The placental DNA methylation landscape is unique, with widespread partially methylated domains (PMDs). The placental "methylome" is conserved across mammals, a shared feature of many cancers, and extensively studied for links with pregnancy complications. Human trophoblast stem cells (hTSCs) offer exciting potential for functional studies to better understand this epigenetic feature; however, whether the hTSC epigenome recapitulates primary trophoblast remains unclear. We find that hTSCs exhibit an atypical methylome compared with trophectoderm and 1st trimester cytotrophoblast. Regardless of cell origin, oxygen levels, or culture conditions, hTSCs show localized DNA methylation within transcribed gene bodies and a complete loss of PMDs. Unlike early human trophoblasts, hTSCs display a notable absence of DNMT3L expression, which is necessary for PMD establishment in mouse trophoblasts. Remarkably, we demonstrate that ectopic expression of DNMT3L in hTSCs restores placental PMDs, supporting a conserved role for DNMT3L in de novo methylation in trophoblast development in human embryogenesis.

Babraham Bioinformatics Babraham Institute Cambridge UK

Centro de Investigación Príncipe Felipe Valencia Spain

Centro de Investigación Príncipe Felipe Valencia Spain; Centro de Biología Molecular Severo Ochoa CSIC UAM Madrid Spain

Department of Development and Regeneration KULeuven Belgium

Faculty of Science University of South Bohemia České Budějovice Czech Republic

Loke Centre for Trophoblast Research University of Cambridge Cambridge UK; Department of Pathology University of Cambridge Cambridge UK

Loke Centre for Trophoblast Research University of Cambridge Cambridge UK; Department of Physiology Development and Neuroscience University of Cambridge Cambridge UK

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