Epigenetic regulation of pluripotency and differentiation

Circulation Research

Volumn 115, Issue 2, 2014, Pages 311-324

  Boland, Michael J ^a   Nazor, Kristopher L ^a   Loring, Jeanne F ^a  

^a SCRIPPS RESEARCH INSTITUTE   (United States)

Author keywords

epigenomics; methylation; pluripotent; stem cell

Indexed keywords

HISTONE; UNTRANSLATED RNA; DIOXYGENASE; DNA (CYTOSINE 5) METHYLTRANSFERASE;

CELL DIFFERENTIATION; CELL FATE; CHROMATIN STRUCTURE; DNA METHYLATION; DNA MODIFICATION; EMBRYO DEVELOPMENT; EPIGENETIC REPRESSION; EPIGENETICS; GENE CONTROL; GENE EXPRESSION; GENOME; HISTONE CODE; HISTONE MODIFICATION; HUMAN; NONHUMAN; NUCLEAR REPROGRAMMING; NUCLEOSOME; ORGANOGENESIS; PLURIPOTENT STEM CELL; PLURIPOTENT STEM CELL LINE; PRIORITY JOURNAL; PROTEIN PROCESSING; REVIEW; X CHROMOSOME INACTIVATION; ACETYLATION; ANIMAL; BIOLOGICAL MODEL; CPG ISLAND; CYTOLOGY; ENHANCER REGION; GENE EXPRESSION REGULATION; GENETIC EPIGENESIS; GENETICS; HEART MUSCLE CELL; METABOLISM; MOUSE; PHOSPHORYLATION; PHYSIOLOGY; PROMOTER REGION;

ACETYLATION; ANIMALS; CELL DIFFERENTIATION; CPG ISLANDS; DIOXYGENASES; DNA (CYTOSINE-5-)-METHYLTRANSFERASE; DNA METHYLATION; ENHANCER ELEMENTS, GENETIC; EPIGENESIS, GENETIC; GENE EXPRESSION REGULATION, DEVELOPMENTAL; HISTONES; HUMANS; MICE; MODELS, BIOLOGICAL; MYOCYTES, CARDIAC; PHOSPHORYLATION; PLURIPOTENT STEM CELLS; PROMOTER REGIONS, GENETIC; PROTEIN PROCESSING, POST-TRANSLATIONAL; X CHROMOSOME INACTIVATION;

EID: 84903945993     PISSN: 00097330     EISSN: 15244571     Source Type: Journal    
DOI: 10.1161/CIRCRESAHA.115.301517     Document Type: Review

References (145)

1. Gaspard N, Bouschet T, Hourez R, Dimidschstein J, Naeije G, van den Ameele J, Espuny-Camacho I, Herpoel A, Passante L, Schiffmann SN, Gaillard A, Vanderhaeghen P. An intrinsic mechanism of corticogenesis from embryonic stem cells. Nature. 2008;455:351-357.
2. Shi Y, Kirwan P, Smith J, Robinson HP, Livesey FJ. Human cerebral cortex development from pluripotent stem cells to functional excitatory synapses. Nat Neurosci. 2012;15:477-486, S1.
3. Espuny-Camacho I, Michelsen KA, Gall D, et al. Pyramidal neurons derived from human pluripotent stem cells integrate efficiently into mouse brain circuits in vivo. Neuron. 2013;77:440-456.
4. Eiraku M, Takata N, Ishibashi H, Kawada M, Sakakura E, Okuda S, Sekiguchi K, Adachi T, Sasai Y. Self-organizing optic-cup morphogenesis in three-dimensional culture. Nature. 2011;472:51-56.
5. Lancaster MA, Renner M, Martin CA, Wenzel D, Bicknell LS, Hurles ME, Homfray T, Penninger JM, Jackson AP, Knoblich JA. Cerebral organoids model human brain development and microcephaly. Nature. 2013;501:373-379.
6. Takebe T, Sekine K, Enomura M, Koike H, Kimura M, Ogaeri T, Zhang RR, Ueno Y, Zheng YW, Koike N, Aoyama S, Adachi Y, Taniguchi H. Vascularized and functional human liver from an iPSC-derived organ bud transplant. Nature. 2013;499:481-484.
7. Boland MJ, Hazen JL, Nazor KL, Rodriguez AR, Gifford W, Martin G, Kupriyanov S, Baldwin KK. Adult mice generated from induced pluripotent stem cells. Nature. 2009;461:91-94.
8. Zhao XY, Li W, Lv Z, Liu L, Tong M, Hai T, Hao J, Guo CL, Ma QW, Wang L, Zeng F, Zhou Q. iPS cells produce viable mice through tetraploid complementation. Nature. 2009;461:86-90.
9. Berger SL, Kouzarides T, Shiekhattar R, Shilatifard A. An operational definition of epigenetics. Genes Dev. 2009;23:781-783.
10. Bird A. Perceptions of epigenetics. Nature. 2007;447:396-398. (Pubitemid 46816744)
11. Christman JK, Price P, Pedrinan L, Acs G. Correlation between hypomethylation of DNA and expression of globin genes in Friend erythroleukemia cells. Eur J Biochem. 1977;81:53-61. (Pubitemid 8214592)
12. McGhee JD, Ginder GD. Specific DNA methylation sites in the vicinity of the chicken beta-globin genes. Nature. 1979;280:419-420. (Pubitemid 9233622)
13. Jones PA, Taylor SM. Cellular differentiation, cytidine analogs and DNA methylation. Cell. 1980;20:85-93. (Pubitemid 10117303)
14. Jenuwein T, Allis CD. Translating the histone code. Science. 2001;293:1074-1080. (Pubitemid 32758077)
15. Taverna SD, Li H, Ruthenburg AJ, Allis CD, Patel DJ. How chromatinbinding modules interpret histone modifications: lessons from professional pocket pickers. Nat Struct Mol Biol. 2007;14:1025-1040. (Pubitemid 350060344)
16. Christman JK. 5-Azacytidine and 5-aza-2'-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy. Oncogene. 2002;21:5483-5495. (Pubitemid 34983483)
17. Lister R, Pelizzola M, Kida YS, et al. Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature. 2011;471:68-73.
18. Xie W, Barr CL, Kim A, Yue F, Lee AY, Eubanks J, Dempster EL, Ren B. Base-resolution analyses of sequence and parent-of-origin dependent DNA methylation in the mouse genome. Cell. 2012;148:816-831.
19. Wienholz BL, Kareta MS, Moarefi AH, Gordon CA, Ginno PA, Chédin F. DNMT3L modulates significant and distinct flanking sequence preference for DNA methylation by DNMT3A and DNMT3B in vivo. PLoS Genet. 2010;6:e1001106.
20. Li E. Chromatin modification and epigenetic reprogramming in mammalian development. Nat Rev Genet. 2002;3:662-673. (Pubitemid 34984255)
21. Tsumura A, Hayakawa T, Kumaki Y, Takebayashi S, Sakaue M, Matsuoka C, Shimotohno K, Ishikawa F, Li E, Ueda HR, Nakayama J, Okano M. Maintenance of self-renewal ability of mouse embryonic stem cells in the absence of DNA methyltransferases Dnmt1, Dnmt3a and Dnmt3b. Genes Cells. 2006;11:805-814. (Pubitemid 43923351)
22. Okano M, Bell DW, Haber DA, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell. 1999;99:247-257. (Pubitemid 29519904)
23. Li E, Bestor TH, Jaenisch R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell. 1992;69:915-926.
24. Klose RJ, Bird AP. Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci. 2006;31:89-97. (Pubitemid 43221841)
25. Fouse SD, Shen Y, Pellegrini M, Cole S, Meissner A, Van Neste L, Jaenisch R, Fan G. Promoter CpG methylation contributes to ES cell gene regulation in parallel with Oct4/Nanog, PcG complex, and histone H3 K4/ K27 trimethylation. Cell Stem Cell. 2008;2:160-169. (Pubitemid 351168712)
26. Mikkelsen TS, Ku M, Jaffe DB, et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature. 2007;448:553-560. (Pubitemid 47206934)
27. Nazor KL, Altun G, Lynch C, et al. Recurrent variations in DNA methylation in human pluripotent stem cells and their differentiated derivatives. Cell Stem Cell. 2012;10:620-634.
28. Bernstein BE, Mikkelsen TS, Xie X, Kamal M, Huebert DJ, Cuff J, Fry B, Meissner A, Wernig M, Plath K, Jaenisch R, Wagschal A, Feil R, Schreiber SL, Lander ES. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell. 2006;125:315-326.
29. Laurent L, Wong E, Li G, Huynh T, Tsirigos A, Ong CT, Low HM, Kin Sung KW, Rigoutsos I, Loring J, Wei CL. Dynamic changes in the human methylome during differentiation. Genome Res. 2010;20:320-331.
30. Ball MP, Li JB, Gao Y, Lee JH, LeProust EM, Park IH, Xie B, Daley GQ, Church GM. Targeted and genome-scale strategies reveal gene-body methylation signatures in human cells. Nat Biotechnol. 2009;27:361-368.
31. Bibikova M, Chudin E, Wu B, et al. Human embryonic stem cells have a unique epigenetic signature. Genome Res. 2006;16:1075-1083. (Pubitemid 44320394)
32. Abbey D, Seshagiri PB. Aza-induced cardiomyocyte differentiation of P19 EC-cells by epigenetic co-regulation and ERK signaling. Gene. 2013;526:364-373.
33. Gu Y, Liu GH, Plongthongkum N, et al. Global DNA methylation and transcriptional analyses of human ESC-derived cardiomyocytes. Protein Cell. 2014;5:59-68.
34. Lister R, Mukamel EA, Nery JR, et al. Global epigenomic reconfiguration during mammalian brain development. Science. 2013;341:1237905.
35. Lister R, Pelizzola M, Dowen RH, et al. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature. 2009;462:315-322.
36. Gowher H, Jeltsch A. Enzymatic properties of recombinant Dnmt3a DNA methyltransferase from mouse: the enzyme modifies DNA in a non-processive manner and also methylates non-CpG [correction of non-CpA] sites. J Mol Biol. 2001;309:1201-1208. (Pubitemid 32623318)
37. Ramsahoye BH, Biniszkiewicz D, Lyko F, Clark V, Bird AP, Jaenisch R. Non-CpG methylation is prevalent in embryonic stem cells and may be mediated by DNA methyltransferase 3a. Proc Natl Acad Sci U S A. 2000;97:5237-5242. (Pubitemid 30313702)
38. Guo JU, Su Y, Zhong C, Ming GL, Song H. Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell. 2011;145:423-434.
39. Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, Agarwal S, Iyer LM, Liu DR, Aravind L, Rao A. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science. 2009;324:930-935.
40. Kriaucionis S, Heintz N. The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science. 2009;324:929-930.
41. Pastor WA, Pape UJ, Huang Y, et al. Genome-wide mapping of 5-hydroxymethylcytosine in embryonic stem cells. Nature. 2011;473:394-397.
42. Szulwach KE, Li X, Li Y, Song CX, Han JW, Kim S, Namburi S, Hermetz K, Kim JJ, Rudd MK, Yoon YS, Ren B, He C, Jin P. Integrating 5- hydroxymethylcytosine into the epigenomic landscape of human embryonic stem cells. PLoS Genet. 2011;7:e1002154.
43. Wu H, D'Alessio AC, Ito S, Wang Z, Cui K, Zhao K, Sun YE, Zhang Y. Genome-wide analysis of 5-hydroxymethylcytosine distribution reveals its dual function in transcriptional regulation in mouse embryonic stem cells. Genes Dev. 2011;25:679-684.
44. Szulwach KE, Li X, Li Y, et al. 5-hmC-mediated epigenetic dynamics during postnatal neurodevelopment and aging. Nat Neurosci. 2011;14:1607-1616.
45. Wu H, Coskun V, Tao J, Xie W, Ge W, Yoshikawa K, Li E, Zhang Y, Sun YE. Dnmt3a-dependent nonpromoter DNA methylation facilitates transcription of neurogenic genes. Science. 2010;329:444-448.
46. Dawlaty MM, Ganz K, Powell BE, Hu YC, Markoulaki S, Cheng AW, Gao Q, Kim J, Choi SW, Page DC, Jaenisch R. Tet1 is dispensable for maintaining pluripotency and its loss is compatible with embryonic and postnatal development. Cell Stem Cell. 2011;9:166-175.
47. Koh KP, Yabuuchi A, Rao S, Huang Y, Cunniff K, Nardone J, Laiho A, Tahiliani M, Sommer CA, Mostoslavsky G, Lahesmaa R, Orkin SH, Rodig SJ, Daley GQ, Rao A. Tet1 and Tet2 regulate 5-hydroxymethylcytosine production and cell lineage specification in mouse embryonic stem cells. Cell Stem Cell. 2011;8:200-213.
48. Ko M, Bandukwala HS, An J, Lamperti ED, Thompson EC, Hastie R, Tsangaratou A, Rajewsky K, Koralov SB, Rao A. Ten-Eleven-Translocation 2 (TET2) negatively regulates homeostasis and differentiation of hematopoietic stem cells in mice. Proc Natl Acad Sci U S A. 2011;108:14566-14571.
49. Quivoron C, Couronné L, Della Valle V, et al. TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis. Cancer Cell. 2011;20:25-38.
50. Dawlaty MM, Breiling A, Le T, Raddatz G, Barrasa MI, Cheng AW, Gao Q, Powell BE, Li Z, Xu M, Faull KF, Lyko F, Jaenisch R. Combined deficiency of Tet1 and Tet2 causes epigenetic abnormalities but is compatible with postnatal development. Dev Cell. 2013;24:310-323.
51. Spruijt CG, Gnerlich F, Smits AH, et al. Dynamic readers for 5-(hydroxy) methylcytosine and its oxidized derivatives. Cell. 2013;152:1146-1159.
52. Hashimoto H, Liu Y, Upadhyay AK, Chang Y, Howerton SB, Vertino PM, Zhang X, Cheng X. Recognition and potential mechanisms for replication and erasure of cytosine hydroxymethylation. Nucleic Acids Res. 2012;40:4841-4849.
53. Jin SG, Kadam S, Pfeifer GP. Examination of the specificity of DNA methylation profiling techniques towards 5-methylcytosine and 5-hydroxymethylcytosine. Nucleic Acids Res. 2010;38:e125.
54. Valinluck V, Tsai HH, Rogstad DK, Burdzy A, Bird A, Sowers LC. Oxidative damage to methyl-CpG sequences inhibits the binding of the methyl-CpG binding domain (MBD) of methyl-CpG binding protein 2 (MeCP2). Nucleic Acids Res. 2004;32:4100-4108. (Pubitemid 39232282)
55. Yildirim O, Li R, Hung JH, Chen PB, Dong X, Ee LS, Weng Z, Rando OJ, Fazzio TG. Mbd3/NURD complex regulates expression of 5-hydroxymethylcytosine marked genes in embryonic stem cells. Cell. 2011;147:1498-1510.
56. Mellén M, Ayata P, Dewell S, Kriaucionis S, Heintz N. MeCP2 binds to 5hmC enriched within active genes and accessible chromatin in the nervous system. Cell. 2012;151:1417-1430.
57. Mayer W, Niveleau A, Walter J, Fundele R, Haaf T. Demethylation of the zygotic paternal genome. Nature. 2000;403:501-502. (Pubitemid 30082186)
58. Oswald J, Engemann S, Lane N, Mayer W, Olek A, Fundele R, Dean W, Reik W, Walter J. Active demethylation of the paternal genome in the mouse zygote. Curr Biol. 2000;10:475-478. (Pubitemid 30247337)
59. Kaas GA, Zhong C, Eason DE, Ross DL, Vachhani RV, Ming GL, King JR, Song H, Sweatt JD. TET1 controls CNS 5-methylcytosine hydroxylation, active DNA demethylation, gene transcription, and memory formation. Neuron. 2013;79:1086-1093.
60. Ma DK, Jang MH, Guo JU, Kitabatake Y, Chang ML, Pow-Anpongkul N, Flavell RA, Lu B, Ming GL, Song H. Neuronal activity-induced Gadd45b promotes epigenetic DNA demethylation and adult neurogenesis. Science. 2009;323:1074-1077.
61. Rudenko A, Dawlaty MM, Seo J, Cheng AW, Meng J, Le T, Faull KF, Jaenisch R, Tsai LH. Tet1 is critical for neuronal activity-regulated gene expression and memory extinction. Neuron. 2013;79:1109-1122.
62. Gehring M, Reik W, Henikoff S. DNA demethylation by DNA repair. Trends Genet. 2009;25:82-90.
63. Bhutani N, Burns DM, Blau HM. DNA demethylation dynamics. Cell. 2011;146:866-872.
64. Sjolund AB, Senejani AG, Sweasy JB. MBD4 and TDG: multifaceted DNA glycosylases with ever expanding biological roles. Mutat Res. 2013;743-744:12-25.
65. Cortellino S, Xu J, Sannai M, et al. Thymine DNA glycosylase is essential for active DNA demethylation by linked deamination-base excision repair. Cell. 2011;146:67-79.
66. Métivier R, Gallais R, Tiffoche C, Le Péron C, Jurkowska RZ, Carmouche RP, Ibberson D, Barath P, Demay F, Reid G, Benes V, Jeltsch A, Gannon F, Salbert G. Cyclical DNA methylation of a transcriptionally active promoter. Nature. 2008;452:45-50. (Pubitemid 351355084)
67. Bhutani N, Brady JJ, Damian M, Sacco A, Corbel SY, Blau HM. Reprogramming towards pluripotency requires AID-dependent DNA demethylation. Nature. 2010;463:1042-1047.
68. Nabel CS, Jia H, Ye Y, Shen L, Goldschmidt HL, Stivers JT, Zhang Y, Kohli RM. AID/APOBEC deaminases disfavor modified cytosines implicated in DNA demethylation. Nat Chem Biol. 2012;8:751-758.
69. Niehrs C, Schäfer A. Active DNA demethylation by Gadd45 and DNA repair. Trends Cell Biol. 2012;22:220-227.
70. Ito S, Shen L, Dai Q, Wu SC, Collins LB, Swenberg JA, He C, Zhang Y. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science. 2011;333:1300-1303.
71. He YF, Li BZ, Li Z, et al. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science. 2011;333:1303-1307.
72. Maiti A, Drohat AC. Thymine DNA glycosylase can rapidly excise 5-formylcytosine and 5-carboxylcytosine: potential implications for active demethylation of CpG sites. J Biol Chem. 2011;286:35334-35338.
73. Shen L, Wu H, Diep D, Yamaguchi S, D'Alessio AC, Fung HL, Zhang K, Zhang Y. Genome-wide analysis reveals TET-and TDG-dependent 5-methylcytosine oxidation dynamics. Cell. 2013;153:692-706.
74. Song CX, Szulwach KE, Dai Q, et al. Genome-wide profiling of 5-formylcytosine reveals its roles in epigenetic priming. Cell. 2013;153:678-691.
75. Gu TP, Guo F, Yang H, et al. The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytes. Nature. 2011;477:606-610.
76. Iqbal K, Jin SG, Pfeifer GP, Szabó PE. Reprogramming of the paternal genome upon fertilization involves genome-wide oxidation of 5-methylcytosine. Proc Natl Acad Sci U S A. 2011;108:3642-3647.
77. Wossidlo M, Nakamura T, Lepikhov K, Marques CJ, Zakhartchenko V, Boiani M, Arand J, Nakano T, Reik W, Walter J. 5-Hydroxymethylcytosine in the mammalian zygote is linked with epigenetic reprogramming. Nat Commun. 2011;2:241.
78. Bannister AJ, Kouzarides T. Regulation of chromatin by histone modifications. Cell Res. 2011;21:381-395.
79. Christophorou MA, Castelo-Branco G, Halley-Stott RP, Oliveira CS, Loos R, Radzisheuskaya A, Mowen KA, Bertone P, Silva JC, Zernicka-Goetz M, Nielsen ML, Gurdon JB, Kouzarides T. Citrullination regulates pluripotency and histone H1 binding to chromatin. Nature. 2014;507:104-108.
80. Ernst J, Kheradpour P, Mikkelsen TS, Shoresh N, Ward LD, Epstein CB, Zhang X, Wang L, Issner R, Coyne M, Ku M, Durham T, Kellis M, Bernstein BE. Mapping and analysis of chromatin state dynamics in nine human cell types. Nature. 2011;473:43-49.
81. Aloia L, Di Stefano B, Di Croce L. Polycomb complexes in stem cells and embryonic development. Development. 2013;140:2525-2534.
82. Leeb M, Pasini D, Novatchkova M, Jaritz M, Helin K, Wutz A. Polycomb complexes act redundantly to repress genomic repeats and genes. Genes Dev. 2010;24:265-276.
83. Leeb M, Wutz A. Ring1B is crucial for the regulation of developmental control genes and PRC1 proteins but not X inactivation in embryonic cells. J Cell Biol. 2007;178:219-229. (Pubitemid 47076459)
84. Klattenhoff CA, Scheuermann JC, Surface LE, Bradley RK, Fields PA, Steinhauser ML, Ding H, Butty VL, Torrey L, Haas S, Abo R, Tabebordbar M, Lee RT, Burge CB, Boyer LA. Braveheart, a long noncoding RNA required for cardiovascular lineage commitment. Cell. 2013;152:570-583.
85. Li X, Li L, Pandey R, Byun JS, Gardner K, Qin Z, Dou Y. The histone acetyltransferase MOF is a key regulator of the embryonic stem cell core transcriptional network. Cell Stem Cell. 2012;11:163-178.
86. Ku M, Koche RP, Rheinbay E, et al. Genomewide analysis of PRC1 and PRC2 occupancy identifies two classes of bivalent domains. PLoS Genet. 2008;4:e1000242.
87. Barrera LO, Li Z, Smith AD, Arden KC, Cavenee WK, Zhang MQ, Green RD, Ren B. Genome-wide mapping and analysis of active promoters in mouse embryonic stem cells and adult organs. Genome Res. 2008;18:46-59.
88. Xie W, Schultz MD, Lister R, et al. Epigenomic analysis of multilineage differentiation of human embryonic stem cells. Cell. 2013;153:1134-1148.
89. Bernstein BE, Birney E, Dunham I, Green ED, Gunter C, Snyder M; ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012;489:57-74.
90. Heintzman ND, Stuart RK, Hon G, Fu Y, Ching CW, Hawkins RD, Barrera LO, Van Calcar S, Qu C, Ching KA, Wang W, Weng Z, Green RD, Crawford GE, Ren B. Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat Genet. 2007;39:311-318. (Pubitemid 46328487)
91. Kornberg RD. Mediator and the mechanism of transcriptional activation. Trends Biochem Sci. 2005;30:235-239. (Pubitemid 40693865)
92. Chen X, Xu H, Yuan P, et al. Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. Cell. 2008;133:1106-1117. (Pubitemid 351787745)
93. Kagey MH, Newman JJ, Bilodeau S, Zhan Y, Orlando DA, van Berkum NL, Ebmeier CC, Goossens J, Rahl PB, Levine SS, Taatjes DJ, Dekker J, Young RA. Mediator and cohesin connect gene expression and chromatin architecture. Nature. 2010;467:430-435.
94. Heintzman ND, Hon GC, Hawkins RD, et al. Histone modifications at human enhancers reflect global cell-type-specific gene expression. Nature. 2009;459:108-112.
95. Rada-Iglesias A, Bajpai R, Swigut T, Brugmann SA, Flynn RA, Wysocka J. A unique chromatin signature uncovers early developmental enhancers in humans. Nature. 2011;470:279-283.
96. Gifford CA, Ziller MJ, Gu H, et al. Transcriptional and epigenetic dynamics during specification of human embryonic stem cells. Cell. 2013;153:1149-1163.
97. Hnisz D, Abraham BJ, Lee TI, Lau A, Saint-André V, Sigova AA, Hoke HA, Young RA. Super-enhancers in the control of cell identity and disease. Cell. 2013;155:934-947.
98. Whyte WA, Orlando DA, Hnisz D, Abraham BJ, Lin CY, Kagey MH, Rahl PB, Lee TI, Young RA. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell. 2013;153:307-319.
99. Hawkins RD, Hon GC, Lee LK, et al. Distinct epigenomic landscapes of pluripotent and lineage-committed human cells. Cell Stem Cell. 2010;6:479-491.
100. Zhu J, Adli M, Zou JY, et al. Genome-wide chromatin state transitions associated with developmental and environmental cues. Cell. 2013;152:642-654.
101. Paige SL, Thomas S, Stoick-Cooper CL, Wang H, Maves L, Sandstrom R, Pabon L, Reinecke H, Pratt G, Keller G, Moon RT, Stamatoyannopoulos J, Murry CE. A temporal chromatin signature in human embryonic stem cells identifies regulators of cardiac development. Cell. 2012;151:221-232.
102. Stergachis AB, Neph S, Reynolds A, Humbert R, Miller B, Paige SL, Vernot B, Cheng JB, Thurman RE, Sandstrom R, Haugen E, Heimfeld S, Murry CE, Akey JM, Stamatoyannopoulos JA. Developmental fate and cellular maturity encoded in human regulatory DNA landscapes. Cell. 2013;154:888-903.
103. Delgado-Olguín P, Huang Y, Li X, Christodoulou D, Seidman CE, Seidman JG, Tarakhovsky A, Bruneau BG. Epigenetic repression of cardiac progenitor gene expression by Ezh2 is required for postnatal cardiac homeostasis. Nat Genet. 2012;44:343-347.
104. Wamstad JA, Alexander JM, Truty RM, et al. Dynamic and coordinated epigenetic regulation of developmental transitions in the cardiac lineage. Cell. 2012;151:206-220.
105. Zhang JA, Mortazavi A, Williams BA, Wold BJ, Rothenberg EV. Dynamic transformations of genome-wide epigenetic marking and transcriptional control establish T cell identity. Cell. 2012;149:467-482.
106. Felsenfeld G, Groudine M. Controlling the double helix. Nature. 2003;421:448-453. (Pubitemid 36157954)
107. de Wit E, de Laat W. A decade of 3C technologies: insights into nuclear organization. Genes Dev. 2012;26:11-24.
108. Bickmore WA, van Steensel B. Genome architecture: domain organization of interphase chromosomes. Cell. 2013;152:1270-1284.
109. Meshorer E, Misteli T. Chromatin in pluripotent embryonic stem cells and differentiation. Nat Rev Mol Cell Biol. 2006;7:540-546. (Pubitemid 44036459)
110. Guelen L, Pagie L, Brasset E, Meuleman W, Faza MB, Talhout W, Eussen BH, de Klein A, Wessels L, de Laat W, van Steensel B. Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions. Nature. 2008;453:948-951. (Pubitemid 351832561)
111. Peric-Hupkes D, Meuleman W, Pagie L, Bruggeman SW, Solovei I, Brugman W, Gräf S, Flicek P, Kerkhoven RM, van Lohuizen M, Reinders M, Wessels L, van Steensel B. Molecular maps of the reorganization of genome-nuclear lamina interactions during differentiation. Mol Cell. 2010;38:603-613.
112. Dixon JR, Selvaraj S, Yue F, Kim A, Li Y, Shen Y, Hu M, Liu JS, Ren B. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature. 2012;485:376-380.
113. Handoko L, Xu H, Li G, et al. CTCF-mediated functional chromatin interactome in pluripotent cells. Nat Genet. 2011;43:630-638.
114. Kim YJ, Cecchini KR, Kim TH. Conserved, developmentally regulated mechanism couples chromosomal looping and heterochromatin barrier activity at the homeobox gene A locus. Proc Natl Acad Sci U S A. 2011;108:7391-7396.
115. Donohoe ME, Silva SS, Pinter SF, Xu N, Lee JT. The pluripotency factor Oct4 interacts with Ctcf and also controls X-chromosome pairing and counting. Nature. 2009;460:128-132.
116. Jin F, Li Y, Dixon JR, Selvaraj S, Ye Z, Lee AY, Yen CA, Schmitt AD, Espinoza CA, Ren B. A high-resolution map of the three-dimensional chromatin interactome in human cells. Nature. 2013;503:290-294.
117. de Wit E, Bouwman BA, Zhu Y, Klous P, Splinter E, Verstegen MJ, Krijger PH, Festuccia N, Nora EP, Welling M, Heard E, Geijsen N, Poot RA, Chambers I, de Laat W. The pluripotent genome in three dimensions is shaped around pluripotency factors. Nature. 2013;501:227-231.
118. Kieffer-Kwon KR, Tang Z, Mathe E, et al. Interactome maps of mouse gene regulatory domains reveal basic principles of transcriptional regulation. Cell. 2013;155:1507-1520.
119. Zhang Y, Wong CH, Birnbaum RY, et al. Chromatin connectivity maps reveal dynamic promoter-enhancer long-range associations. Nature. 2013;504:306-310.
120. Reik W, Walter J. Genomic imprinting: parental influence on the genome. Nat Rev Genet. 2001;2:21-32. (Pubitemid 33674766)
121. Gregg C, Zhang J, Weissbourd B, Luo S, Schroth GP, Haig D, Dulac C. High-resolution analysis of parent-of-origin allelic expression in the mouse brain. Science. 2010;329:643-648.
122. DeVeale B, van der Kooy D, Babak T. Critical evaluation of imprinted gene expression by RNA-Seq: a new perspective. PLoS Genet. 2012;8:e1002600.
123. Millan MJ. An epigenetic framework for neurodevelopmental disorders: from pathogenesis to potential therapy. Neuropharmacology. 2013;68:2-82.
124. Mekhoubad S, Bock C, de Boer AS, Kiskinis E, Meissner A, Eggan K. Erosion of dosage compensation impacts human iPSC disease modeling. Cell Stem Cell. 2012;10:595-609.
125. Shen Y, Matsuno Y, Fouse SD, Rao N, Root S, Xu R, Pellegrini M, Riggs AD, Fan G. X-inactivation in female human embryonic stem cells is in a nonrandom pattern and prone to epigenetic alterations. Proc Natl Acad Sci U S A. 2008;105:4709-4714. (Pubitemid 351753811)
126. Papp B, Plath K. Epigenetics of reprogramming to induced pluripotency. Cell. 2013;152:1324-1343.
127. Mikkelsen TS, Hanna J, Zhang X, Ku M, Wernig M, Schorderet P, Bernstein BE, Jaenisch R, Lander ES, Meissner A. Dissecting direct reprogramming through integrative genomic analysis. Nature. 2008;454:49-55. (Pubitemid 351931978)
128. Rais Y, Zviran A, Geula S, et al. Deterministic direct reprogramming of somatic cells to pluripotency. Nature. 2013;502:65-70.
129. Huangfu D, Maehr R, Guo W, Eijkelenboom A, Snitow M, Chen AE, Melton DA. Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds. Nat Biotechnol. 2008;26:795-797. (Pubitemid 351961456)
130. Hai T, Hao J, Wang L, Jouneau A, Zhou Q. Pluripotency maintenance in mouse somatic cell nuclear transfer embryos and its improvement by treatment with the histone deacetylase inhibitor TSA. Cell Reprogram. 2011;13:47-56.
131. Kim K, Doi A, Wen B, et al. Epigenetic memory in induced pluripotent stem cells. Nature. 2010;467:285-290.
132. Chung YG, Eum JH, Lee JE, Shim SH, Sepilian V, Hong SW, Lee Y, Treff NR, Choi YH, Kimbrel EA, Dittman RE, Lanza R, Lee DR. Human Somatic Cell Nuclear Transfer Using Adult Cells. Cell Stem Cell. 2014;14:777-780.
133. Tachibana M, Amato P, Sparman M, et al. Human embryonic stem cells derived by somatic cell nuclear transfer. Cell. 2013;153:1228-1238.
134. Yamada M, Kuroda H, Yoshida M, Jomen W, Abe T, Sakurai T, Fujii S, Maeda M, Fujita M, Nagashima K, Matsuno T, Sato M, Kato J. Successful Treatment of an essential thrombocythemia patient complicated by Sweet's syndrome with combination of chemotherapy and lenalidomide. Rinsho Ketsueki. 2014;55:440-444.
135. Polo JM, Liu S, Figueroa ME, Kulalert W, Eminli S, Tan KY, Apostolou E, Stadtfeld M, Li Y, Shioda T, Natesan S, Wagers AJ, Melnick A, Evans T, Hochedlinger K. Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells. Nat Biotechnol. 2010;28:848-855.
136. Kim K, Zhao R, Doi A, Ng K, Unternaehrer J, Cahan P, Huo H, Loh YH, Aryee MJ, Lensch MW, Li H, Collins JJ, Feinberg AP, Daley GQ. Donor cell type can influence the epigenome and differentiation potential of human induced pluripotent stem cells. Nat Biotechnol. 2011;29:1117-1119.
137. Bar-Nur O, Russ HA, Efrat S, Benvenisty N. Epigenetic memory and preferential lineage-specific differentiation in induced pluripotent stem cells derived from human pancreatic islet beta cells. Cell Stem Cell. 2011;9:17-23.
138. Ohi Y, Qin H, Hong C, et al. Incomplete DNA methylation underlies a transcriptional memory of somatic cells in human iPS cells. Nat Cell Biol. 2011;13:541-549.
139. Chin MH, Pellegrini M, Plath K, Lowry WE. Molecular analyses of human induced pluripotent stem cells and embryonic stem cells. Cell Stem Cell. 2010;7:263-269.
140. Guenther MG, Frampton GM, Soldner F, Hockemeyer D, Mitalipova M, Jaenisch R, Young RA. Chromatin structure and gene expression programs of human embryonic and induced pluripotent stem cells. Cell Stem Cell. 2010;7:249-257.
141. Bock C, Kiskinis E, Verstappen G, Gu H, Boulting G, Smith ZD, Ziller M, Croft GF, Amoroso MW, Oakley DH, Gnirke A, Eggan K, Meissner A. Reference Maps of human ES and iPS cell variation enable high-throughput characterization of pluripotent cell lines. Cell. 2011;144:439-452.
142. Nishino K, Toyoda M, Yamazaki-Inoue M, Fukawatase Y, Chikazawa E, Sakaguchi H, Akutsu H, Umezawa A. DNA methylation dynamics in human induced pluripotent stem cells over time. PLoS Genet. 2011;7:e1002085.
143. Rugg-Gunn PJ, Ferguson-Smith AC, Pedersen RA. Epigenetic status of human embryonic stem cells. Nat Genet. 2005;37:585-587. (Pubitemid 40770411)
144. Ruthenburg AJ, Li H, Milne TA, Dewell S, McGinty RK, Yuen M, Ueberheide B, Dou Y, Muir TW, Patel DJ, Allis CD. Recognition of a mononucleosomal histone modification pattern by BPTF via multivalent interactions. Cell. 2011;145:692-706.
145. Fanucchi S, Shibayama Y, Burd S, Weinberg MS, Mhlanga MM. Chromosomal contact permits transcription between coregulated genes. Cell. 2013;155:606-620.