Epigenetic conservation at gene regulatory elements revealed by non-methylated DNA profiling in seven vertebrates

Abstract

Two-thirds of gene promoters in mammals are associated with regions of non-methylated DNA, called CpG islands (CGIs), which counteract the repressive effects of DNA methylation on chromatin. In cold-blooded vertebrates, computational CGI predictions often reside away from gene promoters, suggesting a major divergence in gene promoter architecture across vertebrates. By experimentally identifying non-methylated DNA in the genomes of seven diverse vertebrates, we instead reveal that non-methylated islands (NMIs) of DNA are a central feature of vertebrate gene promoters. Furthermore, NMIs are present at orthologous genes across vast evolutionary distances, revealing a surprising level of conservation in this epigenetic feature. By profiling NMIs in different tissues and developmental stages we uncover a unifying set of features that are central to the function of NMIs in vertebrates. Together these findings demonstrate an ancient logic for NMI usage at gene promoters and reveal an unprecedented level of epigenetic conservation across vertebrate evolution.DOI: http://dx.doi.org/10.7554/eLife.00348.001

Short sequences can efficiently recruit histone H3 lysine 27 trimethylation in the absence of enhancer activity and DNA methylation

“…Additionally, we demonstrate that DNA methylation inhibits H3K27me3 deposition at CpG-rich sequences and that this inhibition can be reversed upon chemical removal of DNA methylation. These observations readily explain the occupancy of H3K27me3 and DNA methylation observed throughout the genome (23,24,33,34). They extend previous studies that already suggested a role for CpG dinucleotides in PRC2 recruitment (22,23) but are also more comprehensive and provide novel mechanistic details.…”

“…Thus, loss of Polycomb recruitment coincides with increased susceptibility to DNA methylation. This finding is compatible with the observation of increased H3K27 methylation upon global loss of DNA methylation (23,24,33,34), which we also observe in our genome-wide datasets (Fig. S7A).…”

“…In mammals, PRC2 and the H3K27me3 mark localize mainly to transcriptionally inactive regions rich in CpG dinucleotides, referred to as CpG-islands (CGIs) (20)(21)(22)(23). CGIs are unique to vertebrate genomes that show global DNA methylation (24). These regulatory regions make up two-thirds of all promoters and are under high selection for the presence of regulatory motifs more complex than CG, which are occupied by TFs (25).…”

DNA methyltransferase 3B regulates duration of neural crest production via repression of Sox10

“…Our NanoString and in situ data raise the intriguing possibility that DNMT3B could regulate de novo methylation and subsequent repression of genes involved in the maintenance of neural crest progenitors and EMT, thus preventing continuous neural crest formation. CpG island promoters were recently shown to be largely hypomethylated, even when silenced on different tissues and developmental stages in many vertebrate models (19); thus, we examined the presence of CpG islands in the promoter 0DNMT3B). Treated embryos were characterized as having a strong or a mild prolonged emigration phenotype using the Sox10 marker.…”

Promoter architectures and developmental gene regulation

“…promoters seems substantially lower in amphibians and fish [10]. However, this is likely due to the fact that the definition of the CpG island relies on arbitrary thresholds set upon C+G content, observed over expected ratio of CpG dinucleotide counts and region length [11], which have been optimised for mammalian genomes and do not perform well for genomes with very different nucleotide composition.…”