Epigenetic modifications in the embryonic and induced pluripotent stem cells

Gene Expression Patterns

Volumn 29, Issue , 2018, Pages 1-9

  Godini, Rasoul ^a   Lafta, Haider Yabr ^a,b   Fallahi, Hossein ^a,c  

^a RAZI UNIVERSITY   (Iran)

^b MINISTRY OF SCIENCE AND TECHNOLOGY   (Iraq)

^c KERMANSHAH UNIVERSITY OF MEDICAL SCIENCES   (Iran)

Author keywords

Chromatin remodelling; DNA methylation; Epigenetics; Histone modifications; Stem cells

Indexed keywords

DNA; HISTONE;

ARTICLE; CELL DIFFERENTIATION; CHROMATIN; DNA MODIFICATION; EMBRYONIC STEM CELL; EPIGENETICS; GENE CONTROL; GENOME IMPRINTING; HISTONE ACETYLATION; HISTONE METHYLATION; HISTONE MODIFICATION; HISTONE PHOSPHORYLATION; HUMAN; INDUCED PLURIPOTENT STEM CELL; NONHUMAN; PRIORITY JOURNAL; SOMATIC CELL; X CHROMOSOME INACTIVATION; ANIMAL; CYTOLOGY; DNA METHYLATION; GENETIC EPIGENESIS; METABOLISM; NUCLEAR REPROGRAMMING;

ANIMALS; CELL DIFFERENTIATION; CELLULAR REPROGRAMMING; DNA METHYLATION; EMBRYONIC STEM CELLS; EPIGENESIS, GENETIC; HUMANS; INDUCED PLURIPOTENT STEM CELLS;

EID: 85045005258     PISSN: 1567133X     EISSN: 18727298     Source Type: Journal    
DOI: 10.1016/j.gep.2018.04.001     Document Type: Article

References (111)

1. Amador-Arjona, A., Cimadamore, F., Huang, C.-T., Wright, R., Lewis, S., Gage, F.H., Terskikh, A.V., SOX2 primes the epigenetic landscape in neural precursors enabling proper gene activation during hippocampal neurogenesis. Proc. Natl. Acad. Sci. Unit. States Am. 112 (2015), E1936–E1945.
2. Avgustinova, A., Benitah, S.A., Epigenetic control of adult stem cell function. Nat. Rev. Mol. Cell Biol. 17 (2016), 643–658.
3. Bannister, A.J., Kouzarides, T., Regulation of chromatin by histone modifications. Cell Res. 21 (2011), 381–395.
4. Bannister, A.J., Schneider, R., Kouzarides, T., Histone methylation. Cell 109 (2002), 801–806.
5. Barakat, T.S., Ghazvini, M., de Hoon, B., et al. Stable X chromosome reactivation in female human induced pluripotent stem cells. Stem Cell Rep. 4 (2015), 199–208.
6. Barrera, L.O., Li, Z., Smith, A.D., et al. Genome-wide mapping and analysis of active promoters in mouse embryonic stem cells and adult organs. Genome Res. 18 (2008), 46–59.
7. Bell, R.E., Golan, T., Sheinboim, D., et al. Enhancer methylation dynamics contribute to cancer plasticity and patient mortality. Genome Res. 26 (2016), 601–611.
8. Berdasco, M., Esteller, M., DNA methylation in stem cell renewal and multipotency. Stem Cell Res. Ther., 2, 2011, 42 https://doi.org/10.1186/scrt83.
9. Bhanu, N.V., Sidoli, S., Garcia, B.A., Histone modification profiling reveals differential signatures associated with human embryonic stem cell self-renewal and differentiation. Proteomics 16 (2016), 448–458.
10. Bibikova, M., Laurent, L.C., Ren, B., et al. Unraveling epigenetic regulation in embryonic stem cells. Cell Stem Cell. 2 (2008), 123–134.
11. Bilic, J., Belmonte, J.C.I., Concise review: induced pluripotent stem cells versus embryonic stem cells: close enough or yet too far apart?. Stem Cell. 30 (2012), 33–41.
12. Bird, A.P., Wolffe, A.P., Methylation-induced repression–belts, braces, and chromatin. Cell 99 (1999), 451–454.
13. Borrelli, E., Nestler, E.J., Allis, C.D., Sassone-Corsi, P., Decoding the epigenetic language of neuronal plasticity. Neuron 60 (2008), 961–974.
14. Broccoli, V., Colasante, G., Sessa, A., Rubio, A., Histone modifications controlling native and induced neural stem cell identity. Curr. Opin. Genet. Dev. 34 (2015), 95–101.
15. Bruck, T., Benvenisty, N., Meta-analysis of the heterogeneity of X chromosome inactivation in human pluripotent stem cells. Stem Cell Res. 6 (2011), 187–193.
16. Calo, E., Wysocka, J., Modification of enhancer chromatin: what, how and why?. Mol. Cell., 49, 2013 https://doi.org/10.1016/j.molcel.2013.1001.1038.
17. Cantone, I., Bagci, H., Dormann, D., et al. Ordered chromatin changes and human X chromosome reactivation by cell fusion-mediated pluripotent reprogramming. Nat. Commun., 7, 2016 https://doi.org/10.1038/ncomms12354.
18. Chang, B., Chen, Y., Zhao, Y., Bruick, R.K., JMJD6 is a histone arginine demethylase. Science 318 (2007), 444–447.
19. Chin, M.H., Mason, M.J., Xie, W., et al. Induced pluripotent stem cells and embryonic stem cells are distinguished by gene expression signatures. Cell Stem Cell. 5 (2009), 111–123.
20. Choi, K.-H., Park, J.-K., Son, D., Hwang, J.Y., Lee, D.-K., Ka, H., Lee, C.-K., Reactivation of endogenous genes and epigenetic remodeling are barriers for generating transgene-free induced pluripotent stem cells in pig. PLoS One, 11, 2016 e0158046.
21. Cotton, A.M., Price, E.M., Jones, M.J., et al. Landscape of DNA methylation on the X chromosome reflects CpG density, functional chromatin state and X-chromosome inactivation. Hum. Mol. Genet. 24 (2015), 1528–1539.
22. Cuthbert, G.L., Daujat, S., Snowden, A.W., et al. Histone deimination antagonizes arginine methylation. Cell 118 (2004), 545–553.
23. Daley, G.Q., Lensch, M.W., Jaenisch, R., et al. Broader implications of defining standards for the pluripotency of iPS cells. Cell Stem Cell. 4 (2009), 200–201.
24. Dandulakis, M.G., Meganathan, K., Kroll, K.L., et al. Complexities of X chromosome inactivation status in female human induced pluripotent stem cells—a brief review and scientific update for autism research. J. Neurodev. Disord., 8(22), 2016 https://doi.org/10.1186/s11689-016-9155-8.
25. Dawson, M.A., Bannister, A.J., Gottgens, B., et al. JAK2 phosphorylates histone H3Y41 and excludes HP1[agr] from chromatin. Nature 461 (2009), 819–822.
26. Deindl, S., Hwang, W.L., Hota, S.K., Blosser, T.R., Prasad, P., Bartholomew, B., Zhuang, X., ISWI remodelers slide nucleosomes with coordinated multi-base-pair entry steps and single-base-pair exit steps. Cell 152 (2013), 442–452.
27. Do, J.T., Han, D.W., Gentile, L., et al. Reprogramming of Xist against the pluripotent state in fusion hybrids. J. Cell Sci. 122 (2009), 4122–4129.
28. Dovey, O.M., Foster, C.T., Cowley, S.M., Histone deacetylase 1 (HDAC1), but not HDAC2, controls embryonic stem cell differentiation. Proc. Natl. Acad. Sci. U.S.A. 107 (2010), 8242–8247.
29. Ellis, J., Bruneau, B.G., Keller, G., et al. Alternative induced pluripotent stem cell characterization criteria for in vitro applications. Cell Stem Cell. 4 (2009), 198–199.
30. Ernst, J., Kheradpour, P., Mikkelsen, T.S., et al. Systematic analysis of chromatin state dynamics in nine human cell types. Nature 473 (2011), 43–49.
31. Freberg, C.T., Dahl, J.A., Timoskainen, S., Collas, P., Epigenetic reprogramming of OCT4 and NANOG regulatory regions by embryonal carcinoma cell extract. Mol. Biol. Cell 18 (2007), 1543–1553.
32. Geens, M., Seriola, A., Barbé L., et al. Female human pluripotent stem cells rapidly lose X chromosome inactivation marks and progress to a skewed methylation pattern during culture. Mol. Hum. Reprod. 22 (2016), 285–298.
33. Ghosh, Z., Wilson, K.D., Wu, Y., et al. Persistent donor cell gene expression among human induced pluripotent stem cells contributes to differences with human embryonic stem cells. PLoS One, 5, 2010 e8975 https://doi.org/10.1371/journal.pone.0008975.
34. Gibney, E.R., Nolan, C.M., Epigenetics and gene expression. Heredity 105 (2010), 4–13.
35. Golob, J.L., Paige, S.L., Muskheli, V., Pabon, L., Murry, C.E., Chromatin remodeling during mouse and human embryonic stem cell differentiation. Dev. D 237 (2008), 1389–1398.
36. Greer, E.L., Shi, Y., Histone methylation: a dynamic mark in health, disease and inheritance. Nat. Rev. Genet. 13 (2012), 343–357.
37. Guo, H., Hu, B., Yan, L., et al. DNA methylation and chromatin accessibility profiling of mouse and human fetal germ cells. Cell Res. 2 (2016), 165–183.
38. Guyochin, A., Maenner, S., Chu, E.T.J., et al. Live cell imaging of the nascent inactive X chromosome during the early differentiation process of naive ES cells towards Epiblast stem cells. PLoS One, 9, 2014 e116109 https://doi.org/10.1371/journal.pone.0116109.
39. Hanna, J., Cheng, A.W., Saha, K., et al. Human embryonic stem cells with biological and epigenetic characteristics similar to those of mouse ES cells. Proc. Natl. Acad. Sci. Unit. States Am. 107 (2010), 9222–9227.
40. Harikumar, A., Meshorer, E., Chromatin remodeling and bivalent histone modifications in embryonic stem cells. EMBO Rep. 16 (2015), 1609–1619.
41. Hattori, N., Nishino, K., Ko, Y.-g., Hattori, N., Ohgane, J., Tanaka, S., Shiota, K., Epigenetic control of mouse Oct-4 gene expression in embryonic stem cells and trophoblast stem cells. J. Biol. Chem. 279 (2004), 17063–17069.
42. Hawkins, R.D., Hon, G.C., Lee, L.K., et al. Distinct epigenomic landscapes of pluripotent and lineage-committed human cells. Cell Stem Cell. 6 (2010), 479–491.
43. Hayashi, K., Sasamura, H., Nakamura, M., Azegami, T., Oguchi, H., Sakamaki, Y., Itoh, H., KLF4-dependent epigenetic remodeling modulates podocyte phenotypes and attenuates proteinuria. J. Clin. Invest. 124 (2014), 2523–2537.
44. Heyn, H., Vidal, E., Ferreira, H.J., et al. Epigenomic analysis detects aberrant super-enhancer DNA methylation in human cancer. Genome Biol., 17(11), 2016 https://doi.org/10.1186/s13059-016-0879-2.
45. Ho, L., Ronan, J.L., Wu, J., et al. An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency. Proc. Natl. Acad. Sci. U.S.A. 106 (2009), 5181–5186.
46. Hon, G.C., Rajagopal, N., Shen, Y., et al. Epigenetic memory at embryonic enhancers identified in DNA methylation maps from adult mouse tissues. Nat. Genet. 45 (2013), 1198–1206.
47. Hota, S.K., Bruneau, B.G., ATP-dependent chromatin remodeling during mammalian development. Development 143 (2016), 2882–2897.
48. Huang, B., Li, G., Jiang, X.H., Fate determination in mesenchymal stem cells: a perspective from histone-modifying enzymes. Stem Cell Res. Ther., 6, 2015, 35 https://doi.org/10.1186/s13287-015-0018-0.
49. Jeong, J., Kim, K.N., Chung, M.S., Kim, H.J., Functional comparison of human embryonic stem cells and induced pluripotent stem cells as sources of hepatocyte-like cells. Tissue Eng. Regen. Med. 13 (2016), 740–749.
50. Keenen, B., de la Serna, I.L., Chromatin remodeling in embryonic stem cells: regulating the balance between pluripotency and differentiation. J. Cell. Physiol. 219 (2009), 1–7.
51. Kim, J.S., Choi, H.W., Araúzo-Bravo, M.J., et al. Reactivation of the inactive X chromosome and post-transcriptional reprogramming of Xist in iPSCs. J. Cell Sci. 128 (2015), 81–87.
52. Kuppusamy, K.T., Sperber, H., Ruohola-Baker, H., MicroRNA regulation and role in stem cell maintenance, cardiac differentiation and hypertrophy. Curr. Mol. Med. 13:5 (2013), 757–764.
53. Lewitzky, M., Yamanaka, S., Reprogramming somatic cells towards pluripotency by defined factors. Curr. Opin. Biotechnol. 18 (2007), 467–473.
54. Li, E., Beard, C., Jaenisch, R., Role for DNA methylation in genomic imprinting. Nature, 366, 1993 362–365.26.
55. Lim, D.H.K., Maher, E.R., DNA methylation: a form of epigenetic control of gene expression. Obstet. Gynaecol. 12 (2010), 37–42.
56. Lin, S.H., Wang, J., Saintigny, P., et al. Genes suppressed by DNA methylation in non-small cell lung cancer reveal the epigenetics of epithelial–mesenchymal transition. BMC Genom., 15, 2014, 1079.
57. Liu, L., Luo, G.Z., Yang, W., et al. Activation of the imprinted Dlk1-Dio3 region correlates with pluripotency levels of mouse stem cells. J. Biol. Chem. 285 (2010), 19483–19490.
58. Luo, R.X., Dean, D.C., Chromatin remodeling and transcriptional regulation. J. Natl. Cancer Inst. 91 (1999), 1288–1294.
59. Ma, A.N., Wang, H., Guo, R., et al. Targeted gene suppression by inducing de novo DNA methylation in the gene promoter. Epigenet. Chromatin, 7, 2014, 20 https://doi.org/10.1186/1756-8935-7-20.
60. Maherali, N., Hochedlinger, K., Guidelines and techniques for the generation of induced pluripotent stem cells. Cell Stem Cell. 3 (2008), 595–605.
61. Maherali, N., Sridharan, R., Xie, W., et al. Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell. 1 (2007), 55–70.
62. Mallon, B.S., Hamilton, R.S., Kozhich, O.A., et al. Comparison of the molecular profiles of human embryonic and induced pluripotent stem cells of isogenic origin. Stem Cell Res. 12 (2014), 376–386.
63. Marchetto, M.C.N., Yeo, G.W., Kainohana, O., et al. Transcriptional signature and memory retention of human-induced pluripotent stem cells. PLoS One, 4, 2009 e7076.
64. Mattout, A., Cabianca, D.S., Gasser, S.M., Chromatin states and nuclear organization in development — a view from the nuclear lamina. Genome Biol., 16, 2015, 174 https://doi.org/10.1186/s13059-015-0747-5.
65. Minina, Y.M., Zhdanova, N.S., Shilov, A.G., Tolkunova, E.N., Liskovykh, M.A., Tomilin, A.N., Chromosomal instability of mouse pluripotent cells cultured in vitro. Cell Tissue Biol. 4 (2010), 223–227.
66. Minkovsky, A., Patel, S., Plath, K., Pluripotency and the transcriptional inactivation of the female mammalian X chromosome. Stem Cell. 30 (2012), 48–54.
67. Moarii, M., Boeva, V., Vert, J.P., Reyal, F., Changes in correlation between promoter methylation and gene expression in cancer. BMC Genom., 16, 2015, 873 https://doi.org/10.1186/s12864-015-1994-2.
68. Nagamori, I., Kobayashi, H., Shiromoto, Y., et al. Comprehensive DNA methylation analysis of retrotransposons in male germ cells. Cell Rep. 12 (2015), 1541–1547.
69. Narlikar, G.J., Sundaramoorthy, R., Owen-Hughes, T., Mechanisms and functions of ATP-dependent chromatin-remodeling enzymes. Cell 154 (2013), 490–503.
70. Navarro, P., Chambers, I., Karwacki-Neisius, V., et al. Molecular coupling of Xist regulation and pluripotency. Science 321 (2008), 1693–1695.
71. Nowak, S.J., Aihara, H., Gonzalez, K., Nibu, Y., Baylies, M.K., Akirin links twist-regulated transcription with the brahma chromatin remodeling complex during embryogenesis. PLoS Genet., 8(3), 2012 e1002547.
72. Okita, K., Ichisaka, T., Yamanaka, S., Generation of germline-competent induced pluripotent stem cells. Nature 448 (2007), 313–317.
73. Papp, B., Plath, K., Reprogramming to pluripotency: stepwise resetting of the epigenetic landscape. Cell Res. 21 (2011), 486–501.
74. Patel, S., Bonora, G., Sahakyan, A., et al. Human embryonic stem cells do not change their X inactivation status during differentiation. Cell Rep. 18 (2017), 54–67.
75. Paulsen, M., Ferguson-Smith, A.C., DNA methylation in genomic imprinting, development, and disease. J. Pathol. 195 (2001), 97–110.
76. Perez-Lluch, S., Blanco, E., Tilgner, H., et al. Absence of canonical marks of active chromatin in developmentally regulated genes. Nat. Genet. 47 (2015), 1158–1167.
77. Pisanic, I.T.R., Athamanolap, P., Wang, T.H., Defining, distinguishing and detecting the contribution of heterogeneous methylation to cancer heterogeneity. Semin. Cell Dev. Biol. 64 (2017), 5–17.
78. Prilutsky, D., Palmer, N.P., Smedemark-Margulies, N., et al. iPSC-derived neurons as a higher-throughput readout for autism: promises and pitfalls. Trends Mol. Med. 20 (2014), 91–104.
79. Rossetto, D., Avvakumov, N., Côté J., Histone phosphorylation: a chromatin modification involved in diverse nuclear events. Epigenetics 7 (2012), 1098–1108.
80. Rugg-Gunn, P.J., Cox, B.J., Ralston, A., Rossant, J., Distinct histone modifications in stem cell lines and tissue lineages from the early mouse embryo. Proc. Natl. Acad. Sci. U.S.A. 107 (2010), 10783–10790.
81. Sawicka, A., Seiser, C., Histone H3 phosphorylation – a versatile chromatin modification for different occasions. Biochimie 94 (2012), 2193–2201.
82. Sawicka, A., Seiser, C., Sensing core histone phosphorylation — a matter of perfect timing. Biochim. Biophys. Acta 1839 (2014), 711–718.
83. Schlosberg, C.E., VanderKraats, N.D., Edwards, J.R., Modeling complex patterns of differential DNA methylation that associate with gene expression changes. Nucleic Acids Res. 45 (2017), 5100–5111.
84. Senner, C.E., Krueger, F., Oxley, D., Andrews, S., Hemberger, M., DNA methylation profiles define stem cell identity and reveal a tight embryonic–extraembryonic lineage boundary. Stem Cell. 30 (2012), 2732–2745.
85. Sharp, A.J., Stathaki, E., Migliavacca, E., et al. DNA methylation profiles of human active and inactive X chromosomes. Genome Res. 21 (2011), 1592–1600.
86. Sheaffer, K.L., Kim, R., Aoki, R., et al. DNA methylation is required for the control of stem cell differentiation in the small intestine. Genes Dev. 28 (2014), 652–664.
87. Shi, Y., Lan, F., Matson, C., et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119 (2004), 941–953.
88. Sikorska, M., Sandhu, J.K., Deb-Rinker, P., Jezierski, A., LeBlanc, J., Charlebois, C., Ribecco-Lutkiewicz, M., Bani-Yaghoub, M., Walker, P.R., Epigenetic modifications of SOX2 enhancers, SRR1 and SRR2, correlate with in vitro neural differentiation. J. Neurosci. Res. 86 (2008), 1680–1693.
89. Singer, Z.S., Yong, J., Tischler, J., et al. Dynamic heterogeneity and DNA methylation in embryonic stem cells. Mol. Cell. 55 (2014), 319–331.
90. Srinageshwar, B., Maiti, P., Dunbar, G.L., Rossignol, J., Role of epigenetics in stem cell proliferation and differentiation: implications for treating neurodegenerative diseases. Int. J. Mol. Sci. 17 (2016), 1–15.
91. Stadtfeld, M., Apostolou, E., Akutsu, H., et al. Aberrant silencing of imprinted genes on chromosome 12qF1 in mouse induced pluripotent stem cells. Nature 465 (2010), 175–181.
92. Surani, M.A., Hayashi, K., Hajkova, P., Genetic and epigenetic regulators of pluripotency. Cell 128 (2007), 747–762.
93. Suzuki, M.M., Bird, A., DNA methylation landscapes: provocative insights from epigenomics. Nat. Rev. Genet. 9 (2008), 465–476.
94. Syed, K.M., Joseph, S., Mukherjee, A., Majumder, A., Teixeira, J.M., Dutta, D., Pillai, M.R., Histone chaperone APLF regulates induction of pluripotency in murine fibroblasts. J. Cell Sci. 129 (2016), 4576–4591.
95. Takahashi, K., Yamanaka, S., Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126 (2006), 663–676.
96. Takahashi, N., Okamoto, A., Kobayashi, R., et al. Deletion of Gtl2, imprinted non-coding RNA, with its differentially methylated region induces lethal parent-origin-dependent defects in mice. Hum. Mol. Genet. 18 (2009), 1879–1888.
97. Tchieu, J., Kuoy, E., Chin, M.H., et al. Female human iPS cells retain an inactive X-chromosome. Cell Stem Cell. 7 (2010), 329–342.
98. Tjeertes, J.V., Miller, K.M., Jackson, S.P., Screen for DNA-damage-responsive histone modifications identifies H3K9Ac and H3K56Ac in human cells. EMBO J. 28 (2009), 1878–1889.
99. Vaskova, E.A., Stekleneva, A.E., Medvedev, S.P., Zakian, S.M., Epigenetic memory” phenomenon in induced pluripotent stem cells. Acta Nat. 4 (2013), 15–21.
100. Wagner, J.R., Busche, S., Ge, B., et al. The relationship between DNA methylation, genetic and expression inter-individual variation in untransformed human fibroblasts. Genome Biol., 15, 2014, R37 https://doi.org/doi:10.1186/gb-2014-15-2-r37.
101. Wang, Y., Wysocka, J., Sayegh, J., et al. Human PAD4 regulates histone arginine methylation levels via demethylimination. Science 306 (2004), 279–283.
102. Wang, G.G., Allis, C.D., Chi, P., Chromatin remodeling and cancer, part II: ATP-dependent chromatin remodeling. Trends Mol. Med. 13 (2007), 373–380.
103. Wernig, M., Meissner, A., Foreman, R., et al. In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 448 (2007), 318–324.
104. Whetstine, J.R., Nottke, A., Lan, F., et al. Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases. Cell 125 (2006), 467–481.
105. Williams, L.H., Kalantry, S., Starmer, J., Magnuson, T., Transcription precedes loss of Xist coating and depletion of H3K27me3 during X-chromosome reprogramming in the mouse inner cell mass. Development 138 (2011), 2049–2057.
106. Wu, H., D'Alessio, A.C., Ito, S., et al. Genome-wide analysis of 5-hydroxymethylcytosine distribution reveals its dual function in transcriptional regulation in mouse embryonic stem cells. Genes Dev. 25:7 (2011), 679–684, 10.1101/gad.2036011.
107. Wutz, A., Jaenisch, R., A shift from reversible to irreversible X inactivation is triggered during ES cell differentiation. Mol. Cell. 5 (2000), 695–705.
108. Xi, R., Xie, T., Stem cell self-renewal controlled by chromatin remodeling factors. Science 310 (2005), 1487–1489.
109. Yang, J.-H., Song, T.-Y., Jo, C., Park, J., Lee, H.-Y., Song, I., Cho, E.-J., Differential regulation of the histone chaperone HIRA during muscle cell differentiation by a phosphorylation switch. Exp. Mol. Med., 48, 2016 e252.
110. Yu, J., Vodyanik, M.A., Smuga-Otto, K., et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 318 (2007), 1917–1920.
111. Zhou, Y., Kim, J., Yuan, X., Braun, T., Epigenetic modifications of stem cells. Circ. Res. 109 (2011), 1067–1081.