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CpG islands influence chromatin structure via the CpG-binding protein Cfp1.

TitleCpG islands influence chromatin structure via the CpG-binding protein Cfp1.
Publication TypeJournal Article
Year of Publication2010
AuthorsThomson JP, Skene PJ, Selfridge J, Clouaire T, Guy J, Webb S, Kerr ARW, Deaton A, Andrews R, James KD, Turner DJ, Illingworth R, Bird A
JournalNature
Volume464
Issue7291
Pagination1082-6
Date Published2010 Apr 15
ISSN1476-4687
KeywordsAlleles, Animals, Brain, Cell Line, Chromatin, Chromatin Assembly and Disassembly, Chromatin Immunoprecipitation, CpG Islands, DNA Methylation, Genome, Histone-Lysine N-Methyltransferase, Histones, Methylation, Mice, NIH 3T3 Cells, Promoter Regions, Genetic, Trans-Activators, Zinc Fingers
Abstract

CpG islands (CGIs) are prominent in the mammalian genome owing to their GC-rich base composition and high density of CpG dinucleotides. Most human gene promoters are embedded within CGIs that lack DNA methylation and coincide with sites of histone H3 lysine 4 trimethylation (H3K4me3), irrespective of transcriptional activity. In spite of these intriguing correlations, the functional significance of non-methylated CGI sequences with respect to chromatin structure and transcription is unknown. By performing a search for proteins that are common to all CGIs, here we show high enrichment for Cfp1, which selectively binds to non-methylated CpGs in vitro. Chromatin immunoprecipitation of a mono-allelically methylated CGI confirmed that Cfp1 specifically associates with non-methylated CpG sites in vivo. High throughput sequencing of Cfp1-bound chromatin identified a notable concordance with non-methylated CGIs and sites of H3K4me3 in the mouse brain. Levels of H3K4me3 at CGIs were markedly reduced in Cfp1-depleted cells, consistent with the finding that Cfp1 associates with the H3K4 methyltransferase Setd1 (refs 7, 8). To test whether non-methylated CpG-dense sequences are sufficient to establish domains of H3K4me3, we analysed artificial CpG clusters that were integrated into the mouse genome. Despite the absence of promoters, the insertions recruited Cfp1 and created new peaks of H3K4me3. The data indicate that a primary function of non-methylated CGIs is to genetically influence the local chromatin modification state by interaction with Cfp1 and perhaps other CpG-binding proteins.

DOI10.1038/nature08924
Alternate JournalNature
PubMed ID20393567
PubMed Central IDPMC3730110
Grant List / / Medical Research Council / United Kingdom
091580 / / Wellcome Trust / United Kingdom
098051 / / Wellcome Trust / United Kingdom
079643 / / Wellcome Trust / United Kingdom
/ / Cancer Research UK / United Kingdom
G0800026 / / Medical Research Council / United Kingdom
/ / Wellcome Trust / United Kingdom
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