Control of embryonic stem cells self-renewal and differentiation via coordinated splicing and translation of YY2

Soroush Tahmasebi Tahmasebi, Seyed Mehdi Jafarnejad, Ingrid S. Tam, Thomas Gonatopoulos-Pournatzis, Edna Matta-Camacho, Yoshinori Tsukumo, Akiko Yanagiya, Wencheng Li, Yaser Atlasi, Maxime Caron, Ulrich Braunschweig, Dana Pearl, Arkady Khoutorsky, Christos Gkogkas, Robert Nadon, Guillaume Bourque, Xiang-Jiao Yang, Bin Tian, Hendrik G. Stunnenberg, Yojiro YamanakaBenjamin J. Blencowe, Vincent Giguère, Nahum Sonenberg

Research output: Contribution to journalArticlepeer-review

Abstract

Translational control of gene expression plays a key role during the early phases of embryonic development. Here we describe a transcriptional regulator of mouse embryonic stem cells (mESCs), Yin-yang 2 (YY2), that is controlled by the translation inhibitors, Eukaryotic initiation factor 4E-binding proteins (4E-BPs). YY2 plays a critical role in regulating mESC functions through control of key pluripotency factors, including Octamer-binding protein 4 (Oct4) and Estrogen-related receptor-β (Esrrb). Importantly, overexpression of YY2 directs the differentiation of mESCs into cardiovascular lineages. We show that the splicing regulator Polypyrimidine tract-binding protein 1 (PTBP1) promotes the retention of an intron in the 5′-UTR of Yy2 mRNA that confers sensitivity to 4E-BP–mediated translational suppression. Thus, we conclude that YY2 is a major regulator of mESC self-renewal and lineage commitment and document a multilayer regulatory mechanism that controls its expression.
Original languageEnglish
Pages (from-to)12360–12367
JournalProceedings of the National Academy of Sciences
Early online date24 Oct 2016
DOIs
Publication statusPublished - Nov 2016

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