Abstract
BackgroundUncovering mechanisms of epigenome evolution is an essential step towards understanding the evolution of different cellular phenotypes. While studies have confirmed DNA methylation as a conserved epigenetic mechanism in mammalian development, little is known about the conservation of tissue-specific genome-wide DNA methylation patterns.ResultsUsing a comparative epigenomics approach, we identified and compared the tissue-specific DNA methylation patterns of rat against those of mouse and human across three shared tissue types. We confirmed that tissue-specific differentially methylated regions are strongly associated with tissue-specific regulatory elements. Comparisons between species revealed that at a minimum 11-37% of tissue-specific DNA methylation patterns are conserved, a phenomenon that we define as epigenetic conservation. Conserved DNA methylation is accompanied by conservation of other epigenetic marks including histone modifications. Although a significant amount of locus-specific methylation is epigenetically conserved, the majority of tissue-specific DNA methylation is not conserved across the species and tissue types that we investigated. Examination of the genetic underpinning of epigenetic conservation suggests that primary sequence conservation is a driving force behind epigenetic conservation. In contrast, evolutionary dynamics of tissue-specific DNA methylation are best explained by the maintenance or turnover of binding sites for important transcription factors.ConclusionsOur study extends the limited literature of comparative epigenomics and suggests a new paradigm for epigenetic conservation without genetic conservation through analysis of transcription factor binding sites.
Highlights
Uncovering mechanisms of epigenome evolution is an essential step towards understanding the evolution of different cellular phenotypes
Up to 37% of rat tissue-specific differentially methylated regions are epigenetically conserved in mouse and human We first produced DNA methylomes from three rat tissues using two complementary, sequencing-based technologies (Methylated DNA immunoprecipitation followed by sequencing (MeDIPseq)) and methyl-sensitive restriction enzyme digestion followed by sequencing (MRE-seq)) [9, 27]
Previous research has indicated that the majority of tissue-specific differentially methylated regions (tsDMRs) are hypomethylated rather than hypermethylated in their respective tissues [26], so we focused our analysis on hypomethylated tsDMRs
Summary
Uncovering mechanisms of epigenome evolution is an essential step towards understanding the evolution of different cellular phenotypes. Using pluripotent stem cells of humans, mice, and pigs, Xiao et al discovered strong epigenomic conservation in both rapidly evolving and slowly evolving DNA sequences, but not in neutrally evolving DNA sequences [10] These conserved epigenomic modifications mark regulatory DNA [10, 11]. Prescott et al compared epigenomic profiles of human and chimp induced pluripotent cell-derived cranial neural crest cells and revealed links between cis-regulatory divergence and quantitative expression differences of crucial neural crest regulators [20]. Together, these studies established the importance of epigenome conservation, and revealed that the relationship between genome conservation and epigenome conservation is not linear
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