Cfp1 integrates both CpG content and gene activity for accurate H3K4me3 deposition in embryonic stem cells
- Thomas Clouaire1,
- Shaun Webb1,
- Pete Skene1,
- Robert Illingworth1,
- Alastair Kerr1,
- Robert Andrews2,
- Jeong-Heon Lee3,
- David Skalnik4 and
- Adrian Bird1,5
- 1Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3JR, United Kingdom;
- 2Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom;
- 3Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA;
- 4Biology Department, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana 46202, USA
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.
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Footnotes
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↵5 Corresponding author
E-mail a.bird{at}ed.ac.uk
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.194209.112.
- Received April 13, 2012.
- Accepted June 21, 2012.
- Copyright © 2012 by Cold Spring Harbor Laboratory Press
Freely available online through the Genes & Development Open Access option.