Project description:DNA methylation is essential for mammalian development. Studies of the catalytically inactive DNA methyltransferase Dnmt3l have mainly been limited to mice where Dnmt3l was shown to be essential for fertility, de novo DNA methylation in early embryos and maintenance of DNA methylation patterns in mouse pluripotent stem cells. Recent work revealed that DNMT3L is the most highly enriched chromatin factor in naive human pluripotent stem cells (hPSCs) compared with primed hPSCs. Stem cell-based human embryo models and naive hPSCs provide a unique opportunity to functionally dissect human developmental mechanisms. Here we use naive hPSCs and human blastoids, a 3D human blastocyst model, to investigate the functional impact of DNMT3L on human naive pluripotency and preimplantation development. We demonstrate an essential role of DNMT3L in trophectoderm cell fate induction, maintenance of DNA methylation patterns and chromatin states in naive hPSCs, and blastoid lineage identity. We further show that DNMT3L promotes reprogramming to naive pluripotency, and has integrated a hominoid-specific naive human pluripotency gene regulatory program involving evolutionary recent transposable elements. Therefore, DNMT3L plays conserved and hominoid-specific functions in human naive pluripotency and pre-implantation development.
