NuRD suppresses pluripotency gene expression to promote transcriptional heterogeneity and lineage commitment

Nicola Reynolds, Paulina Latos, Antony Hynes-Allen, Remco Loos, Donna Leaford, Aoife O'Shaughnessy, Olukunbi Mosaku, Jason Signolet, Philip Brennecke, Tüzer Kalkan, Ita Costello, Peter Humphreys, William Mansfield, Kentaro Nakagawa, John Strouboulis, Axel Behrens, Paul Bertone, Brian Hendrich

Research output: Contribution to journalArticlepeer-review

171 Citations (Scopus)

Abstract

Transcriptional heterogeneity within embryonic stem cell (ESC) populations has been suggested as a mechanism by which a seemingly homogeneous cell population can initiate differentiation into an array of different cell types. Chromatin remodeling proteins have been shown to control transcriptional variability in yeast and to be important for mammalian ESC lineage commitment. Here we show that the Nucleosome Remodeling and Deacetylation (NuRD) complex, which is required for ESC lineage commitment, modulates both transcriptional heterogeneity and the dynamic range of a set of pluripotency genes in ESCs. In self-renewing conditions, the influence of NuRD at these genes is balanced by the opposing action of self-renewal factors. Upon loss of self-renewal factors, the action of NuRD is sufficient to silence transcription of these pluripotency genes, allowing cells to exit self-renewal. We propose that modulation of transcription levels by NuRD is key to maintaining the differentiation responsiveness of pluripotent cells.

Original languageEnglish
Pages (from-to)583-94
Number of pages12
JournalCell stem cell
Volume10
Issue number5
DOIs
Publication statusPublished - 4 May 2012

Keywords

  • Animals
  • Cell Differentiation/genetics
  • Cell Lineage/genetics
  • Cells, Cultured
  • DNA-Binding Proteins/genetics
  • Embryonic Stem Cells/physiology
  • Gene Expression Regulation, Developmental
  • Genetic Heterogeneity
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex/genetics
  • Mice
  • Mice, Knockout
  • Pluripotent Stem Cells/physiology
  • Transcription Factors/genetics

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