Skip to main content
SpringerLink
Log in

Establishing and Maintaining Pluripotency: An Epigenetic Perspective

  • Chapter
  • First Online:
Book cover Epigenetic Mechanisms in Cellular Reprogramming

Part of the book series: Epigenetics and Human Health ((EHH))

  • 1792 Accesses

Abstract

Maintaining and changing cellular identity involves a complex interplay between DNA-interacting factors (protein and RNA) and the underlying chromatin structure. One of the most fascinating and unique states from an epigenetic perspective is pluripotency. Pluripotent stem cells self-renew while maintaining the potential to differentiate into representative types of all three germ layers. Moreover, while these cells express many epigenetic regulators at uniquely high levels, they are themselves molecularly and phenotypically unaffected by their deletion until directed to differentiate. Here we will review the key epigenetic mechanisms that are currently known to act in pluripotent cells as well as how these modifications are dynamically regulated during entry into and exit from pluripotency.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Ang YS, Tsai SY, Lee DF, Monk J, Su J, Ratnakumar K, Ding J, Ge Y, Darr H, Chang B et al (2011) Wdr5 mediates self-renewal and reprogramming via the embryonic stem cell core transcriptional network. Cell 145:183–197

    CAS  PubMed Central  PubMed  Google Scholar 

  • Anokye-Danso F, Trivedi CM, Juhr D, Gupta M, Cui Z, Tian Y, Zhang Y, Yang W, Gruber PJ, Epstein JA et al (2011) Highly efficient miRNA-mediated reprogramming of mouse and human somatic cells to pluripotency. Cell Stem Cell 8:376–388

    CAS  PubMed Central  PubMed  Google Scholar 

  • Arita K, Ariyoshi M, Tochio H, Nakamura Y, Shirakawa M (2008) Recognition of hemi-methylated DNA by the SRA protein UHRF1 by a base-flipping mechanism. Nature 455:818–821

    CAS  PubMed  Google Scholar 

  • Athanasiadou R, de Sousa D, Myant K, Merusi C, Stancheva I, Bird A (2010) Targeting of de novo DNA methylation throughout the Oct-4 gene regulatory region in differentiating embryonic stem cells. PLoS One 5:e9937

    PubMed Central  PubMed  Google Scholar 

  • Avvakumov GV, Walker JR, Xue S, Li Y, Duan S, Bronner C, Arrowsmith CH, Dhe-Paganon S (2008) Structural basis for recognition of hemi-methylated DNA by the SRA domain of human UHRF1. Nature 455:822–825

    CAS  PubMed  Google Scholar 

  • Ayton P, Sneddon SF, Palmer DB, Rosewell IR, Owen MJ, Young B, Presley R, Subramanian V (2001) Truncation of the Mll gene in exon 5 by gene targeting leads to early preimplantation lethality of homozygous embryos. Genesis 30:201–212

    CAS  PubMed  Google Scholar 

  • Bernstein BE, Mikkelsen TS, Xie X, Kamal M, Huebert DJ, Cuff J, Fry B, Meissner A, Wernig M, Plath K et al (2006) A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125:315–326

    CAS  PubMed  Google Scholar 

  • Bestor TH (2000) The DNA methyltransferases of mammals. Hum Mol Genet 9:2395–2402

    CAS  PubMed  Google Scholar 

  • Bilodeau S, Kagey MH, Frampton GM, Rahl PB, Young RA (2009) SetDB1 contributes to repression of genes encoding developmental regulators and maintenance of ES cell state. Genes Dev 23:2484–2489

    CAS  PubMed Central  PubMed  Google Scholar 

  • Bostick M, Kim JK, Esteve PO, Clark A, Pradhan S, Jacobsen SE (2007) UHRF1 plays a role in maintaining DNA methylation in mammalian cells. Science (New York, NY) 317:1760–1764

    CAS  Google Scholar 

  • Bourc’his D, Xu GL, Lin CS, Bollman B, Bestor TH (2001) Dnmt3L and the establishment of maternal genomic imprints. Science (New York, NY) 294:2536–2539

    Google Scholar 

  • Boyer LA, Lee TI, Cole MF, Johnstone SE, Levine SS, Zucker JP, Guenther MG, Kumar RM, Murray HL, Jenner RG et al (2005) Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 122:947–956

    CAS  PubMed Central  PubMed  Google Scholar 

  • Boyer LA, Plath K, Zeitlinger J, Brambrink T, Medeiros LA, Lee TI, Levine SS, Wernig M, Tajonar A, Ray MK et al (2006) Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature 441:349–353

    CAS  PubMed  Google Scholar 

  • Chamberlain SJ, Yee D, Magnuson T (2008) Polycomb repressive complex 2 is dispensable for maintenance of embryonic stem cell pluripotency. Stem Cells (Dayton, OH) 26:1496–1505

    CAS  Google Scholar 

  • Chen T, Ueda Y, Dodge JE, Wang Z, Li E (2003) Establishment and maintenance of genomic methylation patterns in mouse embryonic stem cells by Dnmt3a and Dnmt3b. Mol Cell Biol 23:5594–5605

    CAS  PubMed Central  PubMed  Google Scholar 

  • Chen J, Liu H, Liu J, Qi J, Wei B, Yang J, Liang H, Chen Y, Chen J, Wu Y et al (2013) H3K9 methylation is a barrier during somatic cell reprogramming into iPSCs. Nat Genet 45:34–42

    CAS  PubMed  Google Scholar 

  • Choi SH, Heo K, Byun HM, An W, Lu W, Yang AS (2011) Identification of preferential target sites for human DNA methyltransferases. Nucleic Acids Res 39:104–118

    CAS  PubMed Central  PubMed  Google Scholar 

  • Consortium EP, Birney E, Stamatoyannopoulos JA, Dutta A, Guigo R, Gingeras TR, Margulies EH, Weng Z, Snyder M, Dermitzakis ET et al (2007) Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447:799–816

    Google Scholar 

  • Cortellino S, Xu J, Sannai M, Moore R, Caretti E, Cigliano A, Le Coz M, Devarajan K, Wessels A, Soprano D et al (2011) Thymine DNA glycosylase is essential for active DNA demethylation by linked deamination-base excision repair. Cell 146:67–79

    CAS  PubMed Central  PubMed  Google Scholar 

  • Costa Y, Ding J, Theunissen TW, Faiola F, Hore TA, Shliaha PV, Fidalgo M, Saunders A, Lawrence M, Dietmann S et al (2013) NANOG-dependent function of TET1 and TET2 in establishment of pluripotency. Nature 495:370–374

    CAS  PubMed Central  PubMed  Google Scholar 

  • Dawlaty MM, Ganz K, Powell BE, Hu YC, Markoulaki S, Cheng AW, Gao Q, Kim J, Choi SW, Page DC et al (2011) Tet1 is dispensable for maintaining pluripotency and its loss is compatible with embryonic and postnatal development. Cell Stem Cell 9:166–175

    CAS  PubMed Central  PubMed  Google Scholar 

  • Dawlaty MM, Breiling A, Le T, Raddatz G, Barrasa MI, Cheng AW, Gao Q, Powell BE, Li Z, Xu M et al (2013) Combined deficiency of Tet1 and Tet2 causes epigenetic abnormalities but is compatible with postnatal development. Dev Cell 24:310–323

    CAS  PubMed Central  PubMed  Google Scholar 

  • de Napoles M, Mermoud JE, Wakao R, Tang YA, Endoh M, Appanah R, Nesterova TB, Silva J, Otte AP, Vidal M et al (2004) Polycomb group proteins Ring1A/B link ubiquitylation of histone H2A to heritable gene silencing and X inactivation. Dev Cell 7:663–676

    PubMed  Google Scholar 

  • del Mar Lorente M, Marcos-Gutierrez C, Perez C, Schoorlemmer J, Ramirez A, Magin T, Vidal M (2000) Loss- and gain-of-function mutations show a polycomb group function for Ring1A in mice. Development (Cambridge, England) 127:5093–5100

    Google Scholar 

  • Dodge JE, Kang YK, Beppu H, Lei H, Li E (2004) Histone H3-K9 methyltransferase ESET is essential for early development. Mol Cell Biol 24:2478–2486

    CAS  PubMed Central  PubMed  Google Scholar 

  • Dovey OM, Foster CT, Cowley SM (2010) Histone deacetylase 1 (HDAC1), but not HDAC2, controls embryonic stem cell differentiation. Proc Natl Acad Sci U S A 107:8242–8247

    CAS  PubMed Central  PubMed  Google Scholar 

  • Endoh M, Endo TA, Endoh T, Fujimura Y, Ohara O, Toyoda T, Otte AP, Okano M, Brockdorff N, Vidal M et al (2008) Polycomb group proteins Ring1A/B are functionally linked to the core transcriptional regulatory circuitry to maintain ES cell identity. Development (Cambridge, England) 135:1513–1524

    CAS  Google Scholar 

  • Epsztejn-Litman S, Feldman N, Abu-Remaileh M, Shufaro Y, Gerson A, Ueda J, Deplus R, Fuks F, Shinkai Y, Cedar H, et al (2008) De novo DNA methylation promoted by G9a prevents reprogramming of embryonically silenced genes. Nature structural & molecular biology 15: 1176–1183

    Google Scholar 

  • Ernst P, Fisher JK, Avery W, Wade S, Foy D, Korsmeyer SJ (2004) Definitive hematopoiesis requires the mixed-lineage leukemia gene. Dev Cell 6:437–443

    CAS  PubMed  Google Scholar 

  • Faust C, Schumacher A, Holdener B, Magnuson T (1995) The eed mutation disrupts anterior mesoderm production in mice. Development (Cambridge, England) 121:273–285

    CAS  Google Scholar 

  • Fazzio TG, Huff JT, Panning B (2008) An RNAi screen of chromatin proteins identifies Tip60-p400 as a regulator of embryonic stem cell identity. Cell 134:162–174

    CAS  PubMed  Google Scholar 

  • Feldman N, Gerson A, Fang J, Li E, Zhang Y, Shinkai Y, Cedar H, Bergman Y (2006) G9a-mediated irreversible epigenetic inactivation of Oct-3/4 during early embryogenesis. Nat Cell Biol 8:188–194

    CAS  PubMed  Google Scholar 

  • Ficz G, Branco MR, Seisenberger S, Santos F, Krueger F, Hore TA, Marques CJ, Andrews S, Reik W (2011) Dynamic regulation of 5-hydroxymethylcytosine in mouse ES cells and during differentiation. Nature 473:398–402

    CAS  PubMed  Google Scholar 

  • Ficz G, Hore TA, Santos F, Lee HJ, Dean W, Arand J, Krueger F, Oxley D, Paul YL, Walter J et al (2013) FGF signaling inhibition in ESCs drives rapid genome-wide demethylation to the epigenetic ground state of pluripotency. Cell Stem Cell 13:351–359

    CAS  PubMed Central  PubMed  Google Scholar 

  • Fouse SD, Shen Y, Pellegrini M, Cole S, Meissner A, Van Neste L, Jaenisch R, Fan G (2008) 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 2:160–169

    CAS  PubMed Central  PubMed  Google Scholar 

  • Gao Y, Chen J, Li K, Wu T, Huang B, Liu W, Kou X, Zhang Y, Huang H, Jiang Y et al (2013) Replacement of Oct4 by Tet1 during iPSC induction reveals an important role of DNA methylation and hydroxymethylation in reprogramming. Cell Stem Cell 12:453–469

    CAS  PubMed  Google Scholar 

  • Gifford CA, Ziller MJ, Gu H, Trapnell C, Donaghey J, Tsankov A, Shalek AK, Kelley DR, Shishkin AA, Issner R et al (2013) Transcriptional and epigenetic dynamics during specification of human embryonic stem cells. Cell 153:1149–1163

    CAS  PubMed Central  PubMed  Google Scholar 

  • Goll MG, Bestor TH (2005) Eukaryotic cytosine methyltransferases. Annu Rev Biochem 74:481–514

    CAS  PubMed  Google Scholar 

  • Goll MG, Kirpekar F, Maggert KA, Yoder JA, Hsieh CL, Zhang X, Golic KG, Jacobsen SE, Bestor TH (2006) Methylation of tRNAAsp by the DNA methyltransferase homolog Dnmt2. Science (New York, NY) 311:395–398

    CAS  Google Scholar 

  • Gu TP, Guo F, Yang H, Wu HP, Xu GF, Liu W, Xie ZG, Shi L, He X, Jin SG et al (2011) The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytes. Nature 477:606–610

    CAS  PubMed  Google Scholar 

  • Guttman M, Donaghey J, Carey BW, Garber M, Grenier JK, Munson G, Young G, Lucas AB, Ach R, Bruhn L et al (2011) lincRNAs act in the circuitry controlling pluripotency and differentiation. Nature 477:295–300

    CAS  PubMed Central  PubMed  Google Scholar 

  • Habibi E, Brinkman AB, Arand J, Kroeze LI, Kerstens HH, Matarese F, Lepikhov K, Gut M, Brun-Heath I, Hubner NC et al (2013) Whole-genome bisulfite sequencing of two distinct interconvertible DNA methylomes of mouse embryonic stem cells. Cell Stem Cell 13:360–369

    CAS  PubMed  Google Scholar 

  • He YF, Li BZ, Li Z, Liu P, Wang Y, Tang Q, Ding J, Jia Y, Chen Z, Li L et al (2011) Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science (New York, NY) 333:1303–1307

    CAS  Google Scholar 

  • He J, Shen L, Wan M, Taranova O, Wu H, Zhang Y (2013) Kdm2b maintains murine embryonic stem cell status by recruiting PRC1 complex to CpG islands of developmental genes. Nat Cell Biol 15:373–384

    CAS  PubMed Central  PubMed  Google Scholar 

  • Heintzman ND, Stuart RK, Hon G, Fu Y, Ching CW, Hawkins RD, Barrera LO, Van Calcar S, Qu C, Ching KA et al (2007) Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat Genet 39:311–318

    CAS  PubMed  Google Scholar 

  • Heintzman ND, Hon GC, Hawkins RD, Kheradpour P, Stark A, Harp LF, Ye Z, Lee LK, Stuart RK, Ching CW et al (2009) Histone modifications at human enhancers reflect global cell-type-specific gene expression. Nature 459:108–112

    CAS  PubMed Central  PubMed  Google Scholar 

  • Holm TM, Jackson-Grusby L, Brambrink T, Yamada Y, Rideout WM III, Jaenisch R (2005) Global loss of imprinting leads to widespread tumorigenesis in adult mice. Cancer Cell 8:275–285

    CAS  PubMed  Google Scholar 

  • Huangfu D, Maehr R, Guo W, Eijkelenboom A, Snitow M, Chen AE, Melton DA (2008) Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds. Nat Biotechnol 26:795–797

    CAS  PubMed  Google Scholar 

  • Ito S, D’Alessio AC, Taranova OV, Hong K, Sowers LC, Zhang Y (2010) Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature 466:1129–1133

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ito S, Shen L, Dai Q, Wu SC, Collins LB, Swenberg JA, He C, Zhang Y (2011) Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science (New York, NY) 333:1300–1303

    CAS  Google Scholar 

  • Jackson M, Krassowska A, Gilbert N, Chevassut T, Forrester L, Ansell J, Ramsahoye B (2004) Severe global DNA hypomethylation blocks differentiation and induces histone hyperacetylation in embryonic stem cells. Mol Cell Biol 24:8862–8871

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kobayashi H, Sakurai T, Imai M, Takahashi N, Fukuda A, Yayoi O, Sato S, Nakabayashi K, Hata K, Sotomaru Y et al (2012) Contribution of intragenic DNA methylation in mouse gametic DNA methylomes to establish oocyte-specific heritable marks. PLoS Genet 8:e1002440

    CAS  PubMed Central  PubMed  Google Scholar 

  • Koch CM, Andrews RM, Flicek P, Dillon SC, Karaoz U, Clelland GK, Wilcox S, Beare DM, Fowler JC, Couttet P et al (2007) The landscape of histone modifications across 1% of the human genome in five human cell lines. Genome Res 17:691–707

    CAS  PubMed Central  PubMed  Google Scholar 

  • Koche RP, Smith ZD, Adli M, Gu H, Ku M, Gnirke A, Bernstein BE, Meissner A (2011) Reprogramming factor expression initiates widespread targeted chromatin remodeling. Cell Stem Cell 8:96–105

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kouzarides T (2007) Chromatin modifications and their function. Cell 128:693–705

    CAS  PubMed  Google Scholar 

  • 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 178:219–229

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lehnertz B, Ueda Y, Derijck AA, Braunschweig U, Perez-Burgos L, Kubicek S, Chen T, Li E, Jenuwein T, Peters AH (2003) Suv39h-mediated histone H3 lysine 9 methylation directs DNA methylation to major satellite repeats at pericentric heterochromatin. Curr Biol 13:1192–1200

    CAS  PubMed  Google Scholar 

  • Leitch HG, McEwen KR, Turp A, Encheva V, Carroll T, Grabole N, Mansfield W, Nashun B, Knezovich JG, Smith A et al (2013) Naive pluripotency is associated with global DNA hypomethylation. Nat Struct Mol Biol 20:311–316

    CAS  PubMed Central  PubMed  Google Scholar 

  • Li E, Bestor TH, Jaenisch R (1992) Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69:915–926

    CAS  PubMed  Google Scholar 

  • Li Z, Cai X, Cai CL, Wang J, Zhang W, Petersen BE, Yang FC, Xu M (2011) Deletion of Tet2 in mice leads to dysregulated hematopoietic stem cells and subsequent development of myeloid malignancies. Blood 118:4509–4518

    CAS  PubMed Central  PubMed  Google Scholar 

  • Liang G, Taranova O, Xia K, Zhang Y (2010) Butyrate promotes induced pluripotent stem cell generation. J Biol Chem 285:25516–25521

    CAS  PubMed Central  PubMed  Google Scholar 

  • Liang G, He J, Zhang Y (2012) Kdm2b promotes induced pluripotent stem cell generation by facilitating gene activation early in reprogramming. Nat Cell Biol 14:457–466

    CAS  PubMed Central  PubMed  Google Scholar 

  • Loh YH, Wu Q, Chew JL, Vega VB, Zhang W, Chen X, Bourque G, George J, Leong B, Liu J et al (2006) The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells. Nat Genet 38:431–440

    CAS  PubMed  Google Scholar 

  • Loh YH, Zhang W, Chen X, George J, Ng HH (2007) Jmjd1a and Jmjd2c histone H3 Lys 9 demethylases regulate self-renewal in embryonic stem cells. Genes Dev 21:2545–2557

    CAS  PubMed Central  PubMed  Google Scholar 

  • Maiti A, Drohat AC (2011) Thymine DNA glycosylase can rapidly excise 5-formylcytosine and 5-carboxylcytosine: potential implications for active demethylation of CpG sites. J Biol Chem 286:35334–35338

    CAS  PubMed Central  PubMed  Google Scholar 

  • Mali P, Chou BK, Yen J, Ye Z, Zou J, Dowey S, Brodsky RA, Ohm JE, Yu W, Baylin SB et al (2010) Butyrate greatly enhances derivation of human induced pluripotent stem cells by promoting epigenetic remodeling and the expression of pluripotency-associated genes. Stem Cells (Dayton, OH) 28:713–720

    CAS  Google Scholar 

  • Mansour AA, Gafni O, Weinberger L, Zviran A, Ayyash M, Rais Y, Krupalnik V, Zerbib M, Amann-Zalcenstein D, Maza I et al (2012) The H3K27 demethylase Utx regulates somatic and germ cell epigenetic reprogramming. Nature 488:409–413

    CAS  PubMed  Google Scholar 

  • Marks H, Kalkan T, Menafra R, Denissov S, Jones K, Hofemeister H, Nichols J, Kranz A, Stewart AF, Smith A et al (2012) The transcriptional and epigenomic foundations of ground state pluripotency. Cell 149:590–604

    CAS  PubMed Central  PubMed  Google Scholar 

  • Matsui T, Leung D, Miyashita H, Maksakova IA, Miyachi H, Kimura H, Tachibana M, Lorincz MC, Shinkai Y (2010) Proviral silencing in embryonic stem cells requires the histone methyltransferase ESET. Nature 464:927–931

    CAS  PubMed  Google Scholar 

  • McMahon KA, Hiew SY, Hadjur S, Veiga-Fernandes H, Menzel U, Price AJ, Kioussis D, Williams O, Brady HJ (2007) Mll has a critical role in fetal and adult hematopoietic stem cell self-renewal. Cell Stem Cell 1:338–345

    CAS  PubMed  Google Scholar 

  • Meissner A (2010) Epigenetic modifications in pluripotent and differentiated cells. Nat Biotechnol 28:1079–1088

    CAS  PubMed  Google Scholar 

  • Meissner A, Gnirke A, Bell GW, Ramsahoye B, Lander ES, Jaenisch R (2005) Reduced representation bisulfite sequencing for comparative high-resolution DNA methylation analysis. Nucleic Acids Res 33:5868–5877

    CAS  PubMed Central  PubMed  Google Scholar 

  • Meissner A, Mikkelsen TS, Gu H, Wernig M, Hanna J, Sivachenko A, Zhang X, Bernstein BE, Nusbaum C, Jaffe DB et al (2008) Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature 454:766–770

    CAS  PubMed Central  PubMed  Google Scholar 

  • Mertineit C, Yoder JA, Taketo T, Laird DW, Trasler JM, Bestor TH (1998) Sex-specific exons control DNA methyltransferase in mammalian germ cells. Development (Cambridge, England) 125:889–897

    CAS  Google Scholar 

  • Mikkelsen TS, Ku M, Jaffe DB, Issac B, Lieberman E, Giannoukos G, Alvarez P, Brockman W, Kim TK, Koche RP et al (2007) Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448:553–560

    CAS  PubMed Central  PubMed  Google Scholar 

  • Mikkelsen TS, Hanna J, Zhang X, Ku M, Wernig M, Schorderet P, Bernstein BE, Jaenisch R, Lander ES, Meissner A (2008) Dissecting direct reprogramming through integrative genomic analysis. Nature 454:49–55

    CAS  PubMed Central  PubMed  Google Scholar 

  • Montgomery ND, Yee D, Chen A, Kalantry S, Chamberlain SJ, Otte AP, Magnuson T (2005) The murine polycomb group protein Eed is required for global histone H3 lysine-27 methylation. Curr Biol 15:942–947

    CAS  PubMed  Google Scholar 

  • O’Carroll D, Erhardt S, Pagani M, Barton SC, Surani MA, Jenuwein T (2001) The polycomb-group gene Ezh2 is required for early mouse development. Mol Cell Biol 21:4330–4336

    PubMed Central  PubMed  Google Scholar 

  • Ohtani K, Zhao C, Dobreva G, Manavski Y, Kluge B, Braun T, Rieger MA, Zeiher AM, Dimmeler S (2013) Jmjd3 controls mesodermal and cardiovascular differentiation of embryonic stem cells. Circ Res 113:856–862

    CAS  PubMed  Google Scholar 

  • Okada Y, Scott G, Ray MK, Mishina Y, Zhang Y (2007) Histone demethylase JHDM2A is critical for Tnp1 and Prm1 transcription and spermatogenesis. Nature 450:119–123

    CAS  PubMed  Google Scholar 

  • Okano M, Xie S, Li E (1998) Dnmt2 is not required for de novo and maintenance methylation of viral DNA in embryonic stem cells. Nucleic Acids Res 26:2536–2540

    CAS  PubMed Central  PubMed  Google Scholar 

  • Okano M, Bell DW, Haber DA, Li E (1999) DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99:247–257

    CAS  PubMed  Google Scholar 

  • Onder TT, Kara N, Cherry A, Sinha AU, Zhu N, Bernt KM, Cahan P, Marcarci BO, Unternaehrer J, Gupta PB et al (2012) Chromatin-modifying enzymes as modulators of reprogramming. Nature 483:598–602

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ooi SK, Wolf D, Hartung O, Agarwal S, Daley GQ, Goff SP, Bestor TH (2010) Dynamic instability of genomic methylation patterns in pluripotent stem cells. Epigenetics Chromatin 3:17

    PubMed Central  PubMed  Google Scholar 

  • Ostler KR, Davis EM, Payne SL, Gosalia BB, Exposito-Cespedes J, Le Beau MM, Godley LA (2007) Cancer cells express aberrant DNMT3B transcripts encoding truncated proteins. Oncogene 26:5553–5563

    CAS  PubMed Central  PubMed  Google Scholar 

  • Oswald J, Engemann S, Lane N, Mayer W, Olek A, Fundele R, Dean W, Reik W, Walter J (2000) Active demethylation of the paternal genome in the mouse zygote. Curr Biol 10:475–478

    CAS  PubMed  Google Scholar 

  • Pasini D, Bracken AP, Jensen MR, Lazzerini Denchi E, Helin K (2004) Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity. EMBO J 23:4061–4071

    CAS  PubMed Central  PubMed  Google Scholar 

  • Pasini D, Bracken AP, Hansen JB, Capillo M, Helin K (2007) The polycomb group protein Suz12 is required for embryonic stem cell differentiation. Mol Cell Biol 27:3769–3779

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 25:1035–1040

    CAS  PubMed Central  PubMed  Google Scholar 

  • Peters AH, O’Carroll D, Scherthan H, Mechtler K, Sauer S, Schofer C, Weipoltshammer K, Pagani M, Lachner M, Kohlmaier A et al (2001) Loss of the Suv39h histone methyltransferases impairs mammalian heterochromatin and genome stability. Cell 107:323–337

    CAS  PubMed  Google Scholar 

  • Pfaffeneder T, Hackner B, Truss M, Munzel M, Muller M, Deiml CA, Hagemeier C, Carell T (2011) The discovery of 5-formylcytosine in embryonic stem cell DNA. Angew Chem Int Ed Engl 50:7008–7012

    CAS  PubMed  Google Scholar 

  • Santos F, Hendrich B, Reik W, Dean W (2002) Dynamic reprogramming of DNA methylation in the early mouse embryo. Dev Biol 241:172–182

    CAS  PubMed  Google Scholar 

  • Satoh T, Takeuchi O, Vandenbon A, Yasuda K, Tanaka Y, Kumagai Y, Miyake T, Matsushita K, Okazaki T, Saitoh T et al (2010) The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection. Nat Immunol 11:936–944

    CAS  PubMed  Google Scholar 

  • Sharov AA, Masui S, Sharova LV, Piao Y, Aiba K, Matoba R, Xin L, Niwa H, Ko MS (2008) Identification of Pou5f1, Sox2, and Nanog downstream target genes with statistical confidence by applying a novel algorithm to time course microarray and genome-wide chromatin immunoprecipitation data. BMC Genomics 9:269

    PubMed Central  PubMed  Google Scholar 

  • Shen X, Liu Y, Hsu YJ, Fujiwara Y, Kim J, Mao X, Yuan GC, Orkin SH (2008) EZH1 mediates methylation on histone H3 lysine 27 and complements EZH2 in maintaining stem cell identity and executing pluripotency. Mol Cell 32:491–502

    CAS  PubMed Central  PubMed  Google Scholar 

  • Silva J, Smith A (2008) Capturing pluripotency. Cell 132:532–536

    CAS  PubMed Central  PubMed  Google Scholar 

  • Smallwood SA, Tomizawa S, Krueger F, Ruf N, Carli N, Segonds-Pichon A, Sato S, Hata K, Andrews SR, Kelsey G (2011) Dynamic CpG island methylation landscape in oocytes and preimplantation embryos. Nat Genet 43:811–814

    CAS  PubMed Central  PubMed  Google Scholar 

  • Smith ZD, Meissner A (2013) DNA methylation: roles in mammalian development. Nat Rev 14:204–220

    CAS  Google Scholar 

  • Smith ZD, Chan MM, Mikkelsen TS, Gu H, Gnirke A, Regev A, Meissner A (2012) A unique regulatory phase of DNA methylation in the early mammalian embryo. Nature 484:339–344

    CAS  PubMed Central  PubMed  Google Scholar 

  • Soufi A, Donahue G, Zaret KS (2012) Facilitators and impediments of the pluripotency reprogramming factors’ initial engagement with the genome. Cell 151:994–1004

    CAS  PubMed Central  PubMed  Google Scholar 

  • Stadler MB, Murr R, Burger L, Ivanek R, Lienert F, Scholer A, van Nimwegen E, Wirbelauer C, Oakeley EJ, Gaidatzis D et al (2011) DNA-binding factors shape the mouse methylome at distal regulatory regions. Nature 480:490–495

    CAS  PubMed  Google Scholar 

  • Stock JK, Giadrossi S, Casanova M, Brookes E, Vidal M, Koseki H, Brockdorff N, Fisher AG, Pombo A (2007) Ring1-mediated ubiquitination of H2A restrains poised RNA polymerase II at bivalent genes in mouse ES cells. Nat Cell Biol 9:1428–1435

    CAS  PubMed  Google Scholar 

  • Tachibana M, Sugimoto K, Nozaki M, Ueda J, Ohta T, Ohki M, Fukuda M, Takeda N, Niida H, Kato H 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 16:1779–1791

    CAS  PubMed Central  PubMed  Google Scholar 

  • Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676

    CAS  PubMed  Google Scholar 

  • Tateishi K, Okada Y, Kallin EM, Zhang Y (2009) Role of Jhdm2a in regulating metabolic gene expression and obesity resistance. Nature 458:757–761

    CAS  PubMed Central  PubMed  Google Scholar 

  • Terranova R, Agherbi H, Boned A, Meresse S, Djabali M (2006) Histone and DNA methylation defects at Hox genes in mice expressing a SET domain-truncated form of Mll. Proc Natl Acad Sci U S A 103:6629–6634

    CAS  PubMed Central  PubMed  Google Scholar 

  • Thomson JP, Skene PJ, Selfridge J, Clouaire T, Guy J, Webb S, Kerr AR, Deaton A, Andrews R, James KD et al (2010) CpG islands influence chromatin structure via the CpG-binding protein Cfp1. Nature 464:1082–1086

    CAS  PubMed Central  PubMed  Google Scholar 

  • Tsumura A, Hayakawa T, Kumaki Y, Takebayashi S, Sakaue M, Matsuoka C, Shimotohno K, Ishikawa F, Li E, Ueda HR 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 11:805–814

    CAS  PubMed  Google Scholar 

  • Ura H, Usuda M, Kinoshita K, Sun C, Mori K, Akagi T, Matsuda T, Koide H, Yokota T (2008) STAT3 and Oct-3/4 control histone modification through induction of Eed in embryonic stem cells. J Biol Chem 283:9713–9723

    CAS  PubMed  Google Scholar 

  • Vastenhouw NL, Zhang Y, Woods IG, Imam F, Regev A, Liu XS, Rinn J, Schier AF (2010) Chromatin signature of embryonic pluripotency is established during genome activation. Nature 464:922–926

    CAS  PubMed Central  PubMed  Google Scholar 

  • Visel A, Blow MJ, Li Z, Zhang T, Akiyama JA, Holt A, Plajzer-Frick I, Shoukry M, Wright C, Chen F et al (2009) ChIP-seq accurately predicts tissue-specific activity of enhancers. Nature 457:854–858

    CAS  PubMed Central  PubMed  Google Scholar 

  • Voncken JW, Roelen BA, Roefs M, de Vries S, Verhoeven E, Marino S, Deschamps J, van Lohuizen M (2003) Rnf2 (Ring1b) deficiency causes gastrulation arrest and cell cycle inhibition. Proc Natl Acad Sci U S A 100:2468–2473

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wang J, Hevi S, Kurash JK, Lei H, Gay F, Bajko J, Su H, Sun W, Chang H, Xu G et al (2009) The lysine demethylase LSD1 (KDM1) is required for maintenance of global DNA methylation. Nat Genet 41:125–129

    CAS  PubMed  Google Scholar 

  • Wang J, Zhang M, Zhang Y, Kou Z, Han Z, Chen DY, Sun QY, Gao S (2010) The histone demethylase JMJD2C is stage-specifically expressed in preimplantation mouse embryos and is required for embryonic development. Biol Reprod 82:105–111

    CAS  PubMed  Google Scholar 

  • Wang T, Chen K, Zeng X, Yang J, Wu Y, Shi X, Qin B, Zeng L, Esteban MA, Pan G et al (2011) The histone demethylases Jhdm1a/1b enhance somatic cell reprogramming in a vitamin-C-dependent manner. Cell Stem Cell 9:575–587

    CAS  PubMed  Google Scholar 

  • Wang C, Lee JE, Cho YW, Xiao Y, Jin Q, Liu C, Ge K (2012) UTX regulates mesoderm differentiation of embryonic stem cells independent of H3K27 demethylase activity. Proc Natl Acad Sci U S A 109:15324–15329

    CAS  PubMed Central  PubMed  Google Scholar 

  • Whyte WA, Bilodeau S, Orlando DA, Hoke HA, Frampton GM, Foster CT, Cowley SM, Young RA (2012) Enhancer decommissioning by LSD1 during embryonic stem cell differentiation. Nature 482:221–225

    CAS  PubMed Central  PubMed  Google Scholar 

  • Williams K, Christensen J, Pedersen MT, Johansen JV, Cloos PA, Rappsilber J, Helin K (2011) TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelity. Nature 473:343–348

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wu H, D’Alessio AC, Ito S, Xia K, Wang Z, Cui K, Zhao K, Sun YE, Zhang Y (2011) Dual functions of Tet1 in transcriptional regulation in mouse embryonic stem cells. Nature 473:389–393

    CAS  PubMed Central  PubMed  Google Scholar 

  • Xie W, Schultz MD, Lister R, Hou Z, Rajagopal N, Ray P, Whitaker JW, Tian S, Hawkins RD, Leung D et al (2013) Epigenomic analysis of multilineage differentiation of human embryonic stem cells. Cell 153:1134–1148

    CAS  PubMed Central  PubMed  Google Scholar 

  • Zakaria K, Woldemichael T, Abegaz Z (1989) New foci of Bulinus abyssinicus in the lower Awash. Ethiop Med J 27:43–44

    CAS  PubMed  Google Scholar 

  • Ziller MJ, Gu H, Muller F, Donaghey J, Tsai LT, Kohlbacher O, De Jager PL, Rosen ED, Bennett DA, Bernstein BE et al (2013) Charting a dynamic DNA methylation landscape of the human genome. Nature 500:477–481

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA

    Jing Liao & Alexander Meissner

  2. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Jing Liao & Alexander Meissner

Authors
  1. Jing Liao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alexander Meissner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alexander Meissner .

Editor information

Editors and Affiliations

  1. Dpt. of Stem Cell and Regenerative Biol, Harvard University Broad Institute, Bauer Laboratory, Cambridge, Massachusetts, USA

    Alexander Meissner

  2. Dpt. of Genetics & Epigenetics, Universität des Saarlandes FR 8.4 Biosciences, Saarbrücken, Germany

    Jörn Walter

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Liao, J., Meissner, A. (2015). Establishing and Maintaining Pluripotency: An Epigenetic Perspective. In: Meissner, A., Walter, J. (eds) Epigenetic Mechanisms in Cellular Reprogramming. Epigenetics and Human Health. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-31974-7_5

Download citation

Publish with us

Policies and ethics

Search

Navigation