CpG islands and the regulation of transcription

Abstract

Vertebrate CpG islands (CGIs) are short interspersed DNA sequences that deviate significantly from the average genomic pattern by being GC-rich, CpG-rich, and predominantly nonmethylated. Most, perhaps all, CGIs are sites of transcription initiation, including thousands that are remote from currently annotated promoters. Shared DNA sequence features adapt CGIs for promoter function by destabilizing nucleosomes and attracting proteins that create a transcriptionally permissive chromatin state. Silencing of CGI promoters is achieved through dense CpG methylation or polycomb recruitment, again using their distinctive DNA sequence composition. CGIs are therefore generically equipped to influence local chromatin structure and simplify regulation of gene activity.

Figure 1.

The genomic distribution of CGIs. (A) CGIs can be located at annotated TSSs, within gene bodies (Intragenic), or between annotated genes (Intergenic). Intragenic and intergenic CGIs of unknown function are classed as “orphan” CGIs. (Empty circles) Unmethylated CpG residues. (Filled circles) Methylated CpG residues. (B) The genomic distribution of CGIs in the human and mouse genome as determined by Illingworth and colleagues (2010). The total number of CGIs is given at the top of each graph.

Figure 2.

Orphan CGIs are sites of transcriptional initiation. High-throughput sequencing data showing colocalization of orphan CGIs with sites of transcriptional initiation taken from Illingworth et al. (2010). CXXC affinity purification identifies the locations of CGIs that overlap with H3K4me3, RNAPII, GRO-seq (Core et al. 2008), and CAGE tags (Faulkner et al. 2009). Genes (RefSeq) are annotated below the sequencing profiles, with those mapped to the positive and negative strand displayed above and below the chromosome line, respectively. Orphan CGIs are denoted by asterisks.

Figure 3.

Transcription factor-binding sites are, on average, GC-rich. The G+C content of binding sites for 46 mouse transcription factors was calculated using fasta sequences of actual binding sites obtained from the JASPAR database (Bryne et al. 2008). G+C frequency is given on the X-axis, while the Y-axis shows the number of each of these 46 binding sites with a given G+C frequency.

Figure 4.

The chromatin state at CGIs. (A) CGIs usually exist in an unmethylated transcriptionally permissive state. They are marked by histone acetylation (H3/H4Ac) and H3K4me3, which is directed by Cfp1, and show Kdm2a-dependent H3K36me2 depletion. Nucleosome deficiency and constitutive binding of RNAPII may also contribute to this transcriptionally permissive state. (B) DNA methylation is associated with stable long-term silencing of CGI promoters. This can be mediated by MBD proteins, which recruit corepressor complexes associated with HDAC activity, or may be due to directed inhibition of transcription factor binding by DNA methylation. (C) CGIs can also be silenced by PcG proteins and may be key elements involved in polycomb recruitment. An unknown CGI-binding factor could be responsible for recruiting PRC2 to CGIs that then trimethylates H3K27. This H3K27me3 is recognized by PRC1 complexes that act to impede transcriptional elongation, thereby silencing genes. Note that the transcriptionally permissive and polycomb-repressed states can coexist at bivalent CGIs, predominantly in totipotent embryonic cells.