Genetic and epigenetic variations in iPSCs: Potential causes and implications for application

Cell Stem Cell

Volumn 13, Issue 2, 2013, Pages 149-159

  Liang, Gaoyang ^a   Zhang, Yi ^a,b,c  

^a BOSTON CHILDREN S HOSPITAL   (United States)

^b HARVARD MEDICAL SCHOOL   (United States)

^c HARVARD STEM CELL INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

APOPTOSIS; CELL CYCLE ARREST; CELL POPULATION; CHROMOSOME 17; CHROMOSOME 21; CHROMOSOME 8; CHROMOSOME LOSS; CHROMOSOME NUMBER; COMPARATIVE STUDY; COPY NUMBER VARIATION; DNA DAMAGE; DNA END JOINING REPAIR; DNA METHYLATION; DOWN SYNDROME; EPIGENETICS; FOLLOW UP; GENE EXPRESSION REGULATION; GENETIC VARIABILITY; GENOTOXICITY; HISTONE MODIFICATION; HOMOLOGOUS RECOMBINATION; HUMAN; HUMAN CHROMOSOME; IMMUNE RESPONSE; IMMUNOGENICITY; IN VITRO STUDY; LESCH NYHAN SYNDROME; LIMIT OF DETECTION; MOSAICISM; NONHUMAN; OXIDATIVE STRESS; PHENOTYPE; PLURIPOTENT STEM CELL; POINT MUTATION; PRIORITY JOURNAL; REGENERATIVE MEDICINE; REVIEW; SINGLE NUCLEOTIDE POLYMORPHISM; SOMATIC CELL; STOICHIOMETRY; TRISOMY 21; TUMOR SUPPRESSOR GENE; WILD TYPE; X CHROMOSOME; X CHROMOSOME INACTIVATION;

EID: 84881186856     PISSN: 19345909     EISSN: 18759777     Source Type: Journal    
DOI: 10.1016/j.stem.2013.07.001     Document Type: Review

References (84)

1. A. Abyzov, J. Mariani, D. Palejev, Y. Zhang, M.S. Haney, L. Tomasini, A.F. Ferrandino, L.A. Rosenberg Belmaker, A. Szekely, and M. Wilson Somatic copy number mosaicism in human skin revealed by induced pluripotent stem cells Nature 492 2012 438 442
2. M.I. Aladjem, B.T. Spike, L.W. Rodewald, T.J. Hope, M. Klemm, R. Jaenisch, and G.M. Wahl ES cells do not activate p53-dependent stress responses and undergo p53-independent apoptosis in response to DNA damage Curr. Biol. 8 1998 145 155
3. K. Amps, P.W. Andrews, G. Anyfantis, L. Armstrong, S. Avery, H. Baharvand, J. Baker, D. Baker, M.B. Munoz, S. Beil International Stem Cell Initiative Screening ethnically diverse human embryonic stem cells identifies a chromosome 20 minimal amplicon conferring growth advantage Nat. Biotechnol. 29 2011 1132 1144
4. M.C. Anguera, R. Sadreyev, Z. Zhang, A. Szanto, B. Payer, S.D. Sheridan, S. Kwok, S.J. Haggarty, M. Sur, and J. Alvarez Molecular signatures of human induced pluripotent stem cells highlight sex differences and cancer genes Cell Stem Cell 11 2012 75 90
5. R. Araki, M. Uda, Y. Hoki, M. Sunayama, M. Nakamura, S. Ando, M. Sugiura, H. Ideno, A. Shimada, A. Nifuji, and M. Abe Negligible immunogenicity of terminally differentiated cells derived from induced pluripotent or embryonic stem cells Nature 494 2013 100 104
6. D.E. Baker, N.J. Harrison, E. Maltby, K. Smith, H.D. Moore, P.J. Shaw, P.R. Heath, H. Holden, and P.W. Andrews Adaptation to culture of human embryonic stem cells and oncogenesis in vivo Nat. Biotechnol. 25 2007 207 215
7. A. Banito, S.T. Rashid, J.C. Acosta, S. Li, C.F. Pereira, I. Geti, S. Pinho, J.C. Silva, V. Azuara, and M. Walsh Senescence impairs successful reprogramming to pluripotent stem cells Genes Dev. 23 2009 2134 2139
8. O. Bar-Nur, H.A. Russ, S. Efrat, and N. Benvenisty Epigenetic memory and preferential lineage-specific differentiation in induced pluripotent stem cells derived from human pancreatic islet beta cells Cell Stem Cell 9 2011 17 23
9. U. Ben-David, and N. Benvenisty The tumorigenicity of human embryonic and induced pluripotent stem cells Nat. Rev. Cancer 11 2011 268 277
10. U. Ben-David, and N. Benvenisty High prevalence of evolutionarily conserved and species-specific genomic aberrations in mouse pluripotent stem cells Stem Cells 30 2012 612 622
11. C. Bock, E. Kiskinis, G. Verstappen, H. Gu, G. Boulting, Z.D. Smith, M. Ziller, G.F. Croft, M.W. Amoroso, and D.H. Oakley Reference Maps of human ES and iPS cell variation enable high-throughput characterization of pluripotent cell lines Cell 144 2011 439 452
12. B.W. Carey, S. Markoulaki, J.H. Hanna, D.A. Faddah, Y. Buganim, J. Kim, K. Ganz, E.J. Steine, J.P. Cassady, and M.P. Creyghton Reprogramming factor stoichiometry influences the epigenetic state and biological properties of induced pluripotent stem cells Cell Stem Cell 9 2011 588 598
13. S.J. Chamberlain, P.F. Chen, K.Y. Ng, F. Bourgois-Rocha, F. Lemtiri-Chlieh, E.S. Levine, and M. Lalande Induced pluripotent stem cell models of the genomic imprinting disorders Angelman and Prader-Willi syndromes Proc. Natl. Acad. Sci. USA 107 2010 17668 17673
14. L. Cheng, N.F. Hansen, L. Zhao, Y. Du, C. Zou, F.X. Donovan, B.K. Chou, G. Zhou, S. Li, S.N. Dowey NISC Comparative Sequencing Program Low incidence of DNA sequence variation in human induced pluripotent stem cells generated by nonintegrating plasmid expression Cell Stem Cell 10 2012 337 344
15. A.Y. Cheung, L.M. Horvath, D. Grafodatskaya, P. Pasceri, R. Weksberg, A. Hotta, L. Carrel, and J. Ellis Isolation of MECP2-null Rett Syndrome patient hiPS cells and isogenic controls through X-chromosome inactivation Hum. Mol. Genet. 20 2011 2103 2115
16. M.H. Chin, M. Pellegrini, K. Plath, and W.E. Lowry Molecular analyses of human induced pluripotent stem cells and embryonic stem cells Cell Stem Cell 7 2010 263 269
17. J.S. Draper, K. Smith, P. Gokhale, H.D. Moore, E. Maltby, J. Johnson, L. Meisner, T.P. Zwaka, J.A. Thomson, and P.W. Andrews Recurrent gain of chromosomes 17q and 12 in cultured human embryonic stem cells Nat. Biotechnol. 22 2004 53 54
18. M.A. Esteban, T. Wang, B. Qin, J. Yang, D. Qin, J. Cai, W. Li, Z. Weng, J. Chen, and S. Ni Vitamin C enhances the generation of mouse and human induced pluripotent stem cells Cell Stem Cell 6 2010 71 79
19. Q. Feng, S.J. Lu, I. Klimanskaya, I. Gomes, D. Kim, Y. Chung, G.R. Honig, K.S. Kim, and R. Lanza Hemangioblastic derivatives from human induced pluripotent stem cells exhibit limited expansion and early senescence Stem Cells 28 2010 704 712
20. F. Gonzalez, D. Georgieva, F. Vanoli, Z.D. Shi, M. Stadtfeld, T. Ludwig, M. Jasin, and D. Huangfu Homologous Recombination DNA Repair Genes Play a Critical Role in Reprogramming to a Pluripotent State Cell reports 2013
21. A. Gore, Z. Li, H.L. Fung, J.E. Young, S. Agarwal, J. Antosiewicz-Bourget, I. Canto, A. Giorgetti, M.A. Israel, and E. Kiskinis Somatic coding mutations in human induced pluripotent stem cells Nature 471 2011 63 67
22. M.G. Guenther, G.M. Frampton, F. Soldner, D. Hockemeyer, M. Mitalipova, R. Jaenisch, and R.A. Young Chromatin structure and gene expression programs of human embryonic and induced pluripotent stem cells Cell Stem Cell 7 2010 249 257
23. P. Guha, J.W. Morgan, G. Mostoslavsky, N.P. Rodrigues, and A.S. Boyd Lack of immune response to differentiated cells derived from syngeneic induced pluripotent stem cells Cell Stem Cell 12 2013 407 412
24. M. Hamada, L.A. Malureanu, T. Wijshake, W. Zhou, and J.M. van Deursen Reprogramming to pluripotency can conceal somatic cell chromosomal instability PLoS Genet. 8 2012 e1002913
25. J. Hanna, K. Saha, B. Pando, J. van Zon, C.J. Lengner, M.P. Creyghton, A. van Oudenaarden, and R. Jaenisch Direct cell reprogramming is a stochastic process amenable to acceleration Nature 462 2009 595 601
26. T. Hirata, T. Amano, Y. Nakatake, M. Amano, Y. Piao, H.G. Hoang, and M.S. Ko Zscan4 transiently reactivates early embryonic genes during the generation of induced pluripotent stem cells Scientific Reports 2 2012 208
27. B.Y. Hu, J.P. Weick, J. Yu, L.X. Ma, X.Q. Zhang, J.A. Thomson, and S.C. Zhang Neural differentiation of human induced pluripotent stem cells follows developmental principles but with variable potency Proc. Natl. Acad. Sci. USA 107 2010 4335 4340
28. S.M. Hussein, N.N. Batada, S. Vuoristo, R.W. Ching, R. Autio, E. Närvä, S. Ng, M. Sourour, R. Hämäläinen, and C. Olsson Copy number variation and selection during reprogramming to pluripotency Nature 471 2011 58 62
29. S.M. Hussein, J. Elbaz, and A.A. Nagy Genome damage in induced pluripotent stem cells: assessing the mechanisms and their consequences BioEssays 35 2013 152 162
30. J. Ji, S.H. Ng, V. Sharma, D. Neculai, S. Hussein, M. Sam, Q. Trinh, G.M. Church, J.D. McPherson, A. Nagy, and N.N. Batada Elevated coding mutation rate during the reprogramming of human somatic cells into induced pluripotent stem cells Stem Cells 30 2012 435 440
31. J. Jiang, W. Lv, X. Ye, L. Wang, M. Zhang, H. Yang, M. Okuka, C. Zhou, X. Zhang, L. Liu, and J. Li Zscan4 promotes genomic stability during reprogramming and dramatically improves the quality of iPS cells as demonstrated by tetraploid complementation Cell Res. 23 2013 92 106
32. T. Kawamura, J. Suzuki, Y.V. Wang, S. Menendez, L.B. Morera, A. Raya, G.M. Wahl, and J.C. Izpisúa Belmonte Linking the p53 tumour suppressor pathway to somatic cell reprogramming Nature 460 2009 1140 1144
33. K. Kim, A. Doi, B. Wen, K. Ng, R. Zhao, P. Cahan, J. Kim, M.J. Aryee, H. Ji, and L.I. Ehrlich Epigenetic memory in induced pluripotent stem cells Nature 467 2010 285 290
34. K. Kim, R. Zhao, A. Doi, K. Ng, J. Unternaehrer, P. Cahan, H. Huo, Y.H. Loh, M.J. Aryee, and M.W. Lensch Donor cell type can influence the epigenome and differentiation potential of human induced pluripotent stem cells Nat. Biotechnol. 29 2011 1117 1119
35. T. Kinoshita, G. Nagamatsu, T. Kosaka, K. Takubo, A. Hotta, J. Ellis, and T. Suda Ataxia-telangiectasia mutated (ATM) deficiency decreases reprogramming efficiency and leads to genomic instability in iPS cells Biochem. Biophys. Res. Commun. 407 2011 321 326
36. L.C. Laurent, I. Ulitsky, I. Slavin, H. Tran, A. Schork, R. Morey, C. Lynch, J.V. Harness, S. Lee, and M.J. Barrero Dynamic changes in the copy number of pluripotency and cell proliferation genes in human ESCs and iPSCs during reprogramming and time in culture Cell Stem Cell 8 2011 106 118
37. L.B. Li, K.H. Chang, P.R. Wang, R.K. Hirata, T. Papayannopoulou, and D.W. Russell Trisomy correction in Down syndrome induced pluripotent stem cells Cell Stem Cell 11 2012 615 619
38. M. Li, Y. He, W. Dubois, X. Wu, J. Shi, and J. Huang Distinct regulatory mechanisms and functions for p53-activated and p53-repressed DNA damage response genes in embryonic stem cells Mol. Cell 46 2012 30 42
39. G. Liang, and Y. Zhang Embryonic stem cell and induced pluripotent stem cell: an epigenetic perspective Cell Res. 23 2013 49 69
40. T. Lin, C. Chao, S. Saito, S.J. Mazur, M.E. Murphy, E. Appella, and Y. Xu p53 induces differentiation of mouse embryonic stem cells by suppressing Nanog expression Nat. Cell Biol. 7 2005 165 171
41. R. Lister, M. Pelizzola, Y.S. Kida, R.D. Hawkins, J.R. Nery, G. Hon, J. Antosiewicz-Bourget, R. O'Malley, R. Castanon, and S. Klugman Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells Nature 471 2011 68 73
42. L. Liu, G.Z. Luo, W. Yang, X. Zhao, Q. Zheng, Z. Lv, W. Li, H.J. Wu, L. Wang, X.J. Wang, and Q. Zhou Activation of the imprinted Dlk1-Dio3 region correlates with pluripotency levels of mouse stem cells J. Biol. Chem. 285 2010 19483 19490
43. N. Maherali, R. Sridharan, W. Xie, J. Utikal, S. Eminli, K. Arnold, M. Stadtfeld, R. Yachechko, J. Tchieu, and R. Jaenisch Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution Cell Stem Cell 1 2007 55 70
44. M.C. Marchetto, C. Carromeu, A. Acab, D. Yu, G.W. Yeo, Y. Mu, G. Chen, F.H. Gage, and A.R. Muotri A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells Cell 143 2010 527 539
45. R.M. Marión, K. Strati, H. Li, M. Murga, R. Blanco, S. Ortega, O. Fernandez-Capetillo, M. Serrano, and M.A. Blasco A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity Nature 460 2009 1149 1153
46. K. Martins-Taylor, B.S. Nisler, S.M. Taapken, T. Compton, L. Crandall, K.D. Montgomery, M. Lalande, and R.H. Xu Recurrent copy number variations in human induced pluripotent stem cells Nat. Biotechnol. 29 2011 488 491
47. S. Maynard, A.M. Swistowska, J.W. Lee, Y. Liu, S.T. Liu, A.B. Da Cruz, M. Rao, N.C. de Souza-Pinto, X. Zeng, and V.A. Bohr Human embryonic stem cells have enhanced repair of multiple forms of DNA damage Stem Cells 26 2008 2266 2274
48. Y. Mayshar, U. Ben-David, N. Lavon, J.C. Biancotti, B. Yakir, A.T. Clark, K. Plath, W.E. Lowry, and N. Benvenisty Identification and classification of chromosomal aberrations in human induced pluripotent stem cells Cell Stem Cell 7 2010 521 531
49. S. Mekhoubad, C. Bock, A.S. de Boer, E. Kiskinis, A. Meissner, and K. Eggan Erosion of dosage compensation impacts human iPSC disease modeling Cell Stem Cell 10 2012 595 609
50. K. Miura, Y. Okada, T. Aoi, A. Okada, K. Takahashi, K. Okita, M. Nakagawa, M. Koyanagi, K. Tanabe, and M. Ohnuki Variation in the safety of induced pluripotent stem cell lines Nat. Biotechnol. 27 2009 743 745
51. O. Momčilović, C. Navara, and G. Schatten Cell cycle adaptations and maintenance of genomic integrity in embryonic stem cells and induced pluripotent stem cells Results Probl. Cell Differ. 53 2011 415 458
52. K.L. Nazor, G. Altun, C. Lynch, H. Tran, J.V. Harness, I. Slavin, I. Garitaonandia, F.J. Müller, Y.C. Wang, and F.S. Boscolo Recurrent variations in DNA methylation in human pluripotent stem cells and their differentiated derivatives Cell Stem Cell 10 2012 620 634
53. A.M. Newman, and J.B. Cooper Lab-specific gene expression signatures in pluripotent stem cells Cell Stem Cell 7 2010 258 262
54. K. Nishino, M. Toyoda, M. Yamazaki-Inoue, Y. Fukawatase, E. Chikazawa, H. Sakaguchi, H. Akutsu, and A. Umezawa DNA methylation dynamics in human induced pluripotent stem cells over time PLoS Genet. 7 2011 e1002085
55. Y. Ohi, H. Qin, C. Hong, L. Blouin, J.M. Polo, T. Guo, Z. Qi, S.L. Downey, P.D. Manos, and D.J. Rossi Incomplete DNA methylation underlies a transcriptional memory of somatic cells in human iPS cells Nat. Cell Biol. 13 2011 541 549
56. K. Okita, T. Ichisaka, and S. Yamanaka Generation of germline-competent induced pluripotent stem cells Nature 448 2007 313 317
57. K. Okita, N. Nagata, and S. Yamanaka Immunogenicity of induced pluripotent stem cells Circ. Res. 109 2011 720 721
58. I.H. Park, N. Arora, H. Huo, N. Maherali, T. Ahfeldt, A. Shimamura, M.W. Lensch, C. Cowan, K. Hochedlinger, and G.Q. Daley Disease-specific induced pluripotent stem cells Cell 134 2008 877 886
59. M. Pick, Y. Stelzer, O. Bar-Nur, Y. Mayshar, A. Eden, and N. Benvenisty Clone- and gene-specific aberrations of parental imprinting in human induced pluripotent stem cells Stem Cells 27 2009 2686 2690
60. J.M. Polo, S. Liu, M.E. Figueroa, W. Kulalert, S. Eminli, K.Y. Tan, E. Apostolou, M. Stadtfeld, Y. Li, and T. Shioda Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells Nat. Biotechnol. 28 2010 848 855
61. J.M. Polo, E. Anderssen, R.M. Walsh, B.A. Schwarz, C.M. Nefzger, S.M. Lim, M. Borkent, E. Apostolou, S. Alaei, and J. Cloutier A molecular roadmap of reprogramming somatic cells into iPS cells Cell 151 2012 1617 1632
62. O. Pomp, O. Dreesen, D.F. Leong, O. Meller-Pomp, T.T. Tan, F. Zhou, and A. Colman Unexpected X chromosome skewing during culture and reprogramming of human somatic cells can be alleviated by exogenous telomerase Cell Stem Cell 9 2011 156 165
63. A.R. Quinlan, M.J. Boland, M.L. Leibowitz, S. Shumilina, S.M. Pehrson, K.K. Baldwin, and I.M. Hall Genome sequencing of mouse induced pluripotent stem cells reveals retroelement stability and infrequent DNA rearrangement during reprogramming Cell Stem Cell 9 2011 366 373
64. D.A. Robinton, and G.Q. Daley The promise of induced pluripotent stem cells in research and therapy Nature 481 2012 295 305
65. S. Ruiz, D. Diep, A. Gore, A.D. Panopoulos, N. Montserrat, N. Plongthongkum, S. Kumar, H.L. Fung, A. Giorgetti, and J. Bilic Identification of a specific reprogramming-associated epigenetic signature in human induced pluripotent stem cells Proc. Natl. Acad. Sci. USA 109 2012 16196 16201
66. S. Ruiz, A. Gore, Z. Li, A.D. Panopoulos, N. Montserrat, H.L. Fung, A. Giorgetti, J. Bilic, E.M. Batchelder, and H. Zaehres Analysis of protein-coding mutations in hiPSCs and their possible role during somatic cell reprogramming Nat. Comm. 4 2013 1382
67. L. Serrano, L. Liang, Y. Chang, L. Deng, C. Maulion, S. Nguyen, and J.A. Tischfield Homologous recombination conserves DNA sequence integrity throughout the cell cycle in embryonic stem cells Stem Cells Dev. 20 2011 363 374
68. S.S. Silva, R.K. Rowntree, S. Mekhoubad, and J.T. Lee X-chromosome inactivation and epigenetic fluidity in human embryonic stem cells Proc. Natl. Acad. Sci. USA 105 2008 4820 4825
69. Z.D. Smith, I. Nachman, A. Regev, and A. Meissner Dynamic single-cell imaging of direct reprogramming reveals an early specifying event Nat. Biotechnol. 28 2010 521 526
70. M. Stadtfeld, and K. Hochedlinger Induced pluripotency: history, mechanisms, and applications Genes Dev. 24 2010 2239 2263
71. M. Stadtfeld, E. Apostolou, H. Akutsu, A. Fukuda, P. Follett, S. Natesan, T. Kono, T. Shioda, and K. Hochedlinger Aberrant silencing of imprinted genes on chromosome 12qF1 in mouse induced pluripotent stem cells Nature 465 2010 175 181
72. M. Stadtfeld, E. Apostolou, F. Ferrari, J. Choi, R.M. Walsh, T. Chen, S.S. Ooi, S.Y. Kim, T.H. Bestor, and T. Shioda Ascorbic acid prevents loss of Dlk1-Dio3 imprinting and facilitates generation of all-iPS cell mice from terminally differentiated B cells Nat. Genet. 44 2012 398 405 S391-392
73. S.M. Taapken, B.S. Nisler, M.A. Newton, T.L. Sampsell-Barron, K.A. Leonhard, E.M. McIntire, and K.D. Montgomery Karotypic abnormalities in human induced pluripotent stem cells and embryonic stem cells Nat. Biotechnol. 29 2011 313 314
74. M. Tachibana, P. Amato, M. Sparman, N.M. Gutierrez, R. Tippner-Hedges, H. Ma, E. Kang, A. Fulati, H.S. Lee, and H. Sritanaudomchai Human embryonic stem cells derived by somatic cell nuclear transfer Cell 153 2013 1228 1238
75. C.J. Taylor, S. Peacock, A.N. Chaudhry, J.A. Bradley, and E.M. Bolton Generating an iPSC bank for HLA-matched tissue transplantation based on known donor and recipient HLA types Cell Stem Cell 11 2012 147 152
76. J. Tchieu, E. Kuoy, M.H. Chin, H. Trinh, M. Patterson, S.P. Sherman, O. Aimiuwu, A. Lindgren, S. Hakimian, and J.A. Zack Female human iPSCs retain an inactive X chromosome Cell Stem Cell 7 2010 329 342
77. E.D. Tichy, R. Pillai, L. Deng, L. Liang, J. Tischfield, S.J. Schwemberger, G.F. Babcock, and P.J. Stambrook Mouse embryonic stem cells, but not somatic cells, predominantly use homologous recombination to repair double-strand DNA breaks Stem Cells Dev. 19 2010 1699 1711
78. K. Tomoda, K. Takahashi, K. Leung, A. Okada, M. Narita, N.A. Yamada, K.E. Eilertson, P. Tsang, S. Baba, and M.P. White Derivation conditions impact X-inactivation status in female human induced pluripotent stem cells Cell Stem Cell 11 2012 91 99
79. J. Utikal, J.M. Polo, M. Stadtfeld, N. Maherali, W. Kulalert, R.M. Walsh, A. Khalil, J.G. Rheinwald, and K. Hochedlinger Immortalization eliminates a roadblock during cellular reprogramming into iPS cells Nature 460 2009 1145 1148
80. A. Wutz Epigenetic alterations in human pluripotent stem cells: a tale of two cultures Cell Stem Cell 11 2012 9 15
81. Y. Yoshida, K. Takahashi, K. Okita, T. Ichisaka, and S. Yamanaka Hypoxia enhances the generation of induced pluripotent stem cells Cell Stem Cell 5 2009 237 241
82. M.A. Young, D.E. Larson, C.W. Sun, D.R. George, L. Ding, C.A. Miller, L. Lin, K.M. Pawlik, K. Chen, and X. Fan Background mutations in parental cells account for most of the genetic heterogeneity of induced pluripotent stem cells Cell Stem Cell 10 2012 570 582
83. T. Zhao, Z.N. Zhang, Z. Rong, and Y. Xu Immunogenicity of induced pluripotent stem cells Nature 474 2011 212 215
84. J. Zhu, M. Adli, J.Y. Zou, G. Verstappen, M. Coyne, X. Zhang, T. Durham, M. Miri, V. Deshpande, and P.L. De Jager Genome-wide chromatin state transitions associated with developmental and environmental cues Cell 152 2013 642 654