CpG islands influence chromatin structure via the CpG-binding protein Cfp1

By J. Thomson, P. Skene, Jim Selfridge, T. Clouaire, Jacky Guy, Shaun Webb, Alastair R W Kerr, A. Deaton, R. Andrews, K. James and 3 more. Nature, 2010

666 citations recorded by the source corpus.

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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/30373596c7783a43f7caca6fd9c86763343cd971

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In Molecular Biology

1. Yi Zhang
2. Hao Wu
3. A. Bird
4. Manel Esteller
5. Wolf Reik
6. Keith D. Robertson
7. D. Reinberg
8. Luciano Di Croce

Citations in the corpus

• R-loop formation is a distinctive characteristic of unmethylated human CpG island promoters (2012, positive): “Additional recruitment of H3K4me3 to unmethylated CGIs by the CFP1 protein (Thomson et al., 2010) may enable the maintenance of an unmethylated state irrespective of the transcriptional activity of a given promoter in differentiated somatic tissues.”
• DeepCpG: accurate prediction of single-cell DNA methylation states using deep learning (2016, background): “Consistent with previous findings [16, 40, 41], we observed that motifs associated with decreased methylation tended to be CG-rich and were most active in CG-rich promoter regions, transcription start sites, as well as in contexts with active promoter marks such as H3K4me3 and p300 sites (Additional”
• DNA Methylation and Its Basic Function (2013, background): “Cfp1 is a component of the H3K4 methyltransferase complex that targets unmethylated CpG sites often found at murine CpG islands and may play a role in maintaining their hypomethylation (Lee and Skalnik, 2005; Thomson et al, 2010).”
• Charting histone modifications and the functional organization of mammalian genomes (2011, background): “It was recently shown that introducing artificial, promoterless CpG clusters into mouse ES cells was sufficient to recruit the SET1 histone methyltransferase complex and establish H3K4me3 (Ref”
• CpG islands and the regulation of transcription. (2011, positive): “Paradoxically, CpG richness by itself attracts protein complexes that promote H3K4me3 (Thomson et al. 2010), but G+C-rich DNA also recruits H3K27me3 (Mendenhall et al.”
• DNA methylation: superior or subordinate in the epigenetic hierarchy? (2011, background): “High-throughput next-generation sequencing of Cfp1bound chromatin identified a notable concordance between unmethylated CGIs and sites of H3K4me3 in the mouse brain.(53) Levels of H3K4me3 at CGIs are markedly reduced in Cfp1depleted cells, consistent with the finding that CFP1 associates with the H3”
• Epigenetic modifications and human disease (2010, background): “In contrast, unmethylated CpG islands generate a chromatin structure favorable for gene expression by recruiting Cfp1, which associates with histone methyltransferase Setd1, creating domains rich in the histone methylation mark H3K4 trimethylation (H3K4me3; see below”
• Genome Regulation by Polycomb and Trithorax: 70 Years and Counting. (2017, positive): “Moreover, SET1/COMPASS complexes can be recruited to CGIs via their interaction with another CxxC-domain-containing protein, CFP1 (also known as CXXC1), that specifically associates with nonmethylated CGIs (Thomson et al., 2010) (Figure 3A).”
• DNA methylation aging clocks: challenges and recommendations (2019, background): “The co-ordinated nature of the epigenomic machinery through both chromatin modifications and DNA methylation [141, 142], as well as experimental evidence from chromatin regulators, such as DOTL1 [143], implies that aging chromatin clocks could also exist, although without the ease of assay and highl”
• Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidation. (2011, background): “…that, at a majority of CGIs, Cfp1 promotes trimethylation of Lys 4 on histone H3 (H3K4me3) via recruitment of the H3K4me3 methyltransferase Setd1 (Thomson et al. 2010), Kdm2a reduces the level of H3K36me2 (Blackledge et al. 2010), and Tet1 maintains a DNA hypomethylated state by actively…”
• Mechanisms and consequences of alternative polyadenylation (2011, neutral): “The latter case would be analogous to the mechanism by which recognition of H3K4me3 by CHD1 functions, at the 50 ends of actively transcribed genes, to recruit core spliceosomal components, therefore facilitating the efficiency of pre-mRNA splicing (Sims et al., 2007).”