Cfp1 integrates both CpG content and gene activity for accurate H3K4me3 deposition in embryonic stem cells

Thomas Clouaire, Shaun Webb, Pete Skene, Robert Illingworth, Alastair Kerr, Robert Andrews, Jeong Heon Lee, David Skalnik, Adrian Bird

Research output: Contribution to journalArticle

140 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1714-1728
Number of pages15
JournalGenes and Development
Volume26
Issue number15
DOIs
StatePublished - Aug 1 2012

Keywords

  • Cfp1
  • Chromatin
  • CpG islands
  • Epigenetics
  • H3K4me3

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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    Clouaire, T., Webb, S., Skene, P., Illingworth, R., Kerr, A., Andrews, R., Lee, J. H., Skalnik, D., & Bird, A. (2012). Cfp1 integrates both CpG content and gene activity for accurate H3K4me3 deposition in embryonic stem cells. Genes and Development, 26(15), 1714-1728. https://doi.org/10.1101/gad.194209.112