Epigenetic Memory at Embryonic Enhancers Identified in DNA Maps from Adult Mouse Tissues

In human DNA, 5-methylcytosine is found in approximately 1.5% of genomic DNA. In somatic cells, 5-mC occurs almost exclusively in the context of paired symmetrical methylation of a CpG site. An exception to this is seen in embryonic stem (ES) cells, where a substantial amount of 5-mC is also observed in non-CpG contexts. In the bulk of genomic DNA, most CpG sites are heavily methylated while CpG islands (sites of CpG clusters) in germ-line tissues and located near promoters of normal somatic cells, remain unmethylated, thus allowing gene expression to occur. Furthermore, the position of methylation within a transcriptional region can influence the level of gene control (i.e, gene silencing, activation, chromatin stability, etc.). Thus, a full understanding of the function of DNA methylation requires methylation analysis of the entire genome (Jones, 2012). To explore epigenetic variation (of methylation patterns) in normal tissues, researchers at the University of California, San Diego Medical School and the Ludwig Institute for Cancer Research in California performed whole-genome bisulfite sequencing of 17 different tissues spanning all 3 germ layers and extraembryonic placenta derived from a single pregnant female mouse. By mapping base-resolution methylomes (the methylated genome) they were able to characterize the biological roles of tissue-specific differentially methylated regions (tsDMRs).

Their findings are summarized below:

  • Consistent with previous findings, somatic tissues were highly methylated (average median of 78.3% mCG) while, extraembryonic tissue was globally hypomethylated (average median of 45.4% mCG). Furthermore, clustering analysis of the tissues confirmed that DNA methylation patterns contain cell-type specific and lineage-specific information.
  • Using a χ2-based statistic to capture tissue-specific DNA methylation in a CpG context and a hidden Markov Model (HMM) on that statistic to segment the genome of each tissue into methylation domains, they identified 302,864 tsDMRs that exhibit high variance in tissue methylation and significant tissue specificity. Based on these results the authors estimated that at least 6.7% of the mouse genome is variably methylated.
  • The association of tsDMRs with cis-regulatory elements strongly suggests that they are regulatory sequences based on significant enrichment of transcription factor binding motifs at tsDMRs.
  • Newly identified regions termed ‘vestigial’ enhancers, were found to be hypomethylated and lack active histone modifications – such as H3K4me1 and H3k27ac- in adult tissues compared to the same embryonic (developing) tissue.
  • You can get all the details and read more about their findings here: Gary C. Hon, et al. “Epigenetic Memory at Embryonic Enhancers Identified in DNA Maps from Adult Mouse Tissues”. Nature Genetics, 1-9, September, 2013.

Reference: Jones PA. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet, (13), 484-92, 2012.

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