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

Wellcome Trust Centre for Cell Biology, University of Edinburgh, United Kingdom.
Genes & development (Impact Factor: 10.8). 08/2012; 26(15):1714-28. DOI: 10.1101/gad.194209.112
Source: PubMed


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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    • "It has been postulated that dedicated proteins might bind selectively, and with high affinity to methylated CpG-rich sequences, and participate in the recruitment of chromatin remodeling repressor complexes to silence target genes (Bartke et al., 2010; Joulie et al., 2010; Fournier et al., 2012; Spruijt et al., 2013). Conversely, active promoters and enhancers acquired chromatin marks, such as histone H3 lysine 4 monomethylation (at enhancers) or trimethylation (at promoters) that prevent the activity of DNMTs (Thomson et al., 2010; Clouaire et al., 2012; Zhou et al., 2012), hence the unmethylated status of most HCP and ICP promoters in the genome (Fig. 2). The recent advances in the field had a significant impact on our understanding of the role of DNA methylation in mammals, the enzymatic machineries involved in its regulation and its impact on gene expression in normal and pathological contexts. "
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    Journal of Cellular Physiology 04/2015; 230(4). DOI:10.1002/jcp.24836 · 3.84 Impact Factor
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    • "Data analysis was performed as described in the materials and methods section. Alterations in H3K4me3 and H3K27ac were investigated, which are markers associated with promoter activation (transcription start site (TSS), H3K4me3 and H3K27ac) and enhancer activation (primarily H3K27ac) [44], [45]. In addition to the analysis of (differential) modification patterns, motif enrichment of the modified regions was investigated and compared between the cell lines. "
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    PLoS ONE 06/2014; 9(6):e98330. DOI:10.1371/journal.pone.0098330 · 3.23 Impact Factor
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    • "H2A.Z and H3.3 were enriched in regulatory elements (i.e., enhancers, insulators, and CGIs; Figure 3, 4, 5). Various chromatin proteins bind to these regions, including the transcription factors, CTCF and Cfp1, which recruit histone modification enzymes [61], [62]. Therefore, H2A.Z and H3.3 might be recruited to these regions to form nucleosomes that are readily accessible to chromatin proteins. "
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