Epigenetic memory at embryonic enhancers identified in DNA methylation maps from adult mouse tissues

Ludwig Institute for Cancer Research, La Jolla, California, USA.
Nature Genetics (Impact Factor: 29.35). 09/2013; 45(10). DOI: 10.1038/ng.2746
Source: PubMed


Mammalian development requires cytosine methylation, a heritable epigenetic mark of cellular memory believed to maintain a cell's unique gene expression pattern. However, it remains unclear how dynamic DNA methylation relates to cell type-specific gene expression and animal development. Here, by mapping base-resolution methylomes in 17 adult mouse tissues at shallow coverage, we identify 302,864 tissue-specific differentially methylated regions (tsDMRs) and estimate that >6.7% of the mouse genome is variably methylated. Supporting a prominent role for DNA methylation in gene regulation, most tsDMRs occur at distal cis-regulatory elements. Unexpectedly, some tsDMRs mark enhancers that are dormant in adult tissues but active in embryonic development. These 'vestigial' enhancers are hypomethylated and lack active histone modifications in adult tissues but nevertheless exhibit activity during embryonic development. Our results provide new insights into the role of DNA methylation at tissue-specific enhancers and suggest that epigenetic memory of embryonic development may be retained in adult tissues.

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Available from: Nisha Rajagopal, Aug 25, 2014
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    • "Global genomic comparisons of tissue-specific DNA methylation and transcription factor (TF) chromatin immunoprecipitation sequencing (ChIP-seq) data correlated the chromatin with the methylation state (Xie et al., 2013). Thus, many tissue-specific enhancers are hypomethylated in tissues where the target genes are expressed, but are hypermethylated in tissues where the target genes are silent (Hon et al., 2013). "
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    • "data . ( A - C ) Reproduc - ibility of methylation patterns in whole rhesus placenta and isolated rhesus trophoblast cells . ( D - F ) Reproducibility of methylation patterns in whole mouse placenta across labs . MethylC - seq data from our lab using E15 . 5 and E11 . 5 placentas has virtually identical patterns compared to MethylC - seq data from Hon et al . ( 2013 ) ( GSE42836 ) using E15 . 5 placenta . All samples were from C57Bl / 6 mice . ( A , D ) Methylation patterns across the first 120 Mb of each species ' chromosome 1 . Methylation data were compressed into averages of non - overlapping 20 kb windows ( windows with less than 20 CpG sites with methylation information were discarded ) and s"
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    • "uates during early mammalian development ( Reik , 2007 ) , but it is quite stable in most of the cells , which show an average of 70 – 80% of methylated CpGs . Nevertheless , global analyses in different cell types and tissues have shown that a dynamic regulation occurs for almost 22% of autosomal CpGs at enhancers of lineage specific regulators ( Hon et al . , 2013 ; Ziller et al . , 2013 ; Carrió et al . , 2015 ) , suggesting that DNA methylation at CpG sites is an epigenetic feature that determines cellular identity . Therefore , to verify a certain lineage reprograming , conversion , or proper differentiation , instead of monitoring expression of a few markers of these processes , global charac"
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