Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 113, Issue 44, Pages 12360-12367Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1615540113
Keywords
mRNA translation; 4E-BPs; PTBP; embryonic stem cell; YY2
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Funding
- Canadian Institutes of Health Research CIHR [MOP-142200, MOP-125885, MOP-115090, MOP-111197, MOP-14609]
- CIHR Postdoctoral fellowship
- Richard and Edith Strauss fellowship
- Human Frontier Science Program Long Term Fellowship
- EMBO (European Molecular Biology Organization) Fellowship
- Ontario Institute for Regenerative Medicine Fellowship
- Grants-in-Aid for Scientific Research [16K18444] Funding Source: KAKEN
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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-beta (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.
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