{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T01:40:01Z","timestamp":1785548401606,"version":"3.56.0"},"posted":{"date-parts":[[2024,1,29]]},"group-title":"Developmental Biology","reference-count":40,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,1,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Early defects in placenta development are thought to underlie a range of adverse pregnancy conditions including miscarriage, fetal growth abnormalities, preeclampsia, and stillbirth. Differentiating trophoblast stem cells undergo a choreographed allocation of syncytiotrophoblast and extravillous trophoblast cells in response to signaling cues from the developing fetus and the uterine environment. The expression and activity of transcription factors and chromatin modifying enzymes change during differentiation to appropriately reshape the chromatin landscape in each cell type. We have previously found in mice that extraembryonic loss of BCOR, a conserved component of the epigenetic silencing complex Polycomb Repressive Complex 1.1 (PRC1.1), leads to a reduced labyrinth and expanded trophoblast giant cell population in the placenta. Molecular analysis of wild-type and BCOR loss-of-function male and female placentas by RNA-seq identified gene expression changes as early as E6.5. We found that BCOR is required to down regulate stem cell genes and repress factors that promote alternate lineages which leads to reduced levels of syncytiotrophoblasts. ChIP-seq experiments identified a number of directly bound functional targets including\n                  <jats:italic>Pdgfa<\/jats:italic>\n                  and\n                  <jats:italic>Wnt7b<\/jats:italic>\n                  . In humans,\n                  <jats:italic>BCOR<\/jats:italic>\n                  is mutated in X-linked syndromes involving fetal growth restriction and females with a heterozygous null mutation in\n                  <jats:italic>BCOR<\/jats:italic>\n                  can experience recurrent miscarriages. To establish a direct role for\n                  <jats:italic>BCOR<\/jats:italic>\n                  in human placental development, we used CRISPR\/Cas9 to knockout\n                  <jats:italic>BCOR<\/jats:italic>\n                  in male (CT29) and female (CT30) human trophoblast stem cells. Mutant cell lines retained capacity for induced differentiation into syncytiotrophoblast and extravillous trophoblasts and exhibited minimal changes in gene expression. However, in 3D cell culture using trophoblast organoid media,\n                  <jats:italic>BCOR<\/jats:italic>\n                  knockout lines had significantly altered gene expression including homologs of stem cell genes upregulated in\n                  <jats:italic>Bcor<\/jats:italic>\n                  knockout mice. CUT&amp;RUN experiments in self-renewing and 3D cell culture identified genes directly bound by BCOR. Single cell profiling of wild type, knockout, and a P85L pathogenic knock-in\n                  <jats:italic>BCOR<\/jats:italic>\n                  mutation showed a reduced capacity to differentiate into syncytiotrophoblasts after four days of differentiation. Together, these results suggest that BCOR is a conserved regulator of trophoblast development that represses stem cell genes during differentiation and maintains lineage fidelity by repressing genes that promote alternate cell fates.\n                <\/jats:p>","DOI":"10.1101\/2024.01.29.577740","type":"posted-content","created":{"date-parts":[[2024,1,29]],"date-time":"2024-01-29T16:50:22Z","timestamp":1706547022000},"source":"Crossref","is-referenced-by-count":1,"title":["Polycomb Repressive Complex 1.1 Component, BCOR, Promotes Syncytiotrophoblast Differentiation in Mice and Humans"],"prefix":"10.64898","author":[{"given":"Danielle","family":"Sadowski","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Connie M.","family":"Corcoran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riyan","family":"Abdi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teng","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Okae","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Arima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivian J.","family":"Bardwell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9873-1930","authenticated-orcid":false,"given":"Micah D.","family":"Gearhart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2024020107200804000_2024.01.29.577740v1.1","doi-asserted-by":"publisher","DOI":"10.2217\/epi-2018-0195"},{"key":"2024020107200804000_2024.01.29.577740v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2736"},{"issue":"1","key":"2024020107200804000_2024.01.29.577740v1.3","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1038\/npp.2015.231","article-title":"The Placenta as a Mediator of Stress Effects on Neurodevelopmental Reprogramming","volume":"41","year":"2016","journal-title":"Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology"},{"key":"2024020107200804000_2024.01.29.577740v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/ng0598-51"},{"issue":"9","key":"2024020107200804000_2024.01.29.577740v1.5","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1007\/s00439-018-1907-y","article-title":"Identification of Likely Pathogenic and Known Variants in TSPEAR, LAMB3, BCOR, and WNT10A in Four Turkish Families with Tooth Agenesis","volume":"137","year":"2018","journal-title":"Human Genetics"},{"key":"2024020107200804000_2024.01.29.577740v1.6","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.176933"},{"key":"2024020107200804000_2024.01.29.577740v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2012.01.002"},{"key":"2024020107200804000_2024.01.29.577740v1.8","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00630-06"},{"key":"2024020107200804000_2024.01.29.577740v1.9","doi-asserted-by":"publisher","DOI":"10.1101\/gad.9.1.1"},{"issue":"1-2","key":"2024020107200804000_2024.01.29.577740v1.10","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.ydbio.2020.06.013","article-title":"OFCD Syndrome and Extraembryonic Defects Are Revealed by Conditional Mutation of the Polycomb-Group Repressive Complex 1.1 (PRC1.1) Gene BCOR","volume":"468","year":"2020","journal-title":"Developmental Biology"},{"key":"2024020107200804000_2024.01.29.577740v1.11","doi-asserted-by":"publisher","DOI":"10.1242\/dev.00721"},{"key":"2024020107200804000_2024.01.29.577740v1.12","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-022-00499-0"},{"issue":"September","key":"2024020107200804000_2024.01.29.577740v1.13","first-page":"190","article-title":"Human Placental Trophoblast Invasion and Differentiation: A Particular Focus on Wnt Signaling","volume":"4","year":"2013","journal-title":"Frontiers in Genetics"},{"key":"2024020107200804000_2024.01.29.577740v1.14","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20182376"},{"issue":"12","key":"2024020107200804000_2024.01.29.577740v1.15","doi-asserted-by":"crossref","first-page":"2872","DOI":"10.1002\/ajmg.a.40640","article-title":"Microphthalmia Is Not a Mandatory Finding in X-Linked Recessive Syndromic Microphthalmia Caused by the Recurrent BCOR Variant p.Pro85Leu","volume":"176","year":"2018","journal-title":"American Journal of Medical Genetics. 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