Epigenetic Regulation of Stem Cells

The Role of Chromatin in Cell Differentiation
  • Anton WutzEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 786)


The specialized cell types of tissues and organs are generated during development and are replenished over lifetime though the process of differentiation. During differentiation the characteristics and identity of cells are changed to meet their functional requirements. Differentiated cells then faithfully maintain their characteristic gene expression patterns. On the molecular level transcription factors have a key role in instructing specific gene expression programs. They act together with chromatin regulators which stabilize expression patterns. Current evidence indicates that epigenetic mechanisms are essential for maintaining stable cell identities. Conversely, the disruption of chromatin regulators is associated with disease and cellular transformation. In mammals, a large number of chromatin regulators have been identified. The Polycomb group complexes and the DNA methylation system have been widely studied in development. Other chromatin regulators remain to be explored. This chapter focuses on recent advances in understanding epigenetic regulation in embryonic and adult stem cells in mammals. The available data illustrate that several chromatin regulators control key lineage specific genes. Different epigenetic systems potentially could provide stability and guard against loss or mutation of individual components. Recent experiments also suggest intervals in cell differentiation and development when new epigenetic patterns are established. Epigenetic patterns have been observed to change at a progenitor state after stem cells commit to differentiation. This finding is consistent with a role of epigenetic regulation in stabilizing expression patterns after their establishment by transcription factors. However, the available data also suggest that additional, presently unidentified, chromatin regulatory mechanisms exist. Identification of these mechanism is an important aim for future research to obtain a more complete framework for understanding stem cell differentiation during tissue homeostasis.


Polycomb DNA methylation Chromatin Epigenetics Stem cells 



I thank members of my laboratory for discussion and comments on the manuscript. AW was supported by a Wellcome Trust Senior Research Fellowship (grant reference 087530/Z/08/A).


  1. 1.
    Graf T, Enver T (2009) Forcing cells to change lineages. Nature 462(7273):587–594PubMedGoogle Scholar
  2. 2.
    Orkin SH, Hochedlinger K (2011) Chromatin connections to pluripotency and cellular reprogramming. Cell 145(6):835–850PubMedGoogle Scholar
  3. 3.
    Rada-Iglesias A, Wysocka J (2011) Epigenomics of human embryonic stem cells and induced pluripotent stem cells: insights into pluripotency and implications for disease. Genome Med 3(6):36PubMedGoogle Scholar
  4. 4.
    Luger K, Mader AW, Richmond RK, Sargent DF et al (1997) Crystal structure of the nucleosome core particle at 2.8 a resolution. Nature 389(6648):251–260PubMedGoogle Scholar
  5. 5.
    Jenuwein T, Allis CD (2001) Translating the histone code. Science (New York, NY) 293(5532):1074–1080Google Scholar
  6. 6.
    Creyghton MP, Cheng AW, Welstead GG, Kooistra T et al (2010) Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc Natl Acad Sci U S A 107(50):21931–21936PubMedGoogle Scholar
  7. 7.
    Mikkelsen TS, Ku M, Jaffe DB, Issac B et al (2007) Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448(7153):553–560PubMedGoogle Scholar
  8. 8.
    Bernstein BE, Mikkelsen TS, Xie X, Kamal M et al (2006) A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125(2):315–326PubMedGoogle Scholar
  9. 9.
    Cui K, Zang C, Roh TY, Schones DE et al (2009) Chromatin signatures in multipotent human hematopoietic stem cells indicate the fate of bivalent genes during differentiation. Cell Stem Cell 4(1):80–93PubMedGoogle Scholar
  10. 10.
    Ku M, Koche RP, Rheinbay E, Mendenhall EM et al (2008) Genomewide analysis of PRC1 and PRC2 occupancy identifies two classes of bivalent domains. PLoS Genet 4(10):e1000242PubMedGoogle Scholar
  11. 11.
    Ernst J, Kheradpour P, Mikkelsen TS, Shoresh N et al (2011) Mapping and analysis of chromatin state dynamics in nine human cell types. Nature 473(7345):43–49PubMedGoogle Scholar
  12. 12.
    Lien WH, Guo X, Polak L, Lawton LN et al (2011) Genome-wide maps of histone modifications unwind in vivo chromatin states of the hair follicle lineage. Cell Stem Cell 9(3):219–232PubMedGoogle Scholar
  13. 13.
    Adli M, Zhu J, Bernstein BE (2010) Genome-wide chromatin maps derived from limited numbers of hematopoietic progenitors. Nat Methods 7(8):615–618PubMedGoogle Scholar
  14. 14.
    Bracken AP, Dietrich N, Pasini D, Hansen KH et al (2006) Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. Genes Dev 20(9):1123–1136PubMedGoogle Scholar
  15. 15.
    Mohn F, Weber M, Rebhan M, Roloff TC et al (2008) Lineage-specific polycomb targets and de novo DNA methylation define restriction and potential of neuronal progenitors. Mol Cell 30(6):755–766PubMedGoogle Scholar
  16. 16.
    Guttman M, Amit I, Garber M, French C et al (2009) Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature 458(7235):223–227PubMedGoogle Scholar
  17. 17.
    Rada-Iglesias A, Bajpai R, Swigut T, Brugmann SA et al (2011) A unique chromatin signature uncovers early developmental enhancers in humans. Nature 470(7333):279–283PubMedGoogle Scholar
  18. 18.
    Peters AH, O’Carroll D, Scherthan H, Mechtler K et al (2001) Loss of the Suv39h histone methyltransferases impairs mammalian heterochromatin and genome stability. Cell 107(3):323–337PubMedGoogle Scholar
  19. 19.
    Dodge JE, Kang YK, Beppu H, Lei H et al (2004) Histone H3-K9 methyltransferase ESET is essential for early development. Mol Cell Biol 24(6):2478–2486PubMedGoogle Scholar
  20. 20.
    Yeap LS, Hayashi K, Surani MA (2009) ERG-associated protein with SET domain (ESET)-Oct4 interaction regulates pluripotency and represses the trophectoderm lineage. Epigenetics Chromatin 2(1):12PubMedGoogle Scholar
  21. 21.
    Yuan P, Han J, Guo G, Orlov YL et al (2009) Eset partners with Oct4 to restrict extraembryonic trophoblast lineage potential in embryonic stem cells. Genes Dev 23(21):2507–2520PubMedGoogle Scholar
  22. 22.
    Matsui T, Leung D, Miyashita H, Maksakova IA et al (2010) Proviral silencing in embryonic stem cells requires the histone methyltransferase ESET. Nature 464(7290):927–931PubMedGoogle Scholar
  23. 23.
    Gu TP, Guo F, Yang H, Wu HP et al (2011) The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytes. Nature 477:606–610PubMedGoogle Scholar
  24. 24.
    Ang YS, Gaspar-Maia A, Lemischka IR, Bernstein E (2011) Stem cells and reprogramming: breaking the epigenetic barrier? Trends Pharmacol Sci 32(7):394–401PubMedGoogle Scholar
  25. 25.
    Ferguson-Smith AC (2011) Genomic imprinting: the emergence of an epigenetic paradigm. Nat Rev 12(8):565–575Google Scholar
  26. 26.
    Augui S, Nora EP, Heard E (2011) Regulation of X-chromosome inactivation by the X-inactivation centre. Nat Rev 12(6):429–442Google Scholar
  27. 27.
    Wutz A (2007) Xist function: bridging chromatin and stem cells. Trends Genet 23(9):457–464PubMedGoogle Scholar
  28. 28.
    Sasaki H (2010) Mechanisms of trophectoderm fate specification in preimplantation mouse development. Dev Growth Differ 52(3):263–273PubMedGoogle Scholar
  29. 29.
    Ralston A, Cox BJ, Nishioka N, Sasaki H et al (2010) Gata3 regulates trophoblast development downstream of Tead4 and in parallel to Cdx2. Development (Cambridge, England) 137(3):395–403Google Scholar
  30. 30.
    Niwa H, Toyooka Y, Shimosato D, Strumpf D et al (2005) Interaction between Oct3/4 and Cdx2 determines trophectoderm differentiation. Cell 123(5):917–929PubMedGoogle Scholar
  31. 31.
    Li L, Sun L, Gao F, Jiang J et al (2010) Stk40 links the pluripotency factor Oct4 to the Erk/MAPK pathway and controls extraembryonic endoderm differentiation. Proc Natl Acad Sci U S A 107(4):1402–1407PubMedGoogle Scholar
  32. 32.
    Chazaud C, Yamanaka Y, Pawson T, Rossant J (2006) Early lineage segregation between epiblast and primitive endoderm in mouse blastocysts through the Grb2-MAPK pathway. Dev Cell 10(5):615–624PubMedGoogle Scholar
  33. 33.
    Nichols J, Silva J, Roode M, Smith A (2009) Suppression of Erk signalling promotes ground state pluripotency in the mouse embryo. Development (Cambridge, England) 136(19):3215–3222Google Scholar
  34. 34.
    Silva J, Nichols J, Theunissen TW, Guo G et al (2009) Nanog is the gateway to the pluripotent ground state. Cell 138(4):722–737PubMedGoogle Scholar
  35. 35.
    Mitsui K, Tokuzawa Y, Itoh H, Segawa K et al (2003) The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell 113(5):631–642PubMedGoogle Scholar
  36. 36.
    Chambers I, Silva J, Colby D, Nichols J et al (2007) Nanog safeguards pluripotency and mediates germline development. Nature 450(7173):1230–1234PubMedGoogle Scholar
  37. 37.
    Rossant J (2007) Stem cells and lineage development in the mammalian blastocyst. Reprod Fertil Dev 19(1):111–118PubMedGoogle Scholar
  38. 38.
    Kunath T, Arnaud D, Uy GD, Okamoto I et al (2005) Imprinted X-inactivation in extra-embryonic endoderm cell lines from mouse blastocysts. Development (Cambridge, England) 132(7):1649–1661Google Scholar
  39. 39.
    Poueymirou WT, Auerbach W, Frendewey D, Hickey JF et al (2007) F0 generation mice fully derived from gene-targeted embryonic stem cells allowing immediate phenotypic analyses. Nat Biotechnol 25(1):91–99PubMedGoogle Scholar
  40. 40.
    Nagy A, Gocza E, Diaz EM, Prideaux VR et al (1990) Embryonic stem cells alone are able to support fetal development in the mouse. Development (Cambridge, England) 110(3):815–821Google Scholar
  41. 41.
    Hemberger M, Dean W, Reik W (2009) Epigenetic dynamics of stem cells and cell lineage commitment: digging Waddington’s canal. Nat Rev Mol Cell Biol 10(8):526–537PubMedGoogle Scholar
  42. 42.
    Ng RK, Dean W, Dawson C, Lucifero D et al (2008) Epigenetic restriction of embryonic cell lineage fate by methylation of Elf5. Nat Cell Biol 10(11):1280–1290PubMedGoogle Scholar
  43. 43.
    Alder O, Lavial F, Helness A, Brookes E et al (2011) Ring1B and Suv39h1 delineate distinct chromatin states at bivalent genes during early mouse lineage commitment. Development (Cambridge, England) 137(15):2483–2492Google Scholar
  44. 44.
    Brons IG, Smithers LE, Trotter MW, Rugg-Gunn P et al (2007) Derivation of pluripotent epiblast stem cells from mammalian embryos. Nature 448(7150):191–195PubMedGoogle Scholar
  45. 45.
    Tesar PJ, Chenoweth JG, Brook FA, Davies TJ et al (2007) New cell lines from mouse epiblast share defining features with human embryonic stem cells. Nature 448(7150):196–199PubMedGoogle Scholar
  46. 46.
    Bernardo AS, Faial T, Gardner L, Niakan KK et al (2011) BRACHYURY and CDX2 mediate BMP-induced differentiation of human and mouse pluripotent stem cells into embryonic and extraembryonic lineages. Cell Stem Cell 9(2):144–155PubMedGoogle Scholar
  47. 47.
    ten Berge D, Kurek D, Blauwkamp T, Koole W et al (2011) Embryonic stem cells require Wnt proteins to prevent differentiation to epiblast stem cells. Nat Cell Biol 13(9):1070–1075PubMedGoogle Scholar
  48. 48.
    Guo G, Yang J, Nichols J, Hall JS et al (2009) Klf4 reverts developmentally programmed restriction of ground state pluripotency. Development (Cambridge, England) 136(7):1063–1069Google Scholar
  49. 49.
    Nichols J, Smith A (2009) Naive and primed pluripotent states. Cell Stem Cell 4(6):487–492PubMedGoogle Scholar
  50. 50.
    Hanna J, Cheng AW, Saha K, Kim J et al (2010) Human embryonic stem cells with biological and epigenetic characteristics similar to those of mouse ESCs. Proc Natl Acad Sci U S A 107(20):9222–9227PubMedGoogle Scholar
  51. 51.
    Lengner CJ, Gimelbrant AA, Erwin JA, Cheng AW et al (2010) Derivation of pre-X inactivation human embryonic stem cells under physiological oxygen concentrations. Cell 141(5):872–883PubMedGoogle Scholar
  52. 52.
    Han DW, Tapia N, Joo JY, Greber B et al (2010) Epiblast stem cell subpopulations represent mouse embryos of distinct pregastrulation stages. Cell 143(4):617–627PubMedGoogle Scholar
  53. 53.
    Boyer LA, Plath K, Zeitlinger J, Brambrink T et al (2006) Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature 441(7091):349–353PubMedGoogle Scholar
  54. 54.
    Meissner A, Mikkelsen TS, Gu H, Wernig M et al (2008) Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature 454(7205):766–770PubMedGoogle Scholar
  55. 55.
    Xu Y, Wu F, Tan L, Kong L et al (2011) Genome-wide regulation of 5hmC, 5mC, and gene expression by Tet1 hydroxylase in mouse embryonic stem cells. Mol Cell 42(4):451–464PubMedGoogle Scholar
  56. 56.
    Beisel C, Paro R (2011) Silencing chromatin: comparing modes and mechanisms. Nat Rev 12(2):123–135Google Scholar
  57. 57.
    Shaver S, Casas-Mollano JA, Cerny RL, Cerutti H (2010) Origin of the polycomb repressive complex 2 and gene silencing by an E(z) homolog in the unicellular alga Chlamydomonas. Epigenetics 5(4):301–312PubMedGoogle Scholar
  58. 58.
    de Napoles M, Mermoud JE, Wakao R, Tang YA et al (2004) Polycomb group proteins Ring1A/B link ubiquitylation of histone H2A to heritable gene silencing and X inactivation. Dev Cell 7(5):663–676PubMedGoogle Scholar
  59. 59.
    Fang J, Chen T, Chadwick B, Li E et al (2004) Ring1b-mediated H2A ubiquitination associates with inactive X chromosomes and is involved in initiation of X inactivation. J Biol Chem 279(51):52812–52815PubMedGoogle Scholar
  60. 60.
    Cao R, Wang L, Wang H, Xia L et al (2002) Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science (New York, NY) 298(5595):1039–1043Google Scholar
  61. 61.
    Stock JK, Giadrossi S, Casanova M, Brookes E et al (2007) Ring1-mediated ubiquitination of H2A restrains poised RNA polymerase II at bivalent genes in mouse ES cells. Nat Cell Biol 9(12):1428–1435PubMedGoogle Scholar
  62. 62.
    Schuettengruber B, Chourrout D, Vervoort M, Leblanc B et al (2007) Genome regulation by polycomb and trithorax proteins. Cell 128(4):735–745PubMedGoogle Scholar
  63. 63.
    Gehani SS, Agrawal-Singh S, Dietrich N, Christo-phersen NS et al (2010) Polycomb group protein displacement and gene activation through MSK-dependent H3K27me3S28 phosphorylation. Mol Cell 39(6):886–900PubMedGoogle Scholar
  64. 64.
    Seenundun S, Rampalli S, Liu QC, Aziz A et al (2010) UTX mediates demethylation of H3K27me3 at muscle-specific genes during myogenesis. EMBO J 29(8):1401–1411PubMedGoogle Scholar
  65. 65.
    Scheuermann JC, de Ayala Alonso AG, Oktaba K, Ly-Hartig N et al (2010) Histone H2A deubiquitinase activity of the Polycomb repressive complex PR-DUB. Nature 465(7295):243–247PubMedGoogle Scholar
  66. 66.
    Richly H, Rocha-Viegas L, Ribeiro JD, Demajo S et al (2010) Transcriptional activation of polycomb-repressed genes by ZRF1. Nature 468(7327):1124–1128PubMedGoogle Scholar
  67. 67.
    Blewitt ME, Gendrel AV, Pang Z, Sparrow DB et al (2008) SmcHD1, containing a structural-maintenance-of-chromosomes hinge domain, has a critical role in X inactivation. Nat Genet 40(5):663–669PubMedGoogle Scholar
  68. 68.
    Sado T, Fenner MH, Tan SS, Tam P et al (2000) X inactivation in the mouse embryo deficient for Dnmt1: distinct effect of hypomethylation on imprinted and random X inactivation. Dev Biol 225(2):294–303PubMedGoogle Scholar
  69. 69.
    Tahiliani M, Koh KP, Shen Y, Pastor WA et al (2009) Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science (New York, NY) 324(5929):930–935Google Scholar
  70. 70.
    Williams K, Christensen J, Pedersen MT, Johansen JV et al (2011) TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelity. Nature 473(7347):343–348PubMedGoogle Scholar
  71. 71.
    Pastor WA, Pape UJ, Huang Y, Henderson HR et al (2011) Genome-wide mapping of 5-hydroxymethylcytosine in embryonic stem cells. Nature 473(7347):394–397PubMedGoogle Scholar
  72. 72.
    Wu H, D’Alessio AC, Ito S, Xia K et al (2011) Dual functions of Tet1 in transcriptional regulation in mouse embryonic stem cells. Nature 473(7347):389–393PubMedGoogle Scholar
  73. 73.
    Rinn JL, Kertesz M, Wang JK, Squazzo SL et al (2007) Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell 129(7):1311–1323PubMedGoogle Scholar
  74. 74.
    Kohlmaier A, Savarese F, Lachner M, Martens J et al (2004) A chromosomal memory triggered by Xist regulates histone methylation in X inactivation. PLoS Biol 2(7):E171PubMedGoogle Scholar
  75. 75.
    Mak W, Baxter J, Silva J, Newall AE et al (2002) Mitotically stable association of polycomb group proteins eed and enx1 with the inactive x chromosome in trophoblast stem cells. Curr Biol 12(12):1016–1020PubMedGoogle Scholar
  76. 76.
    Plath K, Fang J, Mlynarczyk-Evans SK, Cao R et al (2003) Role of histone H3 lysine 27 methylation in X inactivation. Science (New York, NY) 300(5616):131–135Google Scholar
  77. 77.
    Khalil AM, Guttman M, Huarte M, Garber M et al (2009) Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc Natl Acad Sci U S A 106(28):11667–11672PubMedGoogle Scholar
  78. 78.
    Guttman M, Donaghey J, Carey BW, Garber M et al (2011) lincRNAs act in the circuitry controlling pluripotency and differentiation. Nature 477(7364):295–300PubMedGoogle Scholar
  79. 79.
    Savarese F, Flahndorfer K, Jaenisch R, Busslinger M et al (2006) Hematopoietic precursor cells transiently reestablish permissiveness for X inactivation. Mol Cell Biol 26(19):7167–7177PubMedGoogle Scholar
  80. 80.
    Agrelo R, Souabni A, Novatchkova M, Haslinger C et al (2009) SATB1 defines the developmental context for gene silencing by Xist in lymphoma and embryonic cells. Dev Cell 16(4):507–516PubMedGoogle Scholar
  81. 81.
    Cai S, Lee CC, Kohwi-Shigematsu T (2006) SATB1 packages densely looped, transcriptionally active chromatin for coordinated expression of cytokine genes. Nat Genet 38(11):1278–1288PubMedGoogle Scholar
  82. 82.
    Alvarez JD, Yasui DH, Niida H, Joh T et al (2000) The MAR-binding protein SATB1 orchestrates temporal and spatial expression of multiple genes during T-cell development. Genes Dev 14(5):521–535PubMedGoogle Scholar
  83. 83.
    Agrelo R, Wutz A (2010) ConteXt of change–X inactivation and disease. EMBO Mol Med 2(1):6–15PubMedGoogle Scholar
  84. 84.
    Xu CR, Cole PA, Meyers DJ, Kormish J et al (2011) Chromatin “prepattern” and histone modifiers in a fate choice for liver and pancreas. Science (New York, NY) 332(6032):963–966Google Scholar
  85. 85.
    van Arensbergen J, Garcia-Hurtado J, Moran I, Maestro MA et al (2011) Derepression of Polycomb targets during pancreatic organogenesis allows insulin-producing beta-cells to adopt a neural gene activity program. Genome Res 20(6):722–732Google Scholar
  86. 86.
    Asp P, Blum R, Vethantham V, Parisi F et al (2011) Genome-wide remodeling of the epigenetic landscape during myogenic differentiation. Proc Natl Acad Sci U S A 108(22):E149–E158PubMedGoogle Scholar
  87. 87.
    Mai JC, Ellenbogen RG (2008) SATB1: the convergence of carcinogenesis and chromatin conformation. Neurosurgery 63(2):N6PubMedGoogle Scholar
  88. 88.
    Richon VM (2008) A new path to the cancer epigenome. Nat Biotechnol 26(6):655–656PubMedGoogle Scholar
  89. 89.
    Brockdorff N (2009) SAT in silence. Dev Cell 16(4):483–484PubMedGoogle Scholar
  90. 90.
    Agrelo R, Wutz A (2009) Cancer progenitors and epigenetic contexts: an Xisting connection. Epigenetics 4(8):568–570PubMedGoogle Scholar
  91. 91.
    Li E, Bestor TH, Jaenisch R (1992) Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69(6):915–926PubMedGoogle Scholar
  92. 92.
    Howell CY, Bestor TH, Ding F, Latham KE et al (2001) Genomic imprinting disrupted by a maternal effect mutation in the Dnmt1 gene. Cell 104(6):829–838PubMedGoogle Scholar
  93. 93.
    Okano M, Bell DW, Haber DA, Li E (1999) DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99(3):247–257PubMedGoogle Scholar
  94. 94.
    Bourc’his D, Xu GL, Lin CS, Bollman B et al (2001) Dnmt3L and the establishment of maternal genomic imprints. Science (New York, NY) 294(5551):2536–2539Google Scholar
  95. 95.
    Sharif J, Muto M, Takebayashi S, Suetake I et al (2007) The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA. Nature 450(7171):908–912PubMedGoogle Scholar
  96. 96.
    Sakaue M, Ohta H, Kumaki Y, Oda M et al (2010) DNA methylation is dispensable for the growth and survival of the extraembryonic lineages. Curr Biol 20(16):1452–1457PubMedGoogle Scholar
  97. 97.
    Dawlaty MM, Ganz K, Powell BE, Hu YC et al (2011) Tet1 is dispensable for maintaining pluripotency and its loss is compatible with embryonic and postnatal development. Cell Stem Cell 9(2):166–175PubMedGoogle Scholar
  98. 98.
    Ko M, Bandukwala HS, An J, Lamperti ED et al (2011) Ten-Eleven-Translocation 2 (TET2) negatively regulates homeostasis and differentiation of hematopoietic stem cells in mice. Proc Natl Acad Sci U S A 108(35):14566–14571PubMedGoogle Scholar
  99. 99.
    Li Z, Cai X, Cai CL, Wang J et al (2011) Deletion of Tet2 in mice leads to dysregulated hematopoietic stem cells and subsequent development of myeloid malignancies. Blood 118(17):4509–4518PubMedGoogle Scholar
  100. 100.
    Moran-Crusio K, Reavie L, Shih A, Abdel-Wahab O et al (2011) Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell 20(1):11–24PubMedGoogle Scholar
  101. 101.
    Quivoron C, Couronne L, Della Valle V, Lopez CK et al (2011) TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis. Cancer Cell 20(1):25–38PubMedGoogle Scholar
  102. 102.
    Cortazar D, Kunz C, Selfridge J, Lettieri T et al (2011) Embryonic lethal phenotype reveals a function of TDG in maintaining epigenetic stability. Nature 470(7334):419–423PubMedGoogle Scholar
  103. 103.
    Cortellino S, Xu J, Sannai M, Moore R et al (2011) Thymine DNA glycosylase is essential for active DNA demethylation by linked deamination-base excision repair. Cell 146(1):67–79PubMedGoogle Scholar
  104. 104.
    He YF, Li BZ, Li Z, Liu P et al (2011) Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science (New York, NY) 333(6047):1303–1307Google Scholar
  105. 105.
    O’Carroll D, Erhardt S, Pagani M, Barton SC et al (2001) The polycomb-group gene Ezh2 is required for early mouse development. Mol Cell Biol 21(13):4330–4336PubMedGoogle Scholar
  106. 106.
    Pasini D, Bracken AP, Jensen MR, Lazzerini Denchi E et al (2004) Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity. EMBO J 23(20):4061–4071PubMedGoogle Scholar
  107. 107.
    Schumacher A, Faust C, Magnuson T (1996) Positional cloning of a global regulator of anterior-posterior patterning in mice. Nature 384(6610):648PubMedGoogle Scholar
  108. 108.
    Voncken JW, Roelen BA, Roefs M, de Vries S et al (2003) Rnf2 (Ring1b) deficiency causes gastrulation arrest and cell cycle inhibition. Proc Natl Acad Sci U S A 100(5):2468–2473PubMedGoogle Scholar
  109. 109.
    Tachibana M, Sugimoto K, Nozaki M, Ueda J et al (2002) G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis. Genes Dev 16(14):1779–1791PubMedGoogle Scholar
  110. 110.
    Tachibana M, Matsumura Y, Fukuda M, Kimura H et al (2008) G9a/GLP complexes independently mediate H3K9 and DNA methylation to silence transcription. EMBO J 27(20):2681–2690PubMedGoogle Scholar
  111. 111.
    Wang J, Mager J, Chen Y, Schneider E et al (2001) Imprinted X inactivation maintained by a mouse Polycomb group gene. Nat Genet 28(4):371–375PubMedGoogle Scholar
  112. 112.
    Chamberlain SJ, Yee D, Magnuson T (2008) Polycomb repressive complex 2 is dispensable for maintenance of embryonic stem cell pluripotency. Stem Cells (Dayton, OH) 26(6):1496–1505Google Scholar
  113. 113.
    Leeb M, Wutz A (2007) Ring1B is crucial for the regulation of developmental control genes and PRC1 proteins but not X inactivation in embryonic cells. J Cell Biol 178(2):219–229PubMedGoogle Scholar
  114. 114.
    Schoeftner S, Sengupta AK, Kubicek S, Mechtler K et al (2006) Recruitment of PRC1 function at the initiation of X inactivation independent of PRC2 and silencing. EMBO J 25(13):3110–3122PubMedGoogle Scholar
  115. 115.
    Leeb M, Pasini D, Novatchkova M, Jaritz M et al (2010) Polycomb complexes act redundantly to repress genomic repeats and genes. Genes Dev 24(3):265–276PubMedGoogle Scholar
  116. 116.
    Shen X, Liu Y, Hsu YJ, Fujiwara Y et al (2008) EZH1 mediates methylation on histone H3 lysine 27 and complements EZH2 in maintaining stem cell identity and executing pluripotency. Mol Cell 32(4):491–502PubMedGoogle Scholar
  117. 117.
    Ezhkova E, Lien WH, Stokes N, Pasolli HA et al (2011) EZH1 and EZH2 cogovern histone H3K27 trimethylation and are essential for hair follicle homeostasis and wound repair. Genes Dev 25(5):485–498PubMedGoogle Scholar
  118. 118.
    Herz HM, Shilatifard A (2010) The JARID2-PRC2 duality. Genes Dev 24(9):857–861PubMedGoogle Scholar
  119. 119.
    Li G, Margueron R, Ku M, Chambon P et al (2010) Jarid2 and PRC2, partners in regulating gene expression. Genes Dev 24(4):368–380PubMedGoogle Scholar
  120. 120.
    Landeira D, Sauer S, Poot R, Dvorkina M et al (2010) Jarid2 is a PRC2 component in embryonic stem cells required for multi-lineage differentiation and recruitment of PRC1 and RNA Polymerase II to developmental regulators. Nat Cell Biol 12(6):618–624PubMedGoogle Scholar
  121. 121.
    Pasini D, Cloos PA, Walfridsson J, Olsson L et al (2010) JARID2 regulates binding of the Polycomb repressive complex 2 to target genes in ES cells. Nature 464(7286):306–310PubMedGoogle Scholar
  122. 122.
    Peng JC, Valouev A, Swigut T, Zhang J et al (2009) Jarid2/Jumonji coordinates control of PRC2 enzymatic activity and target gene occupancy in pluripotent cells. Cell 139(7):1290–1302PubMedGoogle Scholar
  123. 123.
    Shen X, Kim W, Fujiwara Y, Simon MD et al (2009) Jumonji modulates polycomb activity and self-renewal versus differentiation of stem cells. Cell 139(7):1303–1314PubMedGoogle Scholar
  124. 124.
    Li X, Isono K, Yamada D, Endo TA et al (2010) Mammalian polycomb-like Pcl2/Mtf2 is a novel regulatory component of PRC2 that can differentially modulate polycomb activity both at the Hox gene cluster and at Cdkn2a genes. Mol Cell Biol 31(2):351–364PubMedGoogle Scholar
  125. 125.
    Casanova M, Preissner T, Cerase A, Poot R et al (2011) Polycomblike 2 facilitates the recruitment of PRC2 Polycomb group complexes to the inactive X chromosome and to target loci in embryonic stem cells. Development (Cambridge, England) 138(8):1471–1482Google Scholar
  126. 126.
    Eskeland R, Leeb M, Grimes GR, Kress C et al (2010) Ring1B compacts chromatin structure and represses gene expression independent of histone ubiquitination. Mol Cell 38(3):452–464PubMedGoogle Scholar
  127. 127.
    Molofsky AV, He S, Bydon M, Morrison SJ et al (2005) Bmi-1 promotes neural stem cell self-renewal and neural development but not mouse growth and survival by repressing the p16Ink4a and p19Arf senescence pathways. Genes Dev 19(12):1432–1437PubMedGoogle Scholar
  128. 128.
    Majewski IJ, Blewitt ME, de Graaf CA, McManus EJ et al (2008) Polycomb repressive complex 2 (PRC2) restricts hematopoietic stem cell activity. PLoS Biol 6(4):e93PubMedGoogle Scholar
  129. 129.
    Iwama A, Oguro H, Negishi M, Kato Y et al (2004) Enhanced self-renewal of hematopoietic stem cells mediated by the polycomb gene product Bmi-1. Immunity 21(6):843–851PubMedGoogle Scholar
  130. 130.
    Tian H, Biehs B, Warming S, Leong KG et al (2011) A reserve stem cell population in small intestine renders Lgr5-positive cells dispensable. Nature 478(7368):255–259PubMedGoogle Scholar
  131. 131.
    Mejetta S, Morey L, Pascual G, Kuebler B et al (2011) Jarid2 regulates mouse epidermal stem cell activation and differentiation. EMBO J 30(17):3635–3646PubMedGoogle Scholar
  132. 132.
    Luis NM, Morey L, Mejetta S, Pascual G et al (2011) Regulation of human epidermal stem cell proliferation and senescence requires polycomb- dependent and -independent functions of Cbx4. Cell Stem Cell 9(3):233–246PubMedGoogle Scholar
  133. 133.
    Juan AH, Derfoul A, Feng X, Ryall JG et al (2011) Polycomb EZH2 controls self-renewal and safeguards the transcriptional identity of skeletal muscle stem cells. Genes Dev 25(8):789–794PubMedGoogle Scholar
  134. 134.
    Bird A (2002) DNA methylation patterns and epigenetic memory. Genes Dev 16(1):6–21PubMedGoogle Scholar
  135. 135.
    Tsumura A, Hayakawa T, Kumaki Y, Takebayashi S et al (2006) Maintenance of self-renewal ability of mouse embryonic stem cells in the absence of DNA methyltransferases Dnmt1, Dnmt3a and Dnmt3b. Genes Cells 11(7):805–814PubMedGoogle Scholar
  136. 136.
    Bostick M, Kim JK, Esteve PO, Clark A et al (2007) UHRF1 plays a role in maintaining DNA methylation in mammalian cells. Science (New York, NY) 317(5845):1760–1764Google Scholar
  137. 137.
    Ficz G, Branco MR, Seisenberger S, Santos F et al (2011) Dynamic regulation of 5-hydroxymethylcytosine in mouse ES cells and during differentiation. Nature 473(7347):398–402PubMedGoogle Scholar
  138. 138.
    Ito S, D’Alessio AC, Taranova OV, Hong K et al (2010) Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature 466(7310):1129–1133PubMedGoogle Scholar
  139. 139.
    Iqbal K, Jin SG, Pfeifer GP, Szabo PE (2011) Reprogramming of the paternal genome upon fertilization involves genome-wide oxidation of 5-methylcytosine. Proc Natl Acad Sci U S A 108(9):3642–3647PubMedGoogle Scholar
  140. 140.
    Nabel CS, Kohli RM (2011) Molecular biology. Demystifying DNA demethylation. Science (New York, NY) 333(6047):1229–1230Google Scholar
  141. 141.
    Fodor BD, Shukeir N, Reuter G, Jenuwein T (2010) Mammalian Su(var) genes in chromatin control. Annu Rev Cell Dev Biol 26:471–501PubMedGoogle Scholar
  142. 142.
    Lohmann F, Loureiro J, Su H, Fang Q et al (2010) KMT1E mediated H3K9 methylation is required for the maintenance of embryonic stem cells by repressing trophectoderm differentiation. Stem Cells (Dayton, OH) 28(2):201–212Google Scholar
  143. 143.
    Kaji K, Nichols J, Hendrich B (2007) Mbd3, a component of the NuRD co-repressor complex, is required for development of pluripotent cells. Development (Cambridge, England) 134(6):1123–1132Google Scholar
  144. 144.
    Kaji K, Caballero IM, MacLeod R, Nichols J et al (2006) The NuRD component Mbd3 is required for pluripotency of embryonic stem cells. Nat Cell Biol 8(3):285–292PubMedGoogle Scholar
  145. 145.
    Erhardt S, Su IH, Schneider R, Barton S et al (2003) Consequences of the depletion of zygotic and embryonic enhancer of zeste 2 during preimplantation mouse development. Development (Cambridge, England) 130(18):4235–4248Google Scholar
  146. 146.
    Smallwood SA, Tomizawa S, Krueger F, Ruf N et al (2011) Dynamic CpG island methylation landscape in oocytes and preimplantation embryos. Nat Genet 43(8):811–814PubMedGoogle Scholar
  147. 147.
    Chotalia M, Smallwood SA, Ruf N, Dawson C et al (2009) Transcription is required for establishment of germline methylation marks at imprinted genes. Genes Dev 23(1):105–117PubMedGoogle Scholar
  148. 148.
    Ciccone DN, Su H, Hevi S, Gay F et al (2009) KDM1B is a histone H3K4 demethylase required to establish maternal genomic imprints. Nature 461(7262):415–418PubMedGoogle Scholar
  149. 149.
    Kubicek S, O’Sullivan RJ, August EM, Hickey ER et al (2007) Reversal of H3K9me2 by a small-molecule inhibitor for the G9a histone methyltransferase. Mol Cell 25(3):473–481PubMedGoogle Scholar
  150. 150.
    Blomen VA, Boonstra J (2011) Stable transmission of reversible modifications: maintenance of epigenetic information through the cell cycle. Cell Mol Life Sci 68(1):27–44PubMedGoogle Scholar
  151. 151.
    Arrigoni R, Alam SL, Wamstad JA, Bardwell VJ et al (2006) The Polycomb-associated protein Rybp is a ubiquitin binding protein. FEBS Lett 580(26):6233–6241PubMedGoogle Scholar
  152. 152.
    Garcia E, Marcos-Gutierrez C, del Mar LM, Moreno JC et al (1999) RYBP, a new repressor protein that interacts with components of the mammalian Polycomb complex, and with the transcription factor YY1. EMBO J 18(12):3404–3418PubMedGoogle Scholar
  153. 153.
    Hansen KH, Bracken AP, Pasini D, Dietrich N et al (2008) A model for transmission of the H3K27me3 epigenetic mark. Nat Cell Biol 10(11):1291–1300PubMedGoogle Scholar
  154. 154.
    Margueron R, Justin N, Ohno K, Sharpe ML et al (2009) Role of the polycomb protein EED in the propagation of repressive histone marks. Nature 461(7265):762–767PubMedGoogle Scholar
  155. 155.
    Fischle W, Wang Y, Jacobs SA, Kim Y et al (2003) Molecular basis for the discrimination of repressive methyl-lysine marks in histone H3 by Polycomb and HP1 chromodomains. Genes Dev 17(15):1870–1881PubMedGoogle Scholar
  156. 156.
    Aguilo F, Zhou MM, Walsh MJ (2011) Long noncoding RNA, polycomb, and the ghosts haunting INK4b-ARF-INK4a expression. Cancer Res 71(16):5365–5369PubMedGoogle Scholar
  157. 157.
    Loughery JE, Dunne PD, O’Neill KM, Meehan RR et al (2011) DNMT1 deficiency triggers mismatch repair defects in human cells through depletion of repair protein levels in a process involving the DNA damage response. Hum Mol Genet 20(16):3241–3255PubMedGoogle Scholar
  158. 158.
    Wutz A (2011) Gene silencing in X-chromosome inactivation: advances in understanding facultative heterochromatin formation. Nat Rev 12(8):542–553Google Scholar
  159. 159.
    Chaumeil J, Le Baccon P, Wutz A, Heard E (2006) A novel role for Xist RNA in the formation of a repressive nuclear compartment into which genes are recruited when silenced. Genes Dev 20(16):2223–2237PubMedGoogle Scholar
  160. 160.
    Pullirsch D, Hartel R, Kishimoto H, Leeb M et al (2010) The Trithorax group protein Ash2l and Saf-A are recruited to the inactive X chromosome at the onset of stable X inactivation. Development (Cambridge, England) 137(6):935–943Google Scholar
  161. 161.
    Csankovszki G, Panning B, Bates B, Pehrson JR et al (1999) Conditional deletion of Xist disrupts histone macroH2A localization but not maintenance of X inactivation. Nat Genet 22(4):323–324PubMedGoogle Scholar
  162. 162.
    Stadtfeld M, Apostolou E, Akutsu H, Fukuda A et al (2010) Aberrant silencing of imprinted genes on chromosome 12qF1 in mouse induced pluripotent stem cells. Nature 465(7295):175–181PubMedGoogle Scholar
  163. 163.
    Kim K, Doi A, Wen B, Ng K et al (2010) Epigenetic memory in induced pluripotent stem cells. Nature 467(7313):285–290PubMedGoogle Scholar
  164. 164.
    Bar-Nur O, Russ HA, Efrat S, Benvenisty N (2011) Epigenetic memory and preferential lineage-specific differentiation in induced pluripotent stem cells derived from human pancreatic islet beta cells. Cell Stem Cell 9(1):17–23PubMedGoogle Scholar
  165. 165.
    Pick M, Stelzer Y, Bar-Nur O, Mayshar Y et al (2009) Clone- and gene-specific aberrations of parental imprinting in human induced pluripotent stem cells. Stem Cells (Dayton, OH) 27(11):2686–2690Google Scholar
  166. 166.
    Ohi Y, Qin H, Hong C, Blouin L et al (2011) Incomplete DNA methylation underlies a transcriptional memory of somatic cells in human iPS cells. Nat Cell Biol 13(5):541–549PubMedGoogle Scholar
  167. 167.
    Pomp O, Dreesen O, Leong DF, Meller-Pomp O et al (2011) Unexpected X chromosome skewing during culture and reprogramming of human somatic cells can be alleviated by exogenous telomerase. Cell Stem Cell 9(2):156–165PubMedGoogle Scholar
  168. 168.
    Tchieu J, Kuoy E, Chin MH, Trinh H et al (2010) Female human iPSCs retain an inactive X chromosome. Cell Stem Cell 7(3):329–342Google Scholar
  169. 169.
    Marro S, Pang ZP, Yang N, Tsai MC et al (2011) Direct lineage conversion of terminally differentiated hepatocytes to functional neurons. Cell Stem Cell 9(4):374–382PubMedGoogle Scholar
  170. 170.
    Vierbuchen T, Ostermeier A, Pang ZP, Kokubu Y et al (2010) Direct conversion of fibroblasts to functional neurons by defined factors. Nature 463(7284):1035–1041PubMedGoogle Scholar
  171. 171.
    Meivar-Levy I, Ferber S (2010) Adult cell fate reprogramming: converting liver to pancreas. Methods Mol Biol (Clifton, NJ) 636:251–283Google Scholar
  172. 172.
    Pawlak M, Jaenisch R (2011) De novo DNA methylation by Dnmt3a and Dnmt3b is dispensable for nuclear reprogramming of somatic cells to a pluripotent state. Genes Dev 25(10):1035–1040PubMedGoogle Scholar
  173. 173.
    Pereira CF, Piccolo FM, Tsubouchi T, Sauer S et al (2010) ESCs require PRC2 to direct the successful reprogramming of differentiated cells toward pluripotency. Cell Stem Cell 6(6):547–556PubMedGoogle Scholar
  174. 174.
    Tan M, Luo H, Lee S, Jin F et al (2011) Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification. Cell 146(6):1016–1028PubMedGoogle Scholar
  175. 175.
    Muers M (2011) Chromatin: a haul of new histone modifications. Nat Rev 12(11):744Google Scholar
  176. 176.
    Hirota T, Lipp JJ, Toh BH, Peters JM (2005) Histone H3 serine 10 phosphorylation by Aurora B causes HP1 dissociation from heterochromatin. Nature 438(7071):1176–1180PubMedGoogle Scholar
  177. 177.
    Fischle W, Tseng BS, Dormann HL, Ueberheide BM et al (2005) Regulation of HP1-chromatin binding by histone H3 methylation and phosphorylation. Nature 438(7071):1116–1122PubMedGoogle Scholar
  178. 178.
    Inoue A, Zhang Y (2011) Replication-dependent loss of 5-hydroxymethylcytosine in mouse preimplantation embryos. Science (New York, NY) 334(6053):194Google Scholar
  179. 179.
    Ottersbach K, Smith A, Wood A, Gottgens B (2011) Ontogeny of haematopoiesis: recent advances and open questions. Br J Haematol 148(3):343–355Google Scholar
  180. 180.
    Medvinsky A, Rybtsov S, Taoudi S (2011) Embryonic origin of the adult hematopoietic system: advances and questions. Development (Cambridge, England) 138(6):1017–1031Google Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  1. 1.Wellcome Trust Centre for Stem Cell Research, Department of BiochemistryUniversity of CambridgeCambridgeUK

Personalised recommendations