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

Nature Genetics volume 45, pages 1198–1206 (2013)Cite this article

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Abstract

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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Figure 1: Distinct tissue-specific methylomes.
Figure 2: Identification of tissue-specific methylated regions.
Figure 3: Tissue-specific methylated regions are predominantly regulatory elements.
Figure 4: Tissue-specific conservation of regulatory elements.
Figure 5: Transcription factor binding motif enrichment near tsDMRs.
Figure 6: AD-I tsDMRs demonstrate features of dormant enhancers.
Figure 7: AD-I tsDMRs are active during development.
Figure 8: Vestigial enhancers across development and strains.

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Acknowledgements

We thank S. Kuan, Z. Ye and L. Edsall for their assistance in sequencing and the initial processing of sequencing reads. This work is funded by the Ludwig Institute for Cancer Research and the US National Institutes of Health (R01 HG003991 and ES017166).

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Authors and Affiliations

  1. Ludwig Institute for Cancer Research, La Jolla, California, USA

    Gary C Hon, Yin Shen, David F McCleary, Feng Yue, My D Dang & Bing Ren

  2. Bioinformatics and Systems Biology Program, University of California, San Diego, La Jolla, California, USA

    Nisha Rajagopal & Bing Ren

  3. Department of Cellular and Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, California, USA

    Bing Ren

  4. Institute of Genomic Medicine, University of California, San Diego School of Medicine, La Jolla, California, USA

    Bing Ren

  5. Moores Cancer Center, University of California, San Diego School of Medicine, La Jolla, California, USA

    Bing Ren

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Contributions

G.C.H., N.R. and F.Y. performed bioinformatics analysis. G.C.H., Y.S., D.F.M. and M.D.D. performed experiments. G.C.H. and B.R. prepared the manuscript.

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Correspondence to Bing Ren.

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Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 and Supplementary Note (PDF 1743 kb)

Supplementary Table 1

tsDMRs in mouse tissues (XLSX 16827 kb)

Supplementary Table 2

Motif analysis of tsDMRs not recovered by known regulatory elements (XLSX 20 kb)

Supplementary Table 3

AD-A and AD-I tsDMRs in mouse tissues (XLSX 12898 kb)

Supplementary Table 4

Overlap of embryonic enhancers with adult AD-I tsDMRs (XLSX 11 kb)

Supplementary Table 5

Predicted enhancers (XLSX 16979 kb)

Supplementary Table 6

Known motifs used in analysis (XLSX 15 kb)

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Hon, G., Rajagopal, N., Shen, Y. et al. Epigenetic memory at embryonic enhancers identified in DNA methylation maps from adult mouse tissues. Nat Genet 45, 1198–1206 (2013). https://doi.org/10.1038/ng.2746

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