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PMID: 18493325 Published · epublish English Journal Article Research Support, Non-U.S. Gov't

Ubiquitin E3 ligase Ring1b/Rnf2 of polycomb repressive complex 1 contributes to stable maintenance of mouse embryonic stem cells.

PloS one ·Vol. 3 ·No. 5 ·2008-05-21 ·Pages e2235

van der Stoop P, Boutsma EA, Hulsman D, Noback S, Heimerikx M, Kerkhoven RM, Voncken JW, Wessels LF, van Lohuizen M

Abstract

Polycomb repressive complex 1 (PRC1) core member Ring1b/Rnf2, with ubiquitin E3 ligase activity towards histone H2A at lysine 119, is essential for early embryogenesis. To obtain more insight into the role of Ring1b in early development, we studied its function in mouse embryonic stem (ES) cells. We investigated the effects of Ring1b ablation on transcriptional regulation using Ring1b conditional knockout ES cells and large-scale gene expression analysis. The absence of Ring1b results in aberrant expression of key developmental genes and deregulation of specific differentiation-related pathways, including TGFbeta signaling, cell cycle regulation and cellular communication. Moreover, ES cell markers, including Zfp42/Rex-1 and Sox2, are downregulated. Importantly, retained expression of ES cell regulators Oct4, Nanog and alkaline phosphatase indicates that Ring1b-deficient ES cells retain important ES cell specific characteristics. Comparative analysis of our expression profiling data with previously published global binding studies shows that the genes that are bound by Ring1b in ES cells have bivalent histone marks, i.e. both active H3K4me3 and repressive H3K27me3, or the active H3K4me3 histone mark alone and are associated with CpG-'rich' promoters. However, deletion of Ring1b results in deregulation, mainly derepression, of only a subset of these genes, suggesting that additional silencing mechanisms are involved in repression of the other Ring1b bound genes in ES cells. Ring1b is essential to stably maintain an undifferentiated state of mouse ES cells by repressing genes with important roles during differentiation and development. These genes are characterized by high CpG content promoters and bivalent histone marks or the active H3K4me3 histone mark alone.

MeSH Terms
Animals Cells, Cultured CpG Islands DNA-Binding Proteins/genetics,physiology Embryonic Stem Cells/cytology Gene Expression Profiling Histones/metabolism Mice Mice, Knockout Polycomb Repressive Complex 1 Promoter Regions, Genetic Repressor Proteins Ubiquitin/metabolism Ubiquitin-Protein Ligases
Chemicals
DNA-Binding Proteins Histones Repressor Proteins Ubiquitin Polycomb Repressive Complex 1 Rnf2 protein, mouse Ubiquitin-Protein Ligases
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
van der Stoop Petra
Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Boutsma Erwin A
Hulsman Danielle
Noback Sonja
Heimerikx Mike
Kerkhoven Ron M
Voncken J Willem
Wessels Lodewyk F A
van Lohuizen Maarten
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Article Info
Journal
PloS one
Abbr.
PLoS One
ISSN
1932-6203
DOI
10.1371/journal.pone.0002235
Published
2008-05-21
Epub
2008-00-21
Pages
e2235
Language
English
Region
United States
NLM ID
101285081
PMCID
PMC2375055
Subset
IM
External Links
PubMed source DOI: 10.1371/journal.pone.0002235 PMC Full Text View journal details
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