed publication\",\n      \"pmids\": [\"41639465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZSCAN20 is a transcription factor that selectively governs terminally exhausted CD8+ T cell (TEXterm) differentiation; its depletion enhanced tumor control, synergized with immune checkpoint blockade, reduced inhibitory receptor expression, and improved effector function in human T cells.\",\n      \"method\": \"In vivo CRISPR screening with in vivo Perturb-seq; targeted deletion with functional tumor control and human T cell effector assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — same findings as peer-reviewed paper but preprint version; orthogonal methods used but not yet peer-reviewed at time of this entry\",\n      \"pmids\": [\"36711632\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"ZSCAN20 is a transcription factor that selectively drives terminally exhausted CD8+ T cell (TEXterm) differentiation, decoupled from protective tissue-resident memory T cell programming; its loss-of-function reduces inhibitory receptor expression, enhances effector function, and improves anti-tumor immunity, synergizing with immune checkpoint blockade.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ZSCAN20 is a transcription factor that selectively governs the differentiation of terminally exhausted CD8+ T cells (TEXterm), a program it drives in a manner decoupled from protective tissue-resident memory T cell (TRM) formation [#0]. Targeted deletion of ZSCAN20 enhances tumor control, reduces expression of inhibitory receptors, and improves effector function in human T cells, with loss synergizing with immune checkpoint blockade [#0]. Beyond this transcriptional control of the exhaustion program, no direct target genes, DNA-binding sites, or protein partners have been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2025,\n      \"claim\": \"Before this work it was unknown which transcription factors selectively control the terminally exhausted CD8+ T cell state versus protective memory programs; an in vivo perturbation screen nominated ZSCAN20 as a selective driver of TEXterm differentiation whose loss improves anti-tumor immunity.\",\n      \"evidence\": \"In vivo CRISPR screening with in vivo Perturb-seq plus targeted deletion and human T cell effector assays (preprint)\",\n      \"pmids\": [\"36711632\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"preprint version of subsequently peer-reviewed findings\",\n      \"gaps\": [\n        \"Preprint not yet peer-reviewed at time of entry\",\n        \"Direct transcriptional targets and DNA-binding sites of ZSCAN20 not defined\",\n        \"Mechanism by which ZSCAN20 distinguishes TEXterm from TRM programming unresolved\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Peer-reviewed confirmation established that ZSCAN20 deletion enhances tumor control and synergizes with checkpoint blockade while sparing TRM formation, defining it as a selective, druggable node in the exhaustion program.\",\n      \"evidence\": \"In vivo CRISPR screen integrated with single-cell RNA sequencing and targeted deletion with functional readouts in human T cells\",\n      \"pmids\": [\"41639465\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No identified ZSCAN20 target genes or cis-regulatory elements\",\n        \"No structural or biochemical characterization of its DNA-binding or zinc-finger/SCAN domains\",\n        \"Cofactors and chromatin context through which it specifies the TEXterm fate are unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ZSCAN20 mechanistically enforces the terminally exhausted transcriptional program — its direct target genes, binding sites, and protein partners — remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No direct transcriptional targets identified\",\n        \"No partner transcription factors or chromatin regulators mapped\",\n        \"No structural basis for fate selectivity (TEXterm vs TRM)\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"faith_supported":2,"faith_total":2,"faith_pct":100.0}}