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. 2017 Jul;19(7):763-773.
doi: 10.1038/ncb3554. Epub 2017 Jun 12.

Pramel7 mediates ground-state pluripotency through proteasomal-epigenetic combined pathways

Urs Graf  1   2   3 , Elisa A Casanova  1 , Sarah Wyck  3   4   5 , Damian Dalcher  3   4 , Marco Gatti  6 , Eva Vollenweider  3   4 , Michal J Okoniewski  7 , Fabienne A Weber  2   3 , Sameera S Patel  2   3 , Marc W Schmid  8 , Jiwen Li  9 , Jafar Sharif  10 , Guido A Wanner  1 , Haruhiko Koseki  10 , Jiemin Wong  9 , Pawel Pelczar  11 , Lorenza Penengo  6 , Raffaella Santoro  4   12 , Paolo Cinelli  1   2   12
Affiliations

Pramel7 mediates ground-state pluripotency through proteasomal-epigenetic combined pathways

Urs Graf et al. Nat Cell Biol. 2017 Jul.

Erratum in

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.

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