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Differential methylation of tissue- and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts

Abstract

Induced pluripotent stem (iPS) cells are derived by epigenetic reprogramming, but their DNA methylation patterns have not yet been analyzed on a genome-wide scale. Here, we find substantial hypermethylation and hypomethylation of cytosine-phosphate-guanine (CpG) island shores in nine human iPS cell lines as compared to their parental fibroblasts. The differentially methylated regions (DMRs) in the reprogrammed cells (denoted R-DMRs) were significantly enriched in tissue-specific (T-DMRs; 2.6-fold, P < 10−4) and cancer-specific DMRs (C-DMRs; 3.6-fold, P < 10−4). Notably, even though the iPS cells are derived from fibroblasts, their R-DMRs can distinguish between normal brain, liver and spleen cells and between colon cancer and normal colon cells. Thus, many DMRs are broadly involved in tissue differentiation, epigenetic reprogramming and cancer. We observed colocalization of hypomethylated R-DMRs with hypermethylated C-DMRs and bivalent chromatin marks, and colocalization of hypermethylated R-DMRs with hypomethylated C-DMRs and the absence of bivalent marks, suggesting two mechanisms for epigenetic reprogramming in iPS cells and cancer.

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Figure 1: Reprogramming differentially methylated regions (R-DMRs).
Figure 2: DNA methylation at R-DMRs distinguishes normal tissues from each other and colon cancer from normal colon.

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References

  1. Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).

    Article  CAS  Google Scholar 

  2. Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007).

    Article  CAS  Google Scholar 

  3. Park, I.H. et al. Reprogramming of human somatic cells to pluripotency with defined factors. Nature 451, 141–146 (2008).

    Article  CAS  Google Scholar 

  4. Yu, J. et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917–1920 (2007).

    Article  CAS  Google Scholar 

  5. Park, I.H. et al. Disease-specific induced pluripotent stem cells. Cell 134, 877–886 (2008).

    Article  CAS  Google Scholar 

  6. Ball, M.P. et al. Targeted and genome-scale strategies reveal gene-body methylation signatures in human cells. Nat. Biotechnol. 27, 485 (2009).

    Article  CAS  Google Scholar 

  7. Deng, J. et al. Targeted bisulfite sequencing reveals changes in DNA methylation associated with nuclear reprogramming. Nat. Biotechnol. 27, 353–360 (2009).

    Article  CAS  Google Scholar 

  8. Irizarry, R.A. et al. The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat. Genet. 41, 178–186 (2009).

    Article  CAS  Google Scholar 

  9. Irizarry, R.A. et al. Comprehensive high-throughput arrays for relative methylation (CHARM). Genome Res. 18, 780–790 (2008).

    Article  CAS  Google Scholar 

  10. Bernstein, B.E. et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125, 315–326 (2006).

    Article  CAS  Google Scholar 

  11. Pan, G. et al. Whole-genome analysis of histone H3 lysine 4 and lysine 27 methylation in human embryonic stem cells. Cell Stem Cell 1, 299–312 (2007).

    Article  CAS  Google Scholar 

  12. Boyer, L.A. et al. Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 122, 947–956 (2005).

    Article  CAS  Google Scholar 

  13. Irizarry, R.A. et al. Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 4, 249–264 (2003).

    Article  Google Scholar 

  14. Dennis, G. Jr. et al. DAVID: database for annotation, visualization, and integrated discovery. Genome Biol. 4, R60 (2003).

    Article  Google Scholar 

  15. Huang, D.W., Sherman, B.T. & Lempicki, R.A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protocols 4, 44–57 (2009).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This research was supported by the US National Institutes of Health (A.P.F. and G.Q.D.). G.Q.D affiliations include the Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School; the Division of Hematology, Brigham and Women's Hospital; Harvard Stem Cell Institute; and the Manton Center for Orphan Disease Research.

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Authors and Affiliations

Authors

Contributions

A.D. performed CHARM, bisulfite pyrosequencing and data analysis; B.W. performed initial experiments and helped design and analyze the study; I.-H.P., J.R., S.L., J.M. and T.S. performed cell culture and prepared nucleic acids; P.M., M.J.A., R.I., B.H. and C.L.-A. performed statistical analysis; G.Q.D. and A.P.F. designed the study, supervised the experiments and wrote the paper with A.D. and B.W.

Corresponding authors

Correspondence to George Q Daley or Andrew P Feinberg.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–3, Supplementary Tables 3–4, 7,9–10 (PDF 1297 kb)

Supplementary Table 1

Reprogramming differentially methylated regions (R-DMRs). (XLS 914 kb)

Supplementary Table 2

Gene ontology functional categories enriched in reprogramming differentially methylated regions (R-DMRs). (XLS 47 kb)

Supplementary Table 5

Regions of differential methylation between 3 additional iPS lines and the fibroblasts from which they were derived. (XLS 424 kb)

Supplementary Table 6

Regions of differential methylation between iPS cells and ES cells. (XLS 32 kb)

Supplementary Table 8

Relationship between differential gene expression and differential methylation at reprogramming differentially methylated regions (R-DMRs). (XLS 131 kb)

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Doi, A., Park, IH., Wen, B. et al. Differential methylation of tissue- and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts. Nat Genet 41, 1350–1353 (2009). https://doi.org/10.1038/ng.471

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