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Proc Natl Acad Sci U S A. 2016 Nov 1;113(44):12360-12367. Epub 2016 Oct 24.

Control of embryonic stem cell self-renewal and differentiation via coordinated alternative splicing and translation of YY2.

Author information

1
Goodman Cancer Research Center, McGill University, Montreal, QC H3A 1A3, Canada.
2
Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada.
3
Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
4
Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers New Jersey Medical School, Newark, NJ 07103.
5
Department of Molecular Biology, Faculty of Science, Radboud University, Nijmegen, 6525GA, The Netherlands.
6
Department of Human Genetics, McGill University, Montreal, QC H3A 1A3, Canada.
7
McGill University and Genome Quebec Innovation Centre, Montreal, QC H3A 0G1, Canada.
8
Department of Anesthesia, McGill University, Montreal, QC, H3G 1Y6, Canada.
9
Patrick Wild Centre, Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XD, United Kingdom.
10
Department of Medicine, McGill University Health Center, Montreal, QC H3A 1A3, Canada.
11
Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
12
Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada; nahum.sonenberg@mcgill.ca.

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.

KEYWORDS:

4E-BPs; PTBP; YY2; embryonic stem cell; mRNA translation

PMID:
27791185
PMCID:
PMC5098618
DOI:
10.1073/pnas.1615540113
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no conflict of interest.

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