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Ectopic expression of DNMT3L in human trophoblast stem cells restores features of the placental methylome

G. Lea, P. Doria-Borrell, A. Ferrero-Micó, A. Varma, C. Simon, H. Anderson, L. Biggins, K. De Clercq, S. Andrews, KK. Niakan, L. Gahurova, N. McGovern, V. Pérez-García, CW. Hanna

. 2025 ; 32 (2) : 276-292.e9. [pub] 20250108

Language English Country United States

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc25009932

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.

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$a The placental DNA methylation landscape is unique, with widespread partially methylated domains (PMDs). The placental "methylome" is conserved across mammals, a shared feature of many cancers, and extensively studied for links with pregnancy complications. Human trophoblast stem cells (hTSCs) offer exciting potential for functional studies to better understand this epigenetic feature; however, whether the hTSC epigenome recapitulates primary trophoblast remains unclear. We find that hTSCs exhibit an atypical methylome compared with trophectoderm and 1st trimester cytotrophoblast. Regardless of cell origin, oxygen levels, or culture conditions, hTSCs show localized DNA methylation within transcribed gene bodies and a complete loss of PMDs. Unlike early human trophoblasts, hTSCs display a notable absence of DNMT3L expression, which is necessary for PMD establishment in mouse trophoblasts. Remarkably, we demonstrate that ectopic expression of DNMT3L in hTSCs restores placental PMDs, supporting a conserved role for DNMT3L in de novo methylation in trophoblast development in human embryogenesis.
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$a Doria-Borrell, Paula $u Centro de Investigación Príncipe Felipe, Valencia, Spain
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$a Ferrero-Micó, Ana $u Centro de Investigación Príncipe Felipe, Valencia, Spain
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$a Varma, Anakha $u Loke Centre for Trophoblast Research, University of Cambridge, Cambridge, UK; Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
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$a Simon, Claire $u Loke Centre for Trophoblast Research, University of Cambridge, Cambridge, UK; Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
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$a Anderson, Holly $u Loke Centre for Trophoblast Research, University of Cambridge, Cambridge, UK; Department of Pathology, University of Cambridge, Cambridge, UK
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$a Biggins, Laura $u Babraham Bioinformatics, Babraham Institute, Cambridge, UK
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$a De Clercq, Katrien $u Department of Development and Regeneration, KULeuven, Belgium
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$a Andrews, Simon $u Babraham Bioinformatics, Babraham Institute, Cambridge, UK
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$a Niakan, Kathy K $u Loke Centre for Trophoblast Research, University of Cambridge, Cambridge, UK; Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
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$a Gahurova, Lenka $u Faculty of Science, University of South Bohemia, České Budějovice, Czech Republic
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$a McGovern, Naomi $u Loke Centre for Trophoblast Research, University of Cambridge, Cambridge, UK; Department of Pathology, University of Cambridge, Cambridge, UK
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$a Pérez-García, Vicente $u Centro de Investigación Príncipe Felipe, Valencia, Spain; Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain. Electronic address: vperez@cbm.csic.es
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$a Hanna, Courtney W $u Loke Centre for Trophoblast Research, University of Cambridge, Cambridge, UK; Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK. Electronic address: cwh36@cam.ac.uk
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