{"gene":"ZNF554","run_date":"2026-04-28T23:00:24","timeline":{"discoveries":[{"year":2018,"finding":"DNA hypermethylation in the regulatory region of ZNF554 leads to gene down-regulation and impaired trophoblast invasion, identifying ZNF554 as a hub transcription factor in placental gene modules associated with preterm preeclampsia.","method":"In vitro experiments on trophoblast cells, placental transcriptomics, DNA methylation analysis, 'virtual' liquid biopsy","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple omics methods converging on mechanism, single study","pmids":["30135684"],"is_preprint":false},{"year":2023,"finding":"ZNF554 knockdown in trophoblast cells (HTR8/SVneo and JEG3) increases ROS production, promotes apoptosis and autophagy (via suppressed P62 and enhanced LC3-II/LC3-I), and inhibits migration and invasion; mechanistically, ZNF554 activates the NRF2 antioxidant signaling pathway through the p62-Keap1-Nrf2 axis.","method":"siRNA knockdown and overexpression plasmid in trophoblast cell lines; ROS assays; apoptosis assays; autophagy marker (LC3-II/LC3-I, P62) western blot; NAC rescue experiments; migration/invasion assays","journal":"Placenta","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function and gain-of-function with multiple orthogonal readouts and chemical rescue, single lab","pmids":["37804692"],"is_preprint":false},{"year":2020,"finding":"Overexpression of ZNF554 in U87 glioblastoma cells causes differential downregulation of 899 genes, arrests the cell cycle, decreases cell proliferation, and most prominently suppresses the PI3K-Akt signaling pathway, consistent with a tumor suppressor transcriptional role.","method":"Transient overexpression in U87 cells; genome-wide transcriptomics; cell proliferation and cell cycle assays","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — gain-of-function with transcriptome-wide profiling and functional cellular assays, single lab","pmids":["32796700"],"is_preprint":false},{"year":2024,"finding":"ZNF554 directly transcriptionally activates RBM5 (confirmed by chromatin immunoprecipitation and luciferase reporter assay), and RBM5 upregulation in turn inactivates the WNT/β-catenin signaling pathway (decreased β-catenin and p-GSK-3β), thereby suppressing endometrial cancer cell proliferation, migration, invasion, and inducing cell cycle arrest.","method":"Chromatin immunoprecipitation (ChIP) assay; luciferase reporter assay; lentiviral stable overexpression and knockdown; CCK-8, wound healing, Transwell invasion assays; PI/FACS cell cycle analysis; RBM5 rescue experiments; western blot for β-catenin and p-GSK-3β","journal":"Current medical science","confidence":"Medium","confidence_rationale":"Tier 1–2 — ChIP and luciferase reporter establish direct transcriptional regulation; rescue epistasis confirms pathway placement; single lab","pmids":["38619681"],"is_preprint":false}],"current_model":"ZNF554 is a KRAB-domain zinc finger transcription factor that directly regulates target gene expression (including RBM5), suppresses the PI3K-Akt and WNT/β-catenin oncogenic pathways, activates NRF2-mediated antioxidant signaling, and is epigenetically silenced by promoter DNA hypermethylation; its loss impairs trophoblast invasion, elevates ROS, promotes apoptosis and autophagy, and de-represses tumor pathways, while its expression is essential for normal placentation and acts as a tumor suppressor in glioma and endometrial cancer."},"narrative":{"teleology":[{"year":2018,"claim":"Establishing that ZNF554 is epigenetically regulated in the placenta answered the question of why trophoblast invasion is impaired in preeclampsia: promoter DNA hypermethylation silences ZNF554, identifying it as a hub transcription factor in placental gene networks.","evidence":"Integrated placental transcriptomics, DNA methylation profiling, and trophoblast cell experiments","pmids":["30135684"],"confidence":"Medium","gaps":["Direct transcriptional targets of ZNF554 in trophoblasts were not identified","Causal relationship between ZNF554 silencing and preeclampsia not tested in vivo","Mechanism by which ZNF554 promotes trophoblast invasion was not delineated"]},{"year":2020,"claim":"Demonstrating that ZNF554 overexpression arrests cell cycle and suppresses PI3K-Akt signaling in glioblastoma cells established its capacity to function as a tumor suppressor transcription factor beyond the placenta.","evidence":"Transient overexpression in U87 glioblastoma cells with genome-wide transcriptomics, proliferation, and cell cycle assays","pmids":["32796700"],"confidence":"Medium","gaps":["No direct target genes were validated by ChIP or reporter assays","Tumor suppressor activity not confirmed in vivo or in patient-derived models","Mechanism of PI3K-Akt suppression (direct vs. indirect) was unresolved"]},{"year":2023,"claim":"Defining the NRF2 antioxidant axis as a downstream effector of ZNF554 in trophoblasts resolved how ZNF554 loss leads to oxidative stress, apoptosis, autophagy, and impaired invasion — linking its silencing mechanistically to placental dysfunction.","evidence":"siRNA knockdown and overexpression in HTR8/SVneo and JEG3 trophoblast lines; ROS, apoptosis, autophagy marker, and migration/invasion assays with NAC rescue","pmids":["37804692"],"confidence":"Medium","gaps":["Whether ZNF554 directly binds NRF2 pathway gene promoters was not tested","In vivo relevance in placental tissue or animal models not demonstrated","Relative contribution of apoptosis versus impaired migration to invasion defect unclear"]},{"year":2024,"claim":"Identifying RBM5 as a direct transcriptional target of ZNF554 and showing that the ZNF554–RBM5–WNT/β-catenin axis suppresses endometrial cancer provided the first ChIP-validated target gene and a defined epistatic pathway for ZNF554's tumor suppressor activity.","evidence":"ChIP and luciferase reporter assays confirming direct RBM5 activation; lentiviral overexpression/knockdown with RBM5 rescue; western blot for β-catenin and p-GSK-3β in endometrial cancer cells","pmids":["38619681"],"confidence":"Medium","gaps":["Genome-wide binding profile of ZNF554 has not been determined","Whether the ZNF554–RBM5 axis operates in trophoblast or glioma contexts is unknown","In vivo tumor suppression by ZNF554 has not been demonstrated"]},{"year":null,"claim":"The genome-wide direct target repertoire of ZNF554, its in vivo roles in placentation and tumorigenesis, and how its KRAB domain contributes to transcriptional activation versus repression remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No ChIP-seq or CUT&RUN data to define the full cistrome","No animal model (knockout or conditional) for ZNF554","Mechanism by which a KRAB-ZNF activates (rather than represses) transcription is unexplained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2,3]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,2,3]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2,3]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3]}],"complexes":[],"partners":["RBM5"],"other_free_text":[]},"mechanistic_narrative":"ZNF554 is a KRAB-domain zinc finger transcription factor that functions as a transcriptional regulator of trophoblast invasion and as a tumor suppressor in multiple cancer contexts. In placental trophoblast cells, ZNF554 activates the NRF2 antioxidant pathway via the p62-Keap1-Nrf2 axis, and its loss elevates reactive oxygen species, promotes apoptosis and autophagy, and impairs cell migration and invasion; epigenetic silencing of ZNF554 by promoter DNA hypermethylation is associated with preterm preeclampsia [PMID:30135684, PMID:37804692]. In cancer cells, ZNF554 directly activates RBM5 transcription to inactivate WNT/β-catenin signaling and suppresses the PI3K-Akt pathway, leading to cell cycle arrest and reduced proliferation, migration, and invasion [PMID:32796700, PMID:38619681]."},"prefetch_data":{"uniprot":{"accession":"Q86TJ5","full_name":"Zinc finger protein 554","aliases":[],"length_aa":538,"mass_kda":60.6,"function":"May be involved in transcriptional regulation","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q86TJ5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ZNF554","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":[{"gene":"MVD","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ZNF554","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ZNF554"},"hgnc":{"alias_symbol":["FLJ34817"],"prev_symbol":[]},"alphafold":{"accession":"Q86TJ5","domains":[{"cath_id":"3.30.160.60","chopping":"325-364","consensus_level":"medium","plddt":84.34,"start":325,"end":364},{"cath_id":"3.30.160.60","chopping":"463-538","consensus_level":"medium","plddt":78.0713,"start":463,"end":538},{"cath_id":"1.10.287","chopping":"46-85","consensus_level":"medium","plddt":81.4085,"start":46,"end":85}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86TJ5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86TJ5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86TJ5-F1-predicted_aligned_error_v6.png","plddt_mean":55.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ZNF554","jax_strain_url":"https://www.jax.org/strain/search?query=ZNF554"},"sequence":{"accession":"Q86TJ5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86TJ5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86TJ5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86TJ5"}},"corpus_meta":[{"pmid":"30135684","id":"PMC_30135684","title":"Integrated Systems Biology Approach Identifies Novel Maternal and Placental Pathways of Preeclampsia.","date":"2018","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30135684","citation_count":149,"is_preprint":false},{"pmid":"37804692","id":"PMC_37804692","title":"Dysfunction of ZNF554 promotes ROS-induced apoptosis and autophagy in Fetal Growth Restriction via the p62-Keap1-Nrf2 pathway.","date":"2023","source":"Placenta","url":"https://pubmed.ncbi.nlm.nih.gov/37804692","citation_count":9,"is_preprint":false},{"pmid":"32796700","id":"PMC_32796700","title":"Decreased Expression of ZNF554 in Gliomas is Associated with the Activation of Tumor Pathways and Shorter Patient Survival.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32796700","citation_count":6,"is_preprint":false},{"pmid":"38619681","id":"PMC_38619681","title":"ZNF554 Inhibits Endometrial Cancer Progression via Regulating RBM5 and Inactivating WNT/β-Catenin Signaling Pathway.","date":"2024","source":"Current medical science","url":"https://pubmed.ncbi.nlm.nih.gov/38619681","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4105,"output_tokens":1129,"usd":0.014625},"stage2":{"model":"claude-opus-4-6","input_tokens":4354,"output_tokens":1550,"usd":0.09078},"total_usd":0.105405,"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\": 2018,\n      \"finding\": \"DNA hypermethylation in the regulatory region of ZNF554 leads to gene down-regulation and impaired trophoblast invasion, identifying ZNF554 as a hub transcription factor in placental gene modules associated with preterm preeclampsia.\",\n      \"method\": \"In vitro experiments on trophoblast cells, placental transcriptomics, DNA methylation analysis, 'virtual' liquid biopsy\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple omics methods converging on mechanism, single study\",\n      \"pmids\": [\"30135684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ZNF554 knockdown in trophoblast cells (HTR8/SVneo and JEG3) increases ROS production, promotes apoptosis and autophagy (via suppressed P62 and enhanced LC3-II/LC3-I), and inhibits migration and invasion; mechanistically, ZNF554 activates the NRF2 antioxidant signaling pathway through the p62-Keap1-Nrf2 axis.\",\n      \"method\": \"siRNA knockdown and overexpression plasmid in trophoblast cell lines; ROS assays; apoptosis assays; autophagy marker (LC3-II/LC3-I, P62) western blot; NAC rescue experiments; migration/invasion assays\",\n      \"journal\": \"Placenta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function and gain-of-function with multiple orthogonal readouts and chemical rescue, single lab\",\n      \"pmids\": [\"37804692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Overexpression of ZNF554 in U87 glioblastoma cells causes differential downregulation of 899 genes, arrests the cell cycle, decreases cell proliferation, and most prominently suppresses the PI3K-Akt signaling pathway, consistent with a tumor suppressor transcriptional role.\",\n      \"method\": \"Transient overexpression in U87 cells; genome-wide transcriptomics; cell proliferation and cell cycle assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain-of-function with transcriptome-wide profiling and functional cellular assays, single lab\",\n      \"pmids\": [\"32796700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZNF554 directly transcriptionally activates RBM5 (confirmed by chromatin immunoprecipitation and luciferase reporter assay), and RBM5 upregulation in turn inactivates the WNT/β-catenin signaling pathway (decreased β-catenin and p-GSK-3β), thereby suppressing endometrial cancer cell proliferation, migration, invasion, and inducing cell cycle arrest.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) assay; luciferase reporter assay; lentiviral stable overexpression and knockdown; CCK-8, wound healing, Transwell invasion assays; PI/FACS cell cycle analysis; RBM5 rescue experiments; western blot for β-catenin and p-GSK-3β\",\n      \"journal\": \"Current medical science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — ChIP and luciferase reporter establish direct transcriptional regulation; rescue epistasis confirms pathway placement; single lab\",\n      \"pmids\": [\"38619681\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ZNF554 is a KRAB-domain zinc finger transcription factor that directly regulates target gene expression (including RBM5), suppresses the PI3K-Akt and WNT/β-catenin oncogenic pathways, activates NRF2-mediated antioxidant signaling, and is epigenetically silenced by promoter DNA hypermethylation; its loss impairs trophoblast invasion, elevates ROS, promotes apoptosis and autophagy, and de-represses tumor pathways, while its expression is essential for normal placentation and acts as a tumor suppressor in glioma and endometrial cancer.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ZNF554 is a KRAB-domain zinc finger transcription factor that functions as a transcriptional regulator of trophoblast invasion and as a tumor suppressor in multiple cancer contexts. In placental trophoblast cells, ZNF554 activates the NRF2 antioxidant pathway via the p62-Keap1-Nrf2 axis, and its loss elevates reactive oxygen species, promotes apoptosis and autophagy, and impairs cell migration and invasion; epigenetic silencing of ZNF554 by promoter DNA hypermethylation is associated with preterm preeclampsia [PMID:30135684, PMID:37804692]. In cancer cells, ZNF554 directly activates RBM5 transcription to inactivate WNT/β-catenin signaling and suppresses the PI3K-Akt pathway, leading to cell cycle arrest and reduced proliferation, migration, and invasion [PMID:32796700, PMID:38619681].\",\n  \"teleology\": [\n    {\n      \"year\": 2018,\n      \"claim\": \"Establishing that ZNF554 is epigenetically regulated in the placenta answered the question of why trophoblast invasion is impaired in preeclampsia: promoter DNA hypermethylation silences ZNF554, identifying it as a hub transcription factor in placental gene networks.\",\n      \"evidence\": \"Integrated placental transcriptomics, DNA methylation profiling, and trophoblast cell experiments\",\n      \"pmids\": [\"30135684\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct transcriptional targets of ZNF554 in trophoblasts were not identified\",\n        \"Causal relationship between ZNF554 silencing and preeclampsia not tested in vivo\",\n        \"Mechanism by which ZNF554 promotes trophoblast invasion was not delineated\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrating that ZNF554 overexpression arrests cell cycle and suppresses PI3K-Akt signaling in glioblastoma cells established its capacity to function as a tumor suppressor transcription factor beyond the placenta.\",\n      \"evidence\": \"Transient overexpression in U87 glioblastoma cells with genome-wide transcriptomics, proliferation, and cell cycle assays\",\n      \"pmids\": [\"32796700\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct target genes were validated by ChIP or reporter assays\",\n        \"Tumor suppressor activity not confirmed in vivo or in patient-derived models\",\n        \"Mechanism of PI3K-Akt suppression (direct vs. indirect) was unresolved\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defining the NRF2 antioxidant axis as a downstream effector of ZNF554 in trophoblasts resolved how ZNF554 loss leads to oxidative stress, apoptosis, autophagy, and impaired invasion — linking its silencing mechanistically to placental dysfunction.\",\n      \"evidence\": \"siRNA knockdown and overexpression in HTR8/SVneo and JEG3 trophoblast lines; ROS, apoptosis, autophagy marker, and migration/invasion assays with NAC rescue\",\n      \"pmids\": [\"37804692\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether ZNF554 directly binds NRF2 pathway gene promoters was not tested\",\n        \"In vivo relevance in placental tissue or animal models not demonstrated\",\n        \"Relative contribution of apoptosis versus impaired migration to invasion defect unclear\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identifying RBM5 as a direct transcriptional target of ZNF554 and showing that the ZNF554–RBM5–WNT/β-catenin axis suppresses endometrial cancer provided the first ChIP-validated target gene and a defined epistatic pathway for ZNF554's tumor suppressor activity.\",\n      \"evidence\": \"ChIP and luciferase reporter assays confirming direct RBM5 activation; lentiviral overexpression/knockdown with RBM5 rescue; western blot for β-catenin and p-GSK-3β in endometrial cancer cells\",\n      \"pmids\": [\"38619681\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Genome-wide binding profile of ZNF554 has not been determined\",\n        \"Whether the ZNF554–RBM5 axis operates in trophoblast or glioma contexts is unknown\",\n        \"In vivo tumor suppression by ZNF554 has not been demonstrated\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The genome-wide direct target repertoire of ZNF554, its in vivo roles in placentation and tumorigenesis, and how its KRAB domain contributes to transcriptional activation versus repression remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No ChIP-seq or CUT&RUN data to define the full cistrome\",\n        \"No animal model (knockout or conditional) for ZNF554\",\n        \"Mechanism by which a KRAB-ZNF activates (rather than represses) transcription is unexplained\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"RBM5\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}