title: NuRD suppresses pluripotency gene expression to promote transcriptional heterogeneity and lineage commitment.
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.
authors.affiliation: Wellcome Trust Centre for Stem Cell Research, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
authors.forename: Nicola
authors.initials: N
authors.lastname: Reynolds
authors.forename: Paulina
authors.initials: P
authors.lastname: Latos
authors.forename: Antony
authors.initials: A
authors.lastname: Hynes-Allen
authors.forename: Remco
authors.initials: R
authors.lastname: Loos
authors.forename: Donna
authors.initials: D
authors.lastname: Leaford
authors.forename: Aoife
authors.initials: A
authors.lastname: O'Shaughnessy
authors.forename: Olukunbi
authors.initials: O
authors.lastname: Mosaku
authors.forename: Jason
authors.initials: J
authors.lastname: Signolet
authors.forename: Philip
authors.initials: P
authors.lastname: Brennecke
authors.forename: Tüzer
authors.initials: T
authors.lastname: Kalkan
authors.forename: Ita
authors.initials: I
authors.lastname: Costello
authors.forename: Peter
authors.initials: P
authors.lastname: Humphreys
authors.forename: William
authors.initials: W
authors.lastname: Mansfield
authors.forename: Kentaro
authors.initials: K
authors.lastname: Nakagawa
authors.forename: John
authors.initials: J
authors.lastname: Strouboulis
authors.forename: Axel
authors.initials: A
authors.lastname: Behrens
authors.forename: Paul
authors.initials: P
authors.lastname: Bertone
authors.forename: Brian
authors.initials: B
authors.lastname: Hendrich
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics; D053595:Embryonic Stem Cells / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D018740:Genetic Heterogeneity; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D039904:Pluripotent Stem Cells / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C492013:Mbd3 protein, mouse; D014157:Transcription Factors; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex