Ectopic expression of DNMT3L in human trophoblast stem cells restores features of the placental methylome.
Por:
Lea G, Doria-Borrell P, Ferrero-Micó A, Varma A, Simon C, Anderson H, Biggins L, De Clercq K, Andrews S, Niakan KK, Gahurova L, McGovern N, Pérez-García V and Hanna CW
Publicada:
6 feb 2025
Ahead of Print:
1 feb 2025
Resumen:
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 1 st 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.
Filiaciones:
Lea G:
Loke Centre for Trophoblast Research, University of Cambridge, Cambridge, UK
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
Doria-Borrell P:
Centro de Investigación Príncipe Felipe, Valencia, Spain
Ferrero-Micó A:
Centro de Investigación Príncipe Felipe, Valencia, Spain
Varma A:
Loke Centre for Trophoblast Research, University of Cambridge, Cambridge, UK
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
Simon C:
Loke Centre for Trophoblast Research, University of Cambridge, Cambridge, UK
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
Anderson H:
Loke Centre for Trophoblast Research, University of Cambridge, Cambridge, UK
Department of Pathology, University of Cambridge, Cambridge, UK
Biggins L:
Babraham Bioinformatics, Babraham Institute, Cambridge, UK
De Clercq K:
Department of Development and Regeneration, KULeuven, Belgium
Andrews S:
Babraham Bioinformatics, Babraham Institute, Cambridge, UK
Niakan KK:
Loke Centre for Trophoblast Research, University of Cambridge, Cambridge, UK
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
Gahurova L:
Faculty of Science, University of South Bohemia, Ceské Budejovice, Czech Republic
McGovern N:
Loke Centre for Trophoblast Research, University of Cambridge, Cambridge, UK
Department of Pathology, University of Cambridge, Cambridge, UK
:
Centro de Investigación Príncipe Felipe, Valencia, Spain
Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain
Hanna CW:
Loke Centre for Trophoblast Research, University of Cambridge, Cambridge, UK
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
Green Submitted, hybrid
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