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.
Highlights
Short contiguous regions of non-methylated DNA are found associated with most human and mouse gene promoters, where they create a transcriptionally permissive chromatin environment (Blackledge et al, 2010; Thomson et al, 2010; Blackledge and Klose, 2011; Deaton and Bird, 2011; Jones, 2012) that opposes the repressive effects of DNA methylation (Klose and Bird, 2006; Weber and Schubeler, 2007)
In order to understand whether the prevailing views about non-methylated DNA function and proposed divergence amongst vertebrate species based on CpG islands (CGIs) prediction are correct, we isolated genomic
Using these new experimentally identified non-methylated island (NMI) maps we initially examined the location of non-methylated DNA across vertebrate genomes by visualising syntenic regions shared among all seven species (Figure 1A and Figure 1—figure supplement 1A and B)
Summary
Short contiguous regions of non-methylated DNA are found associated with most human and mouse gene promoters, where they create a transcriptionally permissive chromatin environment (Blackledge et al, 2010; Thomson et al, 2010; Blackledge and Klose, 2011; Deaton and Bird, 2011; Jones, 2012) that opposes the repressive effects of DNA methylation (Klose and Bird, 2006; Weber and Schubeler, 2007). In non-methylated regions, CpG dinucleotide frequency is elevated compared to surrounding sequence (Bird et al, 1985; Bird, 1987). Taking advantage of the methylation-dependent variations in nucleotide frequency observed in mammals, algorithms were developed to predict non-methylated regions of DNA based primarily on elevated local G+C content and CpG dinucleotide frequency (Gardiner-Garden and Frommer, 1987; Takai and Jones, 2002). For more than two decades, CpG island (CGI) predictions (and other nucleotide-based analyses; Saxonov et al, 2006) have been used as a proxy for non-methylated DNA in vertebrate comparative
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