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DNA methylation dynamics in human induced pluripotent stem cells

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Abstract

Indeed human induced pluripotent stem cells (hiPSCs) are considered to be powerful tools in regenerative medicine. To enable the use of hiPSCs in the field of regenerative medicine, it is necessary to understand the mechanisms of reprogramming during the transformation of somatic cells into hiPSCs. Genome-wide epigenetic modification constitutes a critical event in the generation of iPSCs. In other words, to analyze epigenetic changes in iPSCs means to elucidate reprogramming processes. We have established a large number of hiPSCs derived from various human tissues and have obtained their DNA methylation profiles. Comparison analyses indicated that the epigenetic patterns of various hiPSCs, irrespective of their source tissue, were very similar to one another and were similar to those of human embryonic stem cells (hESCs). However, the profiles of hiPSCs and hESCs exhibited epigenetic differences, which were caused by random aberrant hypermethylation at early passages. Interestingly, continuous passaging of the hiPSCs diminished the differences between DNA methylation profiles of hiPSCs and hESCs. The number of aberrant DNA methylation regions may thus represent a useful epigenetic index for evaluating hiPSCs in the context of therapeutic applications.

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References

  1. Shiota K, Kogo Y, Ohgane J, et al. Epigenetic marks by DNA methylation specific to stem, germ and somatic cells in mice. Genes Cells. 2002;7(9):961–9.

    Article  CAS  PubMed  Google Scholar 

  2. Li E. Chromatin modification and epigenetic reprogramming in mammalian development. Nat Rev Genet. 2002;3(9):662–73.

    Article  CAS  PubMed  Google Scholar 

  3. Reik W. Stability and flexibility of epigenetic gene regulation in mammalian development. Nature. 2007;447(7143):425–32.

    Article  CAS  PubMed  Google Scholar 

  4. Hattori N, Nishino K, Ko YG, et al. Epigenetic control of mouse Oct-4 gene expression in embryonic stem cells and trophoblast stem cells. J Biol Chem. 2004;279(17):17063–9.

    Article  CAS  PubMed  Google Scholar 

  5. Hattori N, Imao Y, Nishino K, et al. Epigenetic regulation of Nanog gene in embryonic stem and trophoblast stem cells. Genes Cells. 2007;12(3):387–96.

    Article  CAS  PubMed  Google Scholar 

  6. Nishino K, Hattori N, Tanaka S, Shiota K. DNA methylation-mediated control of Sry gene expression in mouse gonadal development. J Biol Chem. 2004;279(21):22306–13.

    Article  CAS  PubMed  Google Scholar 

  7. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–76.

    Article  CAS  PubMed  Google Scholar 

  8. Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861–72.

    Article  CAS  PubMed  Google Scholar 

  9. Miura K, Okada Y, Aoi T, et al. Variation in the safety of induced pluripotent stem cell lines. Nat Biotechnol. 2009;27(8):743–5.

    Article  CAS  PubMed  Google Scholar 

  10. Polo JM, Liu S, Figueroa ME, et al. Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells. Nat Biotechnol. 2010;28(8):848–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kim K, Doi A, Wen B, et al. Epigenetic memory in induced pluripotent stem cells. Nature. 2010;467(7313):285–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Nishino K, Toyoda M, Yamazaki-Inoue M, et al. Defining hypo-methylated regions of stem cell-specific promoters in human iPS cells derived from extra-embryonic amnions and lung fibroblasts. PLoS One. 2010;5(9):e13017.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Nagata S, Toyoda M, Yamaguchi S, et al. Efficient reprogramming of human and mouse primary extra-embryonic cells to pluripotent stem cells. Genes Cells. 2009;14(12):1395–404.

    Article  CAS  PubMed  Google Scholar 

  14. Toyoda M, Yamazaki-Inoue M, Itakura Y, et al. Lectin microarray analysis of pluripotent and multipotent stem cells. Genes Cells. 2011;16(1):1–11.

    Article  CAS  PubMed  Google Scholar 

  15. Nishino K, Toyoda M, Yamazaki-Inoue M, et al. DNA methylation dynamics in human induced pluripotent stem cells over time. PLoS Genet. 2011;7(5):e1002085.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 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. 2009;41(12):1350–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Deng J, Shoemaker R, Xie B, et al. Targeted bisulfite sequencing reveals changes in DNA methylation associated with nuclear reprogramming. Nat Biotechnol. 2009;27(4):353–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Nichols J, Smith A. Naive and primed pluripotent states. Cell Stem Cell. 2009;4(6):487–92.

    Article  CAS  PubMed  Google Scholar 

  19. Tesar PJ, Chenoweth JG, Brook FA, et al. New cell lines from mouse epiblast share defining features with human embryonic stem cells. Nature. 2007;448(7150):196–9.

    Article  CAS  PubMed  Google Scholar 

  20. Habibi E, Brinkman AB, Arand J, et al. Whole-genome bisulfite sequencing of two distinct interconvertible DNA methylomes of mouse embryonic stem cells. Cell Stem Cell. 2013;13(3):360–9.

    Article  CAS  PubMed  Google Scholar 

  21. Ficz G, Hore TA, Santos F, et al. FGF signaling inhibition in ESCs drives rapid genome-wide demethylation to the epigenetic ground state of pluripotency. Cell Stem Cell. 2013;13(3):351–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Leitch HG, McEwen KR, Turp A, et al. Naive pluripotency is associated with global DNA hypomethylation. Nat Struct Mol Biol. 2013;20(3):311–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Yu J, Vodyanik MA, Smuga-Otto K, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007;318(5858):1917–20.

    Article  CAS  PubMed  Google Scholar 

  24. Park IH, Zhao R, West JA, et al. Reprogramming of human somatic cells to pluripotency with defined factors. Nature. 2008;451(7175):141–6.

    Article  CAS  PubMed  Google Scholar 

  25. Huangfu D, Osafune K, Maehr R, et al. Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nat Biotechnol. 2008;26(11):1269–75.

    Article  CAS  PubMed  Google Scholar 

  26. Rugg-Gunn PJ, Ferguson-Smith AC, Pedersen RA. Epigenetic status of human embryonic stem cells. Nat Genet. 2005;37(6):585–7.

    Article  CAS  PubMed  Google Scholar 

  27. Rugg-Gunn PJ, Ferguson-Smith AC, Pedersen RA. Status of genomic imprinting in human embryonic stem cells as revealed by a large cohort of independently derived and maintained lines. Hum Mol Genet. 2007;16 Spec No. 2:R243–51.

  28. Stadtfeld M, Apostolou E, Akutsu H, et al. Aberrant silencing of imprinted genes on chromosome 12qF1 in mouse induced pluripotent stem cells. Nature. 2010;465(7295):175–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Chin MH, Pellegrini M, Plath K, Lowry WE. Molecular analyses of human induced pluripotent stem cells and embryonic stem cells. Cell Stem Cell. 2010;7(2):263–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Correspondence to Koichiro Nishino.

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Nishino, K., Umezawa, A. DNA methylation dynamics in human induced pluripotent stem cells. Human Cell 29, 97–100 (2016). https://doi.org/10.1007/s13577-016-0139-5

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  • DOI: https://doi.org/10.1007/s13577-016-0139-5

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