{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T22:28:44Z","timestamp":1783636124581,"version":"3.55.0"},"reference-count":67,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T00:00:00Z","timestamp":1750723200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"U.S. National Institutes of Child Health and Human Development","award":["1U01HD087209"],"award-info":[{"award-number":["1U01HD087209"]}]},{"name":"U.S. National Institutes of Child Health and Human Development","award":["R01HD090180"],"award-info":[{"award-number":["R01HD090180"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The phenotype of human placental extravillous trophoblast (EVT) at the end of pregnancy reflects both differentiation from villous cytotrophoblast (CTB) and later gestational changes, including loss of proliferative and invasive capacity. Invasion abnormalities are central to major obstetric pathologies, including placenta accreta spectrum, early onset preeclampsia, and fetal growth restriction. Characterization of the normal differentiation processes is, thus, essential for the analysis of these pathologies. Our gene expression analysis, employing purified human CTB and EVT cells, demonstrates a mechanism similar to the epithelial\u2013mesenchymal transition (EMT), which underlies CTB\u2013EVT differentiation. In parallel, DNA methylation profiling shows that CTB cells, already hypomethylated relative to non-trophoblast cell lineages, show further genome-wide hypomethylation in the transition to EVT. A small subgroup of genes undergoes gains of methylation (GOM), associated with differential gene expression (DE). Prominent in this GOM-DE group are genes involved in epithelial\u2013mesenchymal plasticity (EMP). An exemplar is the transcription factor RUNX1, for which we demonstrate a functional role in regulating the migratory and invasive capacities of trophoblast cells. This analysis highlights epigenetically regulated genes acting to underpin the epithelial\u2013mesenchymal plasticity characteristic of human trophoblast differentiation. Identification of these elements provides important information for the obstetric disorders in which these processes are dysregulated.<\/jats:p>","DOI":"10.3390\/cells14130970","type":"journal-article","created":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T10:44:41Z","timestamp":1750761881000},"page":"970","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Epigenetic Changes Regulating Epithelial\u2013Mesenchymal Plasticity in Human Trophoblast Differentiation"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7366-3903","authenticated-orcid":false,"given":"William E.","family":"Ackerman IV","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Institute for Health Data Science Research, AI.Health4All Center, University of Illinois Chicago, Chicago, IL 61607, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauricio M.","family":"Rigo","sequence":"additional","affiliation":[{"name":"Hackensack Meridian Health Center for Discovery and Innovation, Nutley, NJ 07110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2721-4626","authenticated-orcid":false,"given":"Sonia C.","family":"DaSilva-Arnold","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Hackensack University Medical Center, Hackensack, NJ 07601, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Do","sequence":"additional","affiliation":[{"name":"Hackensack Meridian Health Center for Discovery and Innovation, Nutley, NJ 07110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariam","family":"Tariq","sequence":"additional","affiliation":[{"name":"Hackensack Meridian Health Center for Discovery and Innovation, Nutley, NJ 07110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martha","family":"Salas","sequence":"additional","affiliation":[{"name":"Hackensack Meridian Health Center for Discovery and Innovation, Nutley, NJ 07110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelica","family":"Castano","sequence":"additional","affiliation":[{"name":"Hackensack Meridian Health Center for Discovery and Innovation, Nutley, NJ 07110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stacy","family":"Zamudio","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Hackensack University Medical Center, Hackensack, NJ 07601, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Tycko","sequence":"additional","affiliation":[{"name":"Hackensack Meridian Health Center for Discovery and Innovation, Nutley, NJ 07110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4336-2832","authenticated-orcid":false,"given":"Nicholas P.","family":"Illsley","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Hackensack University Medical Center, Hackensack, NJ 07601, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3479","DOI":"10.1007\/s00018-019-03104-6","article-title":"Human placenta and trophoblast development: Key molecular mechanisms and model systems","volume":"76","author":"Knofler","year":"2019","journal-title":"Cell Mol. 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