title: Cfp1 integrates both CpG content and gene activity for accurate H3K4me3 deposition in embryonic stem cells.
abstract: Trimethylation of histone H3 Lys 4 (H3K4me3) is a mark of active and poised promoters. The Set1 complex is responsible for most somatic H3K4me3 and contains the conserved subunit CxxC finger protein 1 (Cfp1), which binds to unmethylated CpGs and links H3K4me3 with CpG islands (CGIs). Here we report that Cfp1 plays unanticipated roles in organizing genome-wide H3K4me3 in embryonic stem cells. Cfp1 deficiency caused two contrasting phenotypes: drastic loss of H3K4me3 at expressed CGI-associated genes, with minimal consequences for transcription, and creation of "ectopic" H3K4me3 peaks at numerous regulatory regions. DNA binding by Cfp1 was dispensable for targeting H3K4me3 to active genes but was required to prevent ectopic H3K4me3 peaks. The presence of ectopic peaks at enhancers often coincided with increased expression of nearby genes. This suggests that CpG targeting prevents "leakage" of H3K4me3 to inappropriate chromatin compartments. Our results demonstrate that Cfp1 is a specificity factor that integrates multiple signals, including promoter CpG content and gene activity, to regulate genome-wide patterns of H3K4me3.
authors.affiliation: Wellcome Trust Centre for Cell Biology, University of Edinburgh, United Kingdom.
authors.forename: Thomas
authors.initials: T
authors.lastname: Clouaire
authors.forename: Shaun
authors.initials: S
authors.lastname: Webb
authors.forename: Pete
authors.initials: P
authors.lastname: Skene
authors.forename: Robert
authors.initials: R
authors.lastname: Illingworth
authors.forename: Alastair
authors.initials: A
authors.lastname: Kerr
authors.forename: Robert
authors.initials: R
authors.lastname: Andrews
authors.forename: Jeong-Heon
authors.initials: JH
authors.lastname: Lee
authors.forename: David
authors.initials: D
authors.lastname: Skalnik
authors.forename: Adrian
authors.initials: A
authors.lastname: Bird
mesh_terms: D000818:Animals; D002460:Cell Line; D018899:CpG Islands / Q000502:physiology*; D019175:DNA Methylation; D053595:Embryonic Stem Cells / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D051379:Mice; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: C501971:Cxxc1 protein, mouse; D006657:Histones; D015534:Trans-Activators; D008239:Lysine