Epigenetic conservation at gene regulatory elements revealed by non-methylated DNA profiling in seven vertebrates.
Epigenetic conservation at gene regulatory elements revealed by non-methylated DNA profiling in seven vertebrates.
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DOI：
10.7554/elife.00348
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发表时间：
2013-02-26
期刊：
影响因子：
7.7
通讯作者：
Klose RJ
中科院分区：
文献类型：
--
作者：
Long HK;Sims D;Heger A;Blackledge NP;Kutter C;Wright ML;Grützner F;Odom DT;Patient R;Ponting CP;Klose RJ
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 DNA methylation—the addition of a methyl group to cytosine, one of the four bases found in DNA—is a central process in genetics. By preventing genes from being expressed as proteins, DNA methylation is one of a number of epigenetic mechanisms that can determine which proteins are made in different cell types without changing the underlying DNA sequence. In warm-blooded vertebrates such as mammals most of the genome is methylated, however short regions of non-methylated DNA are known to be associated with gene promoters (regions of DNA that act as binding sites for the enzymes and transcription factors that transcribe the DNA in the gene into RNA). Much of our current understanding of the role of these islands of non-methylated DNA is based on computational predictions rather than experimental data. In cold-blooded vertebrates, for example, computer models often predict that non-methylated islands are not associated with gene promoters, which potentially suggests an evolutionary divergence in the role of methylation amongst vertebrates. However, this idea has not been confirmed by experimental data. Long et al. have performed experiments to compare the location of non-methylated islands in seven different vertebrate species. In general they find that computational models are not a reliable method for identifying non-methylated islands. Moreover they find that non-methylated islands are a central epigenetic feature of gene promoters in all vertebrates analysed–including three mammals, a bird, a lizard, a frog and a fish—and not just in warm-blooded vertebrates as suggested by computational models. This shows that the epigenetic function of these non-methylated islands has been conserved over more than 450 million years of evolution. In addition to the non-methylated islands associated with gene promoters, Long et al. identify two other types: intergenic non-methylated islands that are found away from gene promoters and are said to be ‘plastic’ because the DNA in these islands can acquire methyl groups, and ‘broad’ non-methylated islands that span many of the genes that are involved in embryonic development. By showing that the epigenetic role of non-methylated islands has been conserved over time, and identifying three specific types of island, the work of Long et al. marks an important change in our understanding of epigenetics in vertebrates. DOI: http://dx.doi.org/10.7554/eLife.00348.002
