Pramel7 mediates ground-state pluripotency through proteasomal-epigenetic combined pathways.
Nat Cell Biol
; 19(7): 763-773, 2017 Jul.
Article
em En
| MEDLINE
| ID: mdl-28604677
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Blastocisto
/
Proteínas Nucleares
/
Células-Tronco Pluripotentes
/
Epigênese Genética
/
Complexo de Endopeptidases do Proteassoma
/
Células-Tronco Embrionárias
/
Antígenos de Neoplasias
/
Proteínas de Neoplasias
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article