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

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 g...

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Vydáno v:Nature cell biology Ročník 19; číslo 7; s. 763 - 773
Hlavní autoři: 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
Médium: Journal Article
Jazyk:angličtina
Vydáno: London Nature Publishing Group UK 01.07.2017
Nature Publishing Group
Témata:
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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, 1476-4679
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Shrnutí: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.
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:1465-7392
1476-4679
1476-4679
DOI:10.1038/ncb3554