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

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

Author information

1
Department of Trauma Surgery, Center for Clinical Research, University Hospital Zurich, University of Zurich, Sternwartstrasse 14, CH-8091 Zurich, Switzerland.
2
Institute of Laboratory Animal Science, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
3
Life Science Zurich Graduate School, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
4
Department of Molecular Mechanisms of Disease, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
5
Clinic of Reproductive Medicine, University of Zurich, Winterthurerstrasse 260, CH-8057 Zurich, Switzerland.
6
Institute of Molecular Cancer Research, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
7
Scientific IT Services, ETH Zurich, Weinbergstrasse 11, CH-8092 Zurich, Switzerland.
8
Service and Support for Science IT, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
9
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
10
Developmental Genetics Laboratory, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiuro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan.
11
Center for Transgenic Models, University of Basel, Mattenstrasse 22, CH-4002 Basel, Switzerland.
12
Center for Applied Biotechnology and Molecular Medicine, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.

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.

PMID:
28604677
DOI:
10.1038/ncb3554
[Indexed for MEDLINE]

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