{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T13:44:26Z","timestamp":1783950266676,"version":"3.55.0"},"reference-count":61,"publisher":"The Endocrine Society","issue":"9","license":[{"start":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T00:00:00Z","timestamp":1756857600000},"content-version":"vor","delay-in-days":57,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Fulbright-Monahan Foundation"},{"DOI":"10.13039\/501100021716","name":"University of Paris","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100021716","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Yale University School of Medicine"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,7,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Serotonin (5-hydroxytryptamine; 5-HT) is transported into the human placenta through the serotonin transporter (SERT\/SLC6A4) on the surface of the syncytiotrophoblast. During this transit, a significant amount of 5-HT becomes concentrated in the cytotrophoblast nucleus. We used immunochemistry, inhibitors of SERT and transglutaminase 2, and RNA sequencing to elucidate the mechanism and consequences of this nuclear localization. Exogenous 5-HT recapitulated the uptake of 5-HT into the trophoblasts and its preferential concentration in cytotrophoblast nuclei we observed in the intact placenta. Cystamine eliminated the staining of the nuclei in placental explants by exogenous 5-HT, suggesting that serotonylation mediated this phenomenon. This was confirmed by Western blots and immunoprecipitation that identified histone 3, and specifically the 5th glutamine residue in histone 3, as a site of serotonylation. Inhibiting SERT with escitalopram or transglutaminase 2 with cystamine blocked cytotrophoblast differentiation in vitro and led to marked changes in RNA expression. Of the 38 524 mRNAs identified in these trophoblasts, cystamine changed the expression of 1986 and escitalopram significantly altered 374. Both treatments altered the expression of 155 mRNAs either positively or negatively. The downregulated genes were involved with cell proliferation, morphogenesis, motility, and growth, whereas genes that were upregulated controlled cell survival and protection pathways. These findings suggest that maternal 5-HT promotes placental, embryonic\/fetal, and organismal development through histone serotonylation and consequent alterations in gene expression. They raise the possibility that alterations in 5-HT flux in the placenta affect placental and fetal growth, as well as organismal somatic, neurologic developmental, and pathological trajectories.<\/jats:p>","DOI":"10.1210\/endocr\/bqaf124","type":"journal-article","created":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T02:09:09Z","timestamp":1756692549000},"source":"Crossref","is-referenced-by-count":8,"title":["Role of Serotonin on Gene Expression and Physiology in Human Cytotrophoblasts and Placenta"],"prefix":"10.1210","volume":"166","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-3866-4011","authenticated-orcid":false,"given":"Nolwenn S","family":"Morris","sequence":"first","affiliation":[{"name":"Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine , New Haven, CT 06520 ,","place":["USA"]},{"name":"Learning Planet Institute, University of Paris Cit\u00e9, ED474 , 75006 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0651-8241","authenticated-orcid":false,"given":"Seth","family":"Guller","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine , New Haven, CT 06520 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhonghua","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine , New Haven, CT 06520 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan-Wei","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Guangzhou University , Guangzhou 510006 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin C","family":"Siegman","sequence":"additional","affiliation":[{"name":"Fordham College, Fordham University , Bronx, NY 10458 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristin M","family":"Milano","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine , New Haven, CT 06520 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7622-4110","authenticated-orcid":false,"given":"Gary","family":"Rudnick","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Yale University School of Medicine , New Haven, CT 06520 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2151-7071","authenticated-orcid":false,"given":"Harvey J","family":"Kliman","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine , New Haven, CT 06520 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2025,9,3]]},"reference":[{"issue":"6","key":"2025090300025735000_bqaf124-B1","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1007\/s00018-022-04377-0","article-title":"Early human trophoblast development: from morphology to function","volume":"79","author":"Gauster","year":"2022","journal-title":"Cell Mol Life Sci"},{"issue":"2","key":"2025090300025735000_bqaf124-B2","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/S0143-4004(05)80257-7","article-title":"Serotonin uptake in the ectoplacental cone and placenta of the mouse","volume":"14","author":"Yavarone","year":"1993","journal-title":"Placenta"},{"issue":"12","key":"2025090300025735000_bqaf124-B3","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1038\/nrn1256","article-title":"The developmental role of serotonin: news from mouse molecular genetics","volume":"4","author":"Gaspar","year":"2003","journal-title":"Nat Rev Neurosci"},{"issue":"1","key":"2025090300025735000_bqaf124-B4","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1073\/pnas.0606722104","article-title":"Maternal serotonin is crucial for murine embryonic development","volume":"104","author":"Cote","year":"2007","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"2","key":"2025090300025735000_bqaf124-B5","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1007\/s004410100408","article-title":"Serotonin and serotonin-like substances as regulators of early embryogenesis and morphogenesis","volume":"305","author":"Buznikov","year":"2001","journal-title":"Cell Tissue Res"},{"issue":"4","key":"2025090300025735000_bqaf124-B6","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1242\/dev.102.4.709","article-title":"Serotonin and morphogenesis. 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