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

Letter

Nature 464, 1082-1086 (15 April 2010) | doi:10.1038/nature08924; Received 2 October 2009; Accepted 15 February 2010

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

John P. Thomson1,3, Peter J. Skene1,3, Jim Selfridge1, Thomas Clouaire1, Jacky Guy1, Shaun Webb1, Alastair R. W. Kerr1, Aimée Deaton1, Rob Andrews2, Keith D. James2, Daniel J. Turner2, Robert Illingworth1 & Adrian Bird1

1. Wellcome Trust Centre for Cell Biology, Michael Swann Building, University of Edinburgh, Mayfield Road, Edinburgh EH9 3JR, UK
2. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK
3. These authors contributed equally to this work.

Correspondence to: Adrian Bird1 Correspondence and requests for materials should be addressed to A.B. (Email: a.bird@ed.ac.uk).

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Abstract

CpG islands (CGIs) are prominent in the mammalian genome owing to their GC-rich base composition and high density of CpG dinucleotides1, 2. 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 activity3, 4. 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 vitro5, 6. 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.