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

Proc Natl Acad Sci U S A. 2016 Nov 1;113(44):12360-12367. doi: 10.1073/pnas.1615540113. Epub 2016 Oct 24.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing / physiology*
  • Animals
  • Blastocyst / metabolism
  • Carrier Proteins / metabolism
  • Cell Differentiation*
  • Cell Lineage
  • Cell Self Renewal / genetics
  • Cell Self Renewal / physiology*
  • Embryonic Stem Cells / metabolism*
  • Gene Expression Regulation, Developmental*
  • Heterogeneous-Nuclear Ribonucleoproteins / genetics
  • Introns
  • Mice
  • Mice, Knockout
  • Models, Biological
  • Octamer Transcription Factor-3 / metabolism
  • Phosphoproteins
  • Polypyrimidine Tract-Binding Protein / genetics
  • Protein Biosynthesis / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Receptors, Estrogen / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic / physiology
  • YY1 Transcription Factor / metabolism

Substances

  • Carrier Proteins
  • Esrrb protein, mouse
  • Heterogeneous-Nuclear Ribonucleoproteins
  • Octamer Transcription Factor-3
  • Phosphoproteins
  • Pou5f1 protein, mouse
  • Ptbp1 protein, mouse
  • RNA, Messenger
  • RNA, Small Interfering
  • Receptors, Estrogen
  • Transcription Factors
  • YY1 Transcription Factor
  • YY2 protein, mouse
  • Yy1 protein, mouse
  • Polypyrimidine Tract-Binding Protein