{"gene":"TWIST2","run_date":"2026-04-28T21:43:00","timeline":{"discoveries":[{"year":2025,"finding":"HOXA10 directly represses TWIST2 transcription in human endometrial epithelial cells; derepression of TWIST2 upon HOXA10 loss promotes mesenchymal gene expression and epithelial cell displacement, and TWIST2 knockdown restores epithelial identity and impairs embryo implantation, establishing TWIST2 as a core EMT regulator downstream of HOXA10 in a mutually antagonistic circuit controlling partial epithelial-to-mesenchymal transition (pEMT).","method":"CUT&RUN, transcriptomic profiling, siRNA knockdown in human endometrial epithelial cells, in vivo mouse/hamster/monkey models, cell motility assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (CUT&RUN, transcriptomics, KD with phenotype) in a single preprint lab study","pmids":["bio_10.1101_2025.01.10.631632"],"is_preprint":true}],"current_model":"TWIST2 functions as a core EMT transcription factor that is directly repressed by HOXA10 in endometrial epithelial cells; its derepression drives partial epithelial-to-mesenchymal transition by promoting mesenchymal gene expression and cell displacement, thereby regulating epithelial plasticity during embryo implantation."},"narrative":{"teleology":[{"year":2025,"claim":"It was unknown how epithelial plasticity is transcriptionally controlled during embryo implantation; CUT&RUN and transcriptomic profiling revealed that HOXA10 directly represses TWIST2, and that TWIST2 derepression is both necessary and sufficient to drive pEMT in endometrial epithelium, establishing a mutually antagonistic HOXA10–TWIST2 circuit governing implantation competence.","evidence":"CUT&RUN, transcriptomic profiling, siRNA knockdown in human endometrial epithelial cells, in vivo mouse/hamster/monkey models, cell motility assays (preprint)","pmids":["bio_10.1101_2025.01.10.631632"],"confidence":"Medium","gaps":["Single preprint study; findings have not been independently replicated or peer-reviewed","Direct TWIST2 transcriptional targets in endometrial cells have not been identified","Whether TWIST2 functions similarly in EMT contexts outside the endometrium is not addressed"]},{"year":null,"claim":"The downstream transcriptional targets of TWIST2 in endometrial pEMT, its chromatin-level mechanism of action, and its broader relevance to other EMT-dependent processes remain uncharacterized.","evidence":"","pmids":[],"confidence":"Low","gaps":["No genome-wide identification of direct TWIST2 target genes","No structural or biochemical characterization of TWIST2 DNA-binding specificity in this context","Relationship to other EMT-inducing transcription factors (e.g., SNAI1, ZEB1) not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0]}],"complexes":[],"partners":["HOXA10"],"other_free_text":[]},"mechanistic_narrative":"TWIST2 is a basic helix-loop-helix transcription factor that functions as a regulator of partial epithelial-to-mesenchymal transition (pEMT) in human endometrial epithelial cells, where it is directly repressed by HOXA10; upon HOXA10 loss, TWIST2 derepression drives mesenchymal gene expression and epithelial cell displacement, while TWIST2 knockdown restores epithelial identity and impairs embryo implantation [bio_10.1101_2025.01.10.631632]."},"prefetch_data":{"uniprot":{"accession":"Q8WVJ9","full_name":"Twist-related protein 2","aliases":["Class A basic helix-loop-helix protein 39","bHLHa39","Dermis-expressed protein 1","Dermo-1"],"length_aa":160,"mass_kda":18.1,"function":"Binds to the E-box consensus sequence 5'-CANNTG-3' as a heterodimer and inhibits transcriptional activation by MYOD1, MYOG, MEF2A and MEF2C. Also represses expression of pro-inflammatory cytokines such as TNFA and IL1B. Involved in postnatal glycogen storage and energy metabolism (By similarity). Inhibits the premature or ectopic differentiation of preosteoblast cells during osteogenesis, possibly by changing the internal signal transduction response of osteoblasts to external growth factors","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q8WVJ9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TWIST2","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TWIST2","total_profiled":1310},"omim":[{"mim_id":"617746","title":"SWEENEY-COX SYNDROME; SWCOS","url":"https://www.omim.org/entry/617746"},{"mim_id":"614974","title":"FOCAL FACIAL DERMAL DYSPLASIA 4; FFDD4","url":"https://www.omim.org/entry/614974"},{"mim_id":"608428","title":"CYTOCHROME P450, SUBFAMILY XXVIC, POLYPEPTIDE 1; CYP26C1","url":"https://www.omim.org/entry/608428"},{"mim_id":"607556","title":"TWIST FAMILY bHLH TRANSCRIPTION FACTOR 2; TWIST2","url":"https://www.omim.org/entry/607556"},{"mim_id":"605314","title":"HISTONE DEACETYLASE 4; HDAC4","url":"https://www.omim.org/entry/605314"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"cervix","ntpm":81.7}],"url":"https://www.proteinatlas.org/search/TWIST2"},"hgnc":{"alias_symbol":["DERMO1","Dermo-1","bHLHa39"],"prev_symbol":[]},"alphafold":{"accession":"Q8WVJ9","domains":[{"cath_id":"4.10.280","chopping":"60-150","consensus_level":"medium","plddt":92.3931,"start":60,"end":150}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WVJ9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WVJ9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WVJ9-F1-predicted_aligned_error_v6.png","plddt_mean":73.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TWIST2","jax_strain_url":"https://www.jax.org/strain/search?query=TWIST2"},"sequence":{"accession":"Q8WVJ9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8WVJ9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8WVJ9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WVJ9"}},"corpus_meta":[{"pmid":null,"id":"bio_10.1101_2025.01.10.631632","title":"HOXA10-TWIST2 Antagonism Drives Partial Epithelial-to-Mesenchymal transition for Embryo Implantation","date":"2025-01-10","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.10.631632","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.12.16.24319123","title":"Gene-by-environment interactions involving maternal exposures with orofacial cleft risk in Filipinos","date":"2024-12-17","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.16.24319123","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.12.675839","title":"Telomere-to-telomere gap-free genome assembly of a male donkey and the identification of novel SVs associated with functional genes","date":"2025-09-17","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.12.675839","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":3062,"output_tokens":395,"usd":0.007555},"stage2":{"model":"claude-opus-4-6","input_tokens":3539,"output_tokens":753,"usd":0.05478},"total_usd":0.062335,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2025,\n      \"finding\": \"HOXA10 directly represses TWIST2 transcription in human endometrial epithelial cells; derepression of TWIST2 upon HOXA10 loss promotes mesenchymal gene expression and epithelial cell displacement, and TWIST2 knockdown restores epithelial identity and impairs embryo implantation, establishing TWIST2 as a core EMT regulator downstream of HOXA10 in a mutually antagonistic circuit controlling partial epithelial-to-mesenchymal transition (pEMT).\",\n      \"method\": \"CUT&RUN, transcriptomic profiling, siRNA knockdown in human endometrial epithelial cells, in vivo mouse/hamster/monkey models, cell motility assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (CUT&RUN, transcriptomics, KD with phenotype) in a single preprint lab study\",\n      \"pmids\": [\"bio_10.1101_2025.01.10.631632\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"TWIST2 functions as a core EMT transcription factor that is directly repressed by HOXA10 in endometrial epithelial cells; its derepression drives partial epithelial-to-mesenchymal transition by promoting mesenchymal gene expression and cell displacement, thereby regulating epithelial plasticity during embryo implantation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TWIST2 is a basic helix-loop-helix transcription factor that functions as a regulator of partial epithelial-to-mesenchymal transition (pEMT) in human endometrial epithelial cells, where it is directly repressed by HOXA10; upon HOXA10 loss, TWIST2 derepression drives mesenchymal gene expression and epithelial cell displacement, while TWIST2 knockdown restores epithelial identity and impairs embryo implantation [bio_10.1101_2025.01.10.631632].\",\n  \"teleology\": [\n    {\n      \"year\": 2025,\n      \"claim\": \"It was unknown how epithelial plasticity is transcriptionally controlled during embryo implantation; CUT&RUN and transcriptomic profiling revealed that HOXA10 directly represses TWIST2, and that TWIST2 derepression is both necessary and sufficient to drive pEMT in endometrial epithelium, establishing a mutually antagonistic HOXA10–TWIST2 circuit governing implantation competence.\",\n      \"evidence\": \"CUT&RUN, transcriptomic profiling, siRNA knockdown in human endometrial epithelial cells, in vivo mouse/hamster/monkey models, cell motility assays (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.01.10.631632\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single preprint study; findings have not been independently replicated or peer-reviewed\",\n        \"Direct TWIST2 transcriptional targets in endometrial cells have not been identified\",\n        \"Whether TWIST2 functions similarly in EMT contexts outside the endometrium is not addressed\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The downstream transcriptional targets of TWIST2 in endometrial pEMT, its chromatin-level mechanism of action, and its broader relevance to other EMT-dependent processes remain uncharacterized.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No genome-wide identification of direct TWIST2 target genes\",\n        \"No structural or biochemical characterization of TWIST2 DNA-binding specificity in this context\",\n        \"Relationship to other EMT-inducing transcription factors (e.g., SNAI1, ZEB1) not established\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"HOXA10\"],\n    \"other_free_text\": []\n  }\n}\n```"}