title: CpG islands influence chromatin structure via the CpG-binding protein Cfp1.
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.
authors.affiliation: Wellcome Trust Centre for Cell Biology, Michael Swann Building, University of Edinburgh, Mayfield Road, Edinburgh EH9 3JR, UK.
authors.forename: John P
authors.initials: JP
authors.lastname: Thomson
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Skene
authors.forename: Jim
authors.initials: J
authors.lastname: Selfridge
authors.forename: Thomas
authors.initials: T
authors.lastname: Clouaire
authors.forename: Jacky
authors.initials: J
authors.lastname: Guy
authors.forename: Shaun
authors.initials: S
authors.lastname: Webb
authors.forename: Alastair R W
authors.initials: AR
authors.lastname: Kerr
authors.forename: Aimée
authors.initials: A
authors.lastname: Deaton
authors.forename: Rob
authors.initials: R
authors.lastname: Andrews
authors.forename: Keith D
authors.initials: KD
authors.lastname: James
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Turner
authors.forename: Robert
authors.initials: R
authors.lastname: Illingworth
authors.forename: Adrian
authors.initials: A
authors.lastname: Bird
mesh_terms: D000483:Alleles; D000818:Animals; D001921:Brain / Q000166:cytology; D002460:Cell Line; D002843:Chromatin / Q000235:genetics* / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly; D047369:Chromatin Immunoprecipitation; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D016678:Genome / Q000235:genetics; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D008745:Methylation; D051379:Mice; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic; D015534:Trans-Activators / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016335:Zinc Fingers
chemical_list: D002843:Chromatin; C501971:Cxxc1 protein, mouse; D006657:Histones; D015534:Trans-Activators; D011495:Histone-Lysine N-Methyltransferase
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