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Deficient syncytialization of cytotrophoblasts affects the hormonal secretion and placental development, contributing to pregnancy\u2010associated disorders, including spontaneous miscarriage. To date, the molecular mechanisms, particularly the role of transcription factors (TFs), in STB lineage specification remain incompletely understood. Through targeting direct regulators of a STB lineage\u2010specific marker,\n                    <jats:italic>CGB<\/jats:italic>\n                    (encoding chorionic gonadotropin\u2010\u03b2), by DNA pull\u2010down coupled with mass spectrometry, basic helix\u2010loop\u2010helix family member 40 (BHLHE40) has been identified as a key regulator in human STB differentiation. BHLHE40 expression is increased during STB differentiation but reduced in villous samples from women with miscarriages. CRISPR\/Cas9\u2010mediated knockout of BHLHE40 in human trophoblast stem cells (TSCs) prevents STB differentiation in vitro, impairing gene expression critical for hormone synthesis and cell syncytialization. Mechanistically, BHLHE40 interacts directly with GATA2 and GATA3 to facilitate their chromatin occupancy, thereby activating transcriptional programs essential for STB differentiation. These findings uncover a BHLHE40\u2010GATA2\/3 regulatory network governing human trophoblast lineage commitment, providing insights into placental development and potential therapeutic targets for pregnancy disorders.\n                  <\/jats:p>","DOI":"10.1002\/advs.202507642","type":"journal-article","created":{"date-parts":[[2025,9,5]],"date-time":"2025-09-05T14:59:02Z","timestamp":1757084342000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["BHLHE40 Cooperates with GATA2\/3 to Control Human Syncytiotrophoblast Lineage Differentiation"],"prefix":"10.1002","volume":"12","author":[{"given":"Lijin","family":"Peng","sequence":"first","affiliation":[{"name":"Laboratory of Reproduction Immunology Obstetrics and Gynecology Hospital Fudan University Shanghai Medical College Shanghai 200032 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