| Literature DB >> 28604677 |
Urs Graf1,2,3, Elisa A Casanova1, Sarah Wyck3,4,5, Damian Dalcher3,4, Marco Gatti6, Eva Vollenweider3,4, Michal J Okoniewski7, Fabienne A Weber2,3, Sameera S Patel2,3, Marc W Schmid8, Jiwen Li9, Jafar Sharif10, Guido A Wanner1, Haruhiko Koseki10, Jiemin Wong9, Pawel Pelczar11, Lorenza Penengo6, Raffaella Santoro4,12, Paolo Cinelli1,2,12.
Abstract
Naive pluripotency is established in preimplantation epiblast. Embryonic stem cells (ESCs) represent the immortalization of naive pluripotency. 2i culture has optimized this state, leading to a gene signature and DNA hypomethylation closely comparable to preimplantation epiblast, the developmental ground state. Here we show that Pramel7 (PRAME-like 7), a protein highly expressed in the inner cell mass (ICM) but expressed at low levels in ESCs, targets for proteasomal degradation UHRF1, a key factor for DNA methylation maintenance. Increasing Pramel7 expression in serum-cultured ESCs promotes a preimplantation epiblast-like gene signature, reduces UHRF1 levels and causes global DNA hypomethylation. Pramel7 is required for blastocyst formation and its forced expression locks ESCs in pluripotency. Pramel7/UHRF1 expression is mutually exclusive in ICMs whereas Pramel7-knockout embryos express high levels of UHRF1. Our data reveal an as-yet-unappreciated dynamic nature of DNA methylation through proteasome pathways and offer insights that might help to improve ESC culture to reproduce in vitro the in vivo ground-state pluripotency.Entities:
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Year: 2017 PMID： 28604677 DOI： 10.1038/ncb3554
Source DB: PubMed Journal: Nat Cell Biol ISSN： 1465-7392 Impact factor: 28.824