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

• Published in: Nature cell biology Vol. 19; no. 7; pp. 763 - 773
• Main Authors: Graf, Urs, Casanova, Elisa A., Wyck, Sarah, Dalcher, Damian, Gatti, Marco, Vollenweider, Eva, Okoniewski, Michal J., Weber, Fabienne A., Patel, Sameera S., Schmid, Marc W., Li, Jiwen, Sharif, Jafar, Wanner, Guido A., Koseki, Haruhiko, Wong, Jiemin, Pelczar, Pawel, Penengo, Lorenza, Santoro, Raffaella, Cinelli, Paolo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2017; Nature Publishing Group
• Subjects: 13/100; 13/51; 38/111; 38/47; 38/88; 38/91; 631/136/2086; 631/532/2064; 631/532/2117; 631/80/474/2085; Analysis; Animals; Antigens, Neoplasm - genetics; Antigens, Neoplasm - metabolism; Blastocyst - cytology; Blastocyst - enzymology; Cancer Research; Cell Biology; Cell culture; Cell regulation; Cullin Proteins - metabolism; Deoxyribonucleic acid; Developmental Biology; DNA; DNA Methylation; Embryo cells; Embryonic stem cells; Embryonic Stem Cells - enzymology; Embryos; Epigenesis, Genetic; Epigenetic inheritance; Gene expression; Gene Expression Regulation, Developmental; Ground state; HEK293 Cells; Humans; Immortalization; In vitro methods and tests; Life Sciences; Locks; Mice, Inbred C57BL; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Phenotype; Pluripotency; Pluripotent Stem Cells - enzymology; Proteasome Endopeptidase Complex - metabolism; Proteasomes; Protein Interaction Domains and Motifs; Protein Stability; Proteolysis; RNA Interference; Stem Cells; Time Factors; Transcriptome; Transfection; Ubiquitin-proteasome system; Switzerland
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/ncb3554

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. Graf et al.  demonstrate that Pramel7 maintains ground-state pluripotency by repressing DNA methylation through proteasomal degradation of UHRF1, thus linking the proteasome and epigenetics with cell fate regulation.