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PMID: 21149390 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

LSH and G9a/GLP complex are required for developmentally programmed DNA methylation.

Genome research ·Vol. 21 ·No. 1 ·2011-01-00 ·Pages 83-94

Myant K, Termanis A, Sundaram AY, Boe T, Li C, Merusi C, Burrage J, de Las Heras JI, Stancheva I

Abstract

LSH, a member of the SNF2 family of chromatin remodeling ATPases encoded by the Hells gene, is essential for normal levels of DNA methylation in the mammalian genome. While the role of LSH in the methylation of repetitive DNA sequences is well characterized, its contribution to the regulation of DNA methylation and the expression of protein-coding genes has not been studied in detail. In this report we investigate genome-wide patterns of DNA methylation at gene promoters in Hells(-/-) mouse embryonic fibroblasts (MEFs). We find that in the absence of LSH, DNA methylation is lost or significantly reduced at ∼20% of all normally methylated promoter sequences. As a consequence, a large number of genes are misexpressed in Hells(-/-) MEFs. Comparison of Hells(-/-) MEFs with wild-type MEFs and embryonic stem (ES) cells suggests that LSH is important for de novo DNA methylation events that accompany the establishment and differentiation of embryonic lineage cells. We further show that the generation of normal DNA methylation patterns and stable gene silencing at specific promoters require cooperation between LSH and the G9a/GLP complex of histone methylases. At such loci, G9a recruitment is compromised when LSH is absent or greatly reduced. Taken together, our data suggest a mechanism whereby LSH promotes binding of DNA methyltransferases and the G9a/GLP complex to specific loci and facilitates developmentally programmed DNA methylation and stable gene silencing during lineage commitment and differentiation.

MeSH Terms
Animals Cell Differentiation Cells, Cultured DNA Helicases/genetics,metabolism DNA Methylation Embryonic Stem Cells/cytology,metabolism Fibroblasts/metabolism Gene Expression Regulation, Developmental Gene Silencing Histone-Lysine N-Methyltransferase/genetics,metabolism Methyltransferases/genetics,metabolism Mice
Chemicals
Methyltransferases G9a protein, mouse GLP protein, mouse Histone-Lysine N-Methyltransferase DNA Helicases lymphoid specific helicase, mouse
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Myant Kevin
Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3JR, United Kingdom.
Termanis Ausma
Sundaram Arvind Y M
Boe Tristin
Li Chao
Merusi Cara
Burrage Joe
de Las Heras Jose I
Stancheva Irina
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Article Info
Journal
Genome research
Abbr.
Genome Res
ISSN
1549-5469
DOI
10.1101/gr.108498.110
Published
2011-01-00
Epub
2010-00-13
Pages
83-94
Language
English
Region
United States
NLM ID
9518021
PMCID
PMC3012929
Subset
IM
Grants
Wellcome Trust · United Kingdom
Cancer Research UK · 8983 · United Kingdom
Biotechnology and Biological Sciences Research Council · United Kingdom
Cancer Research UK · C7215/A4399 · United Kingdom
Cancer Research UK · C7215/A8983 · United Kingdom
External Links
PubMed source DOI: 10.1101/gr.108498.110 PMC Full Text View journal details
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