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Mechanisms of pluripotency maintenance in mouse embryonic stem cells

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Abstract

Mouse embryonic stem cells (mESCs), characterized by their pluripotency and capacity for self-renewal, are driven by a complex gene expression program composed of several regulatory mechanisms. These mechanisms collaborate to maintain the delicate balance of pluripotency gene expression and their disruption leads to loss of pluripotency. In this review, we provide an extensive overview of the key pillars of mESC pluripotency by elaborating on the various essential transcription factor networks and signaling pathways that directly or indirectly support this state. Furthermore, we consider the latest developments in the role of epigenetic regulation, such as noncoding RNA signaling or histone modifications.

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References

  1. Solter D (2006) From teratocarcinomas to embryonic stem cells and beyond: a history of embryonic stem cell research. Nat Rev Genet 7:319–327. doi:10.1038/nrg1827

    Article  CAS  PubMed  Google Scholar 

  2. Mintz B, Illmensee K (1975) Normal genetically mosaic mice produced from malignant teratocarcinoma cells. Proc Natl Acad Sci USA 72:3585–3589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Illmensee K, Mintz B (1976) Totipotency and normal differentiation of single teratocarcinoma cells cloned by injection into blastocysts. Proc Natl Acad Sci USA 73:549–553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Evans MJ, Kaufman MH (1981) Establishment in culture of pluripotential cells from mouse embryos. Nature 292:154–156

    Article  CAS  PubMed  Google Scholar 

  5. Loh KM, Lim B (2011) A precarious balance: pluripotency factors as lineage specifiers. Cell Stem Cell 8:363–369. doi:10.1016/j.stem.2011.03.013

    Article  CAS  PubMed  Google Scholar 

  6. Thomson M, Liu SJ, Zou LN, Smith Z, Meissner A, Ramanathan S (2011) Pluripotency factors in embryonic stem cells regulate differentiation into germ layers. Cell 145:875–889. doi:10.1016/j.cell.2011.05.017

    Article  CAS  PubMed  Google Scholar 

  7. Tomioka M, Nishimoto M, Miyagi S, Katayanagi T, Fukui N, Niwa H, Muramatsu M, Okuda A (2002) Identification of Sox-2 regulatory region which is under the control of Oct-3/4-Sox-2 complex. Nucleic Acids Res 30:3202–3213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Yuan H, Corbi N, Basilico C, Dailey L (1995) Developmental-specific activity of the FGF-4 enhancer requires the synergistic action of Sox2 and Oct-3. Genes Dev 9:2635–2645

    Article  CAS  PubMed  Google Scholar 

  9. Ambrosetti DC, Scholer HR, Dailey L, Basilico C (2000) Modulation of the activity of multiple transcriptional activation domains by the DNA binding domains mediates the synergistic action of Sox2 and Oct-3 on the fibroblast growth factor-4 enhancer. J Biol Chem 275:23387–23397. doi:10.1074/jbc.M000932200

    Article  CAS  PubMed  Google Scholar 

  10. Guo Y, Costa R, Ramsey H, Starnes T, Vance G, Robertson K, Kelley M, Reinbold R, Scholer H, Hromas R (2002) The embryonic stem cell transcription factors Oct-4 and FoxD3 interact to regulate endodermal-specific promoter expression. Proc Natl Acad Sci USA 99:3663–3667. doi:10.1073/pnas.062041099

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Nichols J, Zevnik B, Anastassiadis K, Niwa H, Klewe-Nebenius D, Chambers I, Scholer H, Smith A (1998) Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell 95:379–391

    Article  CAS  PubMed  Google Scholar 

  12. Niwa H (2001) Molecular mechanism to maintain stem cell renewal of ES cells. Cell Struct Funct 26:137–148

    Article  CAS  PubMed  Google Scholar 

  13. Niwa H, Miyazaki J, Smith AG (2000) Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nat Genet 24:372–376. doi:10.1038/74199

    Article  CAS  PubMed  Google Scholar 

  14. Yeom YI, Fuhrmann G, Ovitt CE, Brehm A, Ohbo K, Gross M, Hubner K, Scholer HR (1996) Germline regulatory element of Oct-4 specific for the totipotent cycle of embryonal cells. Development 122:881–894

    CAS  PubMed  Google Scholar 

  15. Ben-Shushan E, Pikarsky E, Klar A, Bergman Y (1993) Extinction of Oct-3/4 gene expression in embryonal carcinoma × fibroblast somatic cell hybrids is accompanied by changes in the methylation status, chromatin structure, and transcriptional activity of the Oct-3/4 upstream region. Mol Cell Biol 13:891–901

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gubbay J, Collignon J, Koopman P, Capel B, Economou A, Munsterberg A, Vivian N, Goodfellow P, Lovell-Badge R (1990) A gene mapping to the sex-determining region of the mouse Y chromosome is a member of a novel family of embryonically expressed genes. Nature 346:245–250. doi:10.1038/346245a0

    Article  CAS  PubMed  Google Scholar 

  17. Avilion AA, Nicolis SK, Pevny LH, Perez L, Vivian N, Lovell-Badge R (2003) Multipotent cell lineages in early mouse development depend on SOX2 function. Genes Dev 17:126–140. doi:10.1101/gad.224503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Dailey L, Basilico C (2001) Coevolution of HMG domains and homeodomains and the generation of transcriptional regulation by Sox/POU complexes. J Cell Physiol 186:315–328. doi:10.1002/1097-4652(2001)9999:9999<000:AID-JCP1046>3.0.CO;2-Y

    Article  CAS  PubMed  Google Scholar 

  19. Wang SH, Tsai MS, Chiang MF, Li H (2003) A novel NK-type homeobox gene, ENK (early embryo specific NK), preferentially expressed in embryonic stem cells. Gene Expr Patterns 3:99–103

    Article  CAS  PubMed  Google Scholar 

  20. Mitsui K, Tokuzawa Y, Itoh H, Segawa K, Murakami M, Takahashi K, Maruyama M, Maeda M, Yamanaka S (2003) The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell 113:631–642

    Article  CAS  PubMed  Google Scholar 

  21. Chambers I, Colby D, Robertson M, Nichols J, Lee S, Tweedie S, Smith A (2003) Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell 113:643–655

    Article  CAS  PubMed  Google Scholar 

  22. Lin T, Chao C, Saito S, Mazur SJ, Murphy ME, Appella E, Xu Y (2005) p53 induces differentiation of mouse embryonic stem cells by suppressing Nanog expression. Nat Cell Biol 7:165–171. doi:10.1038/ncb1211

    Article  CAS  PubMed  Google Scholar 

  23. Shigeta M, Ohtsuka S, Nishikawa-Torikai S, Yamane M, Fujii S, Murakami K, Niwa H (2013) Maintenance of pluripotency in mouse ES cells without Trp53. Sci Reports 3:2944. doi:10.1038/srep02944

    Google Scholar 

  24. Loh YH, Wu Q, Chew JL, Vega VB, Zhang W, Chen X, Bourque G, George J, Leong B, Liu J, Wong KY, Sung KW, Lee CW, Zhao XD, Chiu KP, Lipovich L, Kuznetsov VA, Robson P, Stanton LW, Wei CL, Ruan Y, Lim B, Ng HH (2006) The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells. Nat Genet 38:431–440. doi:10.1038/ng1760

    Article  CAS  PubMed  Google Scholar 

  25. Hanna LA, Foreman RK, Tarasenko IA, Kessler DS, Labosky PA (2002) Requirement for Foxd3 in maintaining pluripotent cells of the early mouse embryo. Genes Dev 16:2650–2661. doi:10.1101/gad.1020502

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Pan G, Li J, Zhou Y, Zheng H, Pei D (2006) A negative feedback loop of transcription factors that controls stem cell pluripotency and self-renewal. FASEB J 20:1730–1732. doi:10.1096/fj.05-5543fje

    Article  CAS  PubMed  Google Scholar 

  27. Navarro P, Festuccia N, Colby D, Gagliardi A, Mullin NP, Zhang W, Karwacki-Neisius V, Osorno R, Kelly D, Robertson M, Chambers I (2012) OCT4/SOX2-independent Nanog autorepression modulates heterogeneous Nanog gene expression in mouse ES cells. EMBO J 31(24):4547–4562. doi:10.1038/emboj.2012.321

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Schwarz BA, Bar-Nur O, Silva JC, Hochedlinger K (2014) Nanog is dispensable for the generation of induced pluripotent stem cells. Curr Biol 24(3):347–350. doi:10.1016/j.cub.2013.12.050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Jiang J, Chan YS, Loh YH, Cai J, Tong GQ, Lim CA, Robson P, Zhong S, Ng HH (2008) A core Klf circuitry regulates self-renewal of embryonic stem cells. Nat Cell Biol 10:353–360. doi:10.1038/ncb1698

    Article  PubMed  CAS  Google Scholar 

  30. Bourillot PY, Savatier P (2010) Kruppel-like transcription factors and control of pluripotency. BMC Biol 8:125. doi:10.1186/1741-7007-8-125

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Hall J, Guo G, Wray J, Eyres I, Nichols J, Grotewold L, Morfopoulou S, Humphreys P, Mansfield W, Walker R, Tomlinson S, Smith A (2009) Oct4 and LIF/Stat3 additively induce Kruppel factors to sustain embryonic stem cell self-renewal. Cell Stem Cell 5:597–609. doi:10.1016/j.stem.2009.11.003

    Article  CAS  PubMed  Google Scholar 

  32. Dunn SJ, Martello G, Yordanov B, Emmott S, Smith AG (2014) Defining an essential transcription factor program for naive pluripotency. Science 344:1156–1160. doi:10.1126/science.1248882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Williams RL, Hilton DJ, Pease S, Willson TA, Stewart CL, Gearing DP, Wagner EF, Metcalf D, Nicola NA, Gough NM (1988) Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells. Nature 336:684–687. doi:10.1038/336684a0

    Article  CAS  PubMed  Google Scholar 

  34. Niwa H, Burdon T, Chambers I, Smith A (1998) Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3. Genes Dev 12:2048–2060

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Boeuf H, Hauss C, Graeve FD, Baran N, Kedinger C (1997) Leukemia inhibitory factor-dependent transcriptional activation in embryonic stem cells. J Cell Biol 138:1207–1217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Stahl N, Farruggella TJ, Boulton TG, Zhong Z, Darnell JE Jr, Yancopoulos GD (1995) Choice of STATs and other substrates specified by modular tyrosine-based motifs in cytokine receptors. Science 267:1349–1353

    Article  CAS  PubMed  Google Scholar 

  37. Matsuda T, Nakamura T, Nakao K, Arai T, Katsuki M, Heike T, Yokota T (1999) STAT3 activation is sufficient to maintain an undifferentiated state of mouse embryonic stem cells. EMBO J 18:4261–4269. doi:10.1093/emboj/18.15.4261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Chen CY, Lee DS, Yan YT, Shen CN, Hwang SM, Lee ST, Hsieh PC (2015) Bcl3 Bridges LIF-STAT3 to Oct4 Signaling in the Maintenance of Naive Pluripotency. Stem Cells 33:3468–3480. doi:10.1002/stem.2201

    Article  CAS  PubMed  Google Scholar 

  39. Niwa H, Ogawa K, Shimosato D, Adachi K (2009) A parallel circuit of LIF signalling pathways maintains pluripotency of mouse ES cells. Nature 460:118–122. doi:10.1038/nature08113

    Article  CAS  PubMed  Google Scholar 

  40. Jirmanova L, Afanassieff M, Gobert-Gosse S, Markossian S, Savatier P (2002) Differential contributions of ERK and PI3-kinase to the regulation of cyclin D1 expression and to the control of the G1/S transition in mouse embryonic stem cells. Oncogene 21:5515–5528. doi:10.1038/sj.onc.1205728

    Article  CAS  PubMed  Google Scholar 

  41. Burdon T, Stracey C, Chambers I, Nichols J, Smith A (1999) Suppression of SHP-2 and ERK signalling promotes self-renewal of mouse embryonic stem cells. Dev Biol 210:30–41. doi:10.1006/dbio.1999.9265

    Article  CAS  PubMed  Google Scholar 

  42. Hamazaki T, Kehoe SM, Nakano T, Terada N (2006) The Grb2/Mek pathway represses Nanog in murine embryonic stem cells. Mol Cell Biol 26:7539–7549. doi:10.1128/MCB.00508-06

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Tamm C, Bower N, Anneren C (2011) Regulation of mouse embryonic stem cell self-renewal by a Yes-YAP-TEAD2 signaling pathway downstream of LIF. J Cell Sci 124:1136–1144. doi:10.1242/jcs.075796

    Article  PubMed  Google Scholar 

  44. Shi Y, Massague J (2003) Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113:685–700

    Article  CAS  PubMed  Google Scholar 

  45. Murakami G, Watabe T, Takaoka K, Miyazono K, Imamura T (2003) Cooperative inhibition of bone morphogenetic protein signaling by Smurf1 and inhibitory Smads. Mol Biol Cell 14:2809–2817. doi:10.1091/mbc.E02-07-0441

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ruzinova MB, Benezra R (2003) Id proteins in development, cell cycle and cancer. Trends Cell Biol 13:410–418

    Article  CAS  PubMed  Google Scholar 

  47. Aubert J, Dunstan H, Chambers I, Smith A (2002) Functional gene screening in embryonic stem cells implicates Wnt antagonism in neural differentiation. Nat Biotechnol 20:1240–1245. doi:10.1038/nbt763

    Article  CAS  PubMed  Google Scholar 

  48. Yoshikawa Y, Fujimori T, McMahon AP, Takada S (1997) Evidence that absence of Wnt-3a signaling promotes neuralization instead of paraxial mesoderm development in the mouse. Dev Biol 183:234–242. doi:10.1006/dbio.1997.8502

    Article  CAS  PubMed  Google Scholar 

  49. Nguyen H, Rendl M, Fuchs E (2006) Tcf3 governs stem cell features and represses cell fate determination in skin. Cell 127:171–183. doi:10.1016/j.cell.2006.07.036

    Article  CAS  PubMed  Google Scholar 

  50. Kelly KF, Ng DY, Jayakumaran G, Wood GA, Koide H, Doble BW (2011) beta-catenin enhances Oct-4 activity and reinforces pluripotency through a TCF-independent mechanism. Cell Stem Cell 8:214–227. doi:10.1016/j.stem.2010.12.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Faunes F, Hayward P, Descalzo SM, Chatterjee SS, Balayo T, Trott J, Christoforou A, Ferrer-Vaquer A, Hadjantonakis AK, Dasgupta R, Arias AM (2013) A membrane-associated beta-catenin/Oct4 complex correlates with ground-state pluripotency in mouse embryonic stem cells. Development 140:1171–1183. doi:10.1242/dev.085654

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Guan KL, Figueroa C, Brtva TR, Zhu T, Taylor J, Barber TD, Vojtek AB (2000) Negative regulation of the serine/threonine kinase B-Raf by Akt. J Biol Chem 275:27354–27359. doi:10.1074/jbc.M004371200

    CAS  PubMed  Google Scholar 

  53. Basu S, Totty NF, Irwin MS, Sudol M, Downward J (2003) Akt phosphorylates the Yes-associated protein, YAP, to induce interaction with 14-3-3 and attenuation of p73-mediated apoptosis. Mol Cell 11:11–23

    Article  CAS  PubMed  Google Scholar 

  54. Sears R, Nuckolls F, Haura E, Taya Y, Tamai K, Nevins JR (2000) Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability. Genes Dev 14:2501–2514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Rajan P, Panchision DM, Newell LF, McKay RD (2003) BMPs signal alternately through a SMAD or FRAP-STAT pathway to regulate fate choice in CNS stem cells. J Cell Biol 161:911–921. doi:10.1083/jcb.200211021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Ying QL, Wray J, Nichols J, Batlle-Morera L, Doble B, Woodgett J, Cohen P, Smith A (2008) The ground state of embryonic stem cell self-renewal. Nature 453:519–523. doi:10.1038/nature06968

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kanda A, Sotomaru Y, Shiozawa S, Hiyama E (2012) Establishment of ES cells from inbred strain mice by dual inhibition (2i). J Reprod Dev 58(1):77–83

    Article  CAS  PubMed  Google Scholar 

  58. Lee Y, Ahn C, Han J, Choi H, Kim J, Yim J, Lee J, Provost P, Radmark O, Kim S, Kim VN (2003) The nuclear RNase III Drosha initiates microRNA processing. Nature 425:415–419. doi:10.1038/nature01957

    Article  CAS  PubMed  Google Scholar 

  59. Park JE, Heo I, Tian Y, Simanshu DK, Chang H, Jee D, Patel DJ, Kim VN (2011) Dicer recognizes the 5′ end of RNA for efficient and accurate processing. Nature 475:201–205. doi:10.1038/nature10198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Lin SL, Chang D, Ying SY (2005) Asymmetry of intronic pre-miRNA structures in functional RISC assembly. Gene 356:32–38. doi:10.1016/j.gene.2005.04.036

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Meister G (2013) Argonaute proteins: functional insights and emerging roles. Nat Rev Genet 14:447–459. doi:10.1038/nrg3462

    Article  CAS  PubMed  Google Scholar 

  62. Fazi F, Nervi C (2008) MicroRNA: basic mechanisms and transcriptional regulatory networks for cell fate determination. Cardiovasc Res 79:553–561. doi:10.1093/cvr/cvn151

    Article  CAS  PubMed  Google Scholar 

  63. Kanellopoulou C, Muljo SA, Kung AL, Ganesan S, Drapkin R, Jenuwein T, Livingston DM, Rajewsky K (2005) Dicer-deficient mouse embryonic stem cells are defective in differentiation and centromeric silencing. Genes Dev 19:489–501. doi:10.1101/gad.1248505

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Wang Y, Medvid R, Melton C, Jaenisch R, Blelloch R (2007) DGCR8 is essential for microRNA biogenesis and silencing of embryonic stem cell self-renewal. Nat Genet 39:380–385. doi:10.1038/ng1969

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Wang Y, Baskerville S, Shenoy A, Babiarz JE, Baehner L, Blelloch R (2008) Embryonic stem cell-specific microRNAs regulate the G1-S transition and promote rapid proliferation. Nat Genet 40:1478–1483. doi:10.1038/ng.250

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Houbaviy HB, Murray MF, Sharp PA (2003) Embryonic stem cell-specific microRNAs. Dev Cell 5:351–358

    Article  CAS  PubMed  Google Scholar 

  67. Houbaviy HB, Dennis L, Jaenisch R, Sharp PA (2005) Characterization of a highly variable eutherian microRNA gene. RNA 11:1245–1257. doi:10.1261/rna.2890305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Chen C, Ridzon D, Lee CT, Blake J, Sun Y, Strauss WM (2007) Defining embryonic stem cell identity using differentiation-related microRNAs and their potential targets. Mamm Genome 18:316–327. doi:10.1007/s00335-007-9032-6

    Article  CAS  PubMed  Google Scholar 

  69. Marson A, Levine SS, Cole MF, Frampton GM, Brambrink T, Johnstone S, Guenther MG, Johnston WK, Wernig M, Newman J, Calabrese JM, Dennis LM, Volkert TL, Gupta S, Love J, Hannett N, Sharp PA, Bartel DP, Jaenisch R, Young RA (2008) Connecting microRNA genes to the core transcriptional regulatory circuitry of embryonic stem cells. Cell 134:521–533. doi:10.1016/j.cell.2008.07.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Sinkkonen L, Hugenschmidt T, Berninger P, Gaidatzis D, Mohn F, Artus-Revel CG, Zavolan M, Svoboda P, Filipowicz W (2008) MicroRNAs control de novo DNA methylation through regulation of transcriptional repressors in mouse embryonic stem cells. Nat Struct Mol Biol 15:259–267. doi:10.1038/nsmb.1391

    Article  CAS  PubMed  Google Scholar 

  71. Judson RL, Babiarz JE, Venere M, Blelloch R (2009) Embryonic stem cell-specific microRNAs promote induced pluripotency. Nat Biotechnol 27:459–461. doi:10.1038/nbt.1535

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Mercer TR, Dinger ME, Mattick JS (2009) Long non-coding RNAs: insights into functions. Nat Rev Genet 10:155–159. doi:10.1038/nrg2521

    Article  CAS  PubMed  Google Scholar 

  73. Quinn JJ, Chang HY (2015) Unique features of long non-coding RNA biogenesis and function. Nat Rev Genet 17:47–62. doi:10.1038/nrg.2015.10

    Article  CAS  Google Scholar 

  74. Wang KC, Chang HY (2011) Molecular mechanisms of long noncoding RNAs. Mol Cell 43:904–914. doi:10.1016/j.molcel.2011.08.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Schmitz SU, Grote P, Herrmann BG (2016) Mechanisms of long noncoding RNA function in development and disease. Cell Mol Life Sci. doi:10.1007/s00018-016-2174-5

    PubMed  PubMed Central  Google Scholar 

  76. Brown CJ, Hendrich BD, Rupert JL, Lafreniere RG, Xing Y, Lawrence J, Willard HF (1992) The human XIST gene: analysis of a 17 kb inactive X-specific RNA that contains conserved repeats and is highly localized within the nucleus. Cell 71:527–542

    Article  CAS  PubMed  Google Scholar 

  77. Brockdorff N, Ashworth A, Kay GF, McCabe VM, Norris DP, Cooper PJ, Swift S, Rastan S (1992) The product of the mouse Xist gene is a 15 kb inactive X-specific transcript containing no conserved ORF and located in the nucleus. Cell 71:515–526

    Article  CAS  PubMed  Google Scholar 

  78. Borsani G, Tonlorenzi R, Simmler MC, Dandolo L, Arnaud D, Capra V, Grompe M, Pizzuti A, Muzny D, Lawrence C, Willard HF, Avner P, Ballabio A (1991) Characterization of a murine gene expressed from the inactive X chromosome. Nature 351:325–329. doi:10.1038/351325a0

    Article  CAS  PubMed  Google Scholar 

  79. Penny GD, Kay GF, Sheardown SA, Rastan S, Brockdorff N (1996) Requirement for Xist in X chromosome inactivation. Nature 379:131–137. doi:10.1038/379131a0

    Article  CAS  PubMed  Google Scholar 

  80. Heard E (2004) Recent advances in X-chromosome inactivation. Curr Opin Cell Biol 16:247–255. doi:10.1016/j.ceb.2004.03.005

    Article  CAS  PubMed  Google Scholar 

  81. Nichols J, Smith A (2009) Naive and primed pluripotent states. Cell Stem Cell 4:487–492. doi:10.1016/j.stem.2009.05.015

    Article  CAS  PubMed  Google Scholar 

  82. Zhao J, Sun BK, Erwin JA, Song JJ, Lee JT (2008) Polycomb proteins targeted by a short repeat RNA to the mouse X chromosome. Science 322:750–756. doi:10.1126/science.1163045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Navarro P, Chambers I, Karwacki-Neisius V, Chureau C, Morey C, Rougeulle C, Avner P (2008) Molecular coupling of Xist regulation and pluripotency. Science 321:1693–1695. doi:10.1126/science.1160952

    Article  CAS  PubMed  Google Scholar 

  84. Pasque V, Tchieu J, Karnik R, Uyeda M, Sadhu Dimashkie A, Case D, Papp B, Bonora G, Patel S, Ho R, Schmidt R, McKee R, Sado T, Tada T, Meissner A, Plath K (2014) X chromosome reactivation dynamics reveal stages of reprogramming to pluripotency. Cell 159:1681–1697. doi:10.1016/j.cell.2014.11.040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Guttman M, Amit I, Garber M, French C, Lin MF, Feldser D, Huarte M, Zuk O, Carey BW, Cassady JP, Cabili MN, Jaenisch R, Mikkelsen TS, Jacks T, Hacohen N, Bernstein BE, Kellis M, Regev A, Rinn JL, Lander ES (2009) Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature 458:223–227. doi:10.1038/nature07672

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Guttman M, Donaghey J, Carey BW, Garber M, Grenier JK, Munson G, Young G, Lucas AB, Ach R, Bruhn L, Yang XP, Amit I, Meissner A, Regev A, Rinn JL, Root DE, Lander ES (2011) lincRNAs act in the circuitry controlling pluripotency and differentiation. Nature 477:U260–U295. doi:10.1038/nature10398

    Article  CAS  Google Scholar 

  87. Sheik Mohamed J, Gaughwin PM, Lim B, Robson P, Lipovich L (2010) Conserved long noncoding RNAs transcriptionally regulated by Oct4 and Nanog modulate pluripotency in mouse embryonic stem cells. RNA 16:324–337. doi:10.1261/rna.1441510

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Savic N, Bar D, Leone S, Frommel SC, Weber FA, Vollenweider E, Ferrari E, Ziegler U, Kaech A, Shakhova O, Cinelli P, Santoro R (2014) lncRNA maturation to initiate heterochromatin formation in the nucleolus is required for exit from pluripotency in ESCs. Cell Stem Cell 15:720–734. doi:10.1016/j.stem.2014.10.005

    Article  CAS  PubMed  Google Scholar 

  89. Ho L, Crabtree GR (2010) Chromatin remodelling during development. Nature 463:474–484. doi:10.1038/nature08911

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Lewis EB (1978) A gene complex controlling segmentation in Drosophila. Nature 276:565–570

    Article  CAS  PubMed  Google Scholar 

  91. Struhl G (1981) A gene product required for correct initiation of segmental determination in Drosophila. Nature 293:36–41

    Article  CAS  PubMed  Google Scholar 

  92. Endoh M, Endo TA, Endoh T, Fujimura Y, Ohara O, Toyoda T, Otte AP, Okano M, Brockdorff N, Vidal M, Koseki H (2008) Polycomb group proteins Ring1A/B are functionally linked to the core transcriptional regulatory circuitry to maintain ES cell identity. Development 135(8):1513–1524. doi:10.1242/dev.014340

    Article  CAS  PubMed  Google Scholar 

  93. Eskeland R, Leeb M, Grimes GR, Kress C, Boyle S, Sproul D, Gilbert N, Fan Y, Skoultchi AI, Wutz A, Bickmore WA (2010) Ring1B compacts chromatin structure and represses gene expression independent of histone ubiquitination. Mol Cell 38:452–464. doi:10.1016/j.molcel.2010.02.032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Simon JA, Kingston RE (2009) Mechanisms of polycomb gene silencing: knowns and unknowns. Nat Rev Mol Cell Biol 10:697–708. doi:10.1038/nrm2763

    Article  CAS  PubMed  Google Scholar 

  95. Cao R, Zhang Y (2004) SUZ12 is required for both the histone methyltransferase activity and the silencing function of the EED-EZH2 complex. Mol Cell 15:57–67. doi:10.1016/j.molcel.2004.06.020

    Article  CAS  PubMed  Google Scholar 

  96. Nekrasov M, Klymenko T, Fraterman S, Papp B, Oktaba K, Kocher T, Cohen A, Stunnenberg HG, Wilm M, Muller J (2007) Pcl-PRC2 is needed to generate high levels of H3-K27 trimethylation at Polycomb target genes. EMBO J 26:4078–4088. doi:10.1038/sj.emboj.7601837

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Walker E, Chang WY, Hunkapiller J, Cagney G, Garcha K, Torchia J, Krogan NJ, Reiter JF, Stanford WL (2010) Polycomb-like 2 associates with PRC2 and regulates transcriptional networks during mouse embryonic stem cell self-renewal and differentiation. Cell Stem Cell 6:153–166. doi:10.1016/j.stem.2009.12.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Sarma K, Margueron R, Ivanov A, Pirrotta V, Reinberg D (2008) Ezh2 requires PHF1 to efficiently catalyze H3 lysine 27 trimethylation in vivo. Mol Cell Biol 28:2718–2731. doi:10.1128/MCB.02017-07

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Savla U, Benes J, Zhang J, Jones RS (2008) Recruitment of Drosophila Polycomb-group proteins by Polycomblike, a component of a novel protein complex in larvae. Development 135:813–817. doi:10.1242/dev.016006

    Article  CAS  PubMed  Google Scholar 

  100. Boyer LA, Plath K, Zeitlinger J, Brambrink T, Medeiros LA, Lee TI, Levine SS, Wernig M, Tajonar A, Ray MK, Bell GW, Otte AP, Vidal M, Gifford DK, Young RA, Jaenisch R (2006) Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature 441:349–353. doi:10.1038/nature04733

    Article  CAS  PubMed  Google Scholar 

  101. Chamberlain SJ, Yee D, Magnuson T (2008) Polycomb repressive complex 2 is dispensable for maintenance of embryonic stem cell pluripotency. Stem Cells 26(6):1496–1505. doi:10.1634/stemcells.2008-0102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Li G, Margueron R, Ku M, Chambon P, Bernstein BE, Reinberg D (2010) Jarid2 and PRC2, partners in regulating gene expression. Genes Dev 24:368–380. doi:10.1101/gad.1886410

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Landeira D, Sauer S, Poot R, Dvorkina M, Mazzarella L, Jorgensen HF, Pereira CF, Leleu M, Piccolo FM, Spivakov M, Brookes E, Pombo A, Fisher C, Skarnes WC, Snoek T, Bezstarosti K, Demmers J, Klose RJ, Casanova M, Tavares L, Brockdorff N, Merkenschlager M, Fisher AG (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 12:618–624. doi:10.1038/ncb2065

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Peters AH, Kubicek S, Mechtler K, O’Sullivan RJ, Derijck AA, Perez-Burgos L, Kohlmaier A, Opravil S, Tachibana M, Shinkai Y, Martens JH, Jenuwein T (2003) Partitioning and plasticity of repressive histone methylation states in mammalian chromatin. Mol Cell 12:1577–1589

    Article  CAS  PubMed  Google Scholar 

  105. Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, Wang Z, Wei G, Chepelev I, Zhao K (2007) High-resolution profiling of histone methylations in the human genome. Cell 129:823–837. doi:10.1016/j.cell.2007.05.009

    Article  CAS  PubMed  Google Scholar 

  106. Azuara V, Perry P, Sauer S, Spivakov M, Jorgensen HF, John RM, Gouti M, Casanova M, Warnes G, Merkenschlager M, Fisher AG (2006) Chromatin signatures of pluripotent cell lines. Nat Cell Biol 8:532–538. doi:10.1038/ncb1403

    Article  CAS  PubMed  Google Scholar 

  107. 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 (2006) A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125:315–326. doi:10.1016/j.cell.2006.02.041

    Article  CAS  PubMed  Google Scholar 

  108. Ku M, Koche RP, Rheinbay E, Mendenhall EM, Endoh M, Mikkelsen TS, Presser A, Nusbaum C, Xie X, Chi AS, Adli M, Kasif S, Ptaszek LM, Cowan CA, Lander ES, Koseki H, Bernstein BE (2008) Genomewide analysis of PRC1 and PRC2 occupancy identifies two classes of bivalent domains. PLoS Genet 4:e1000242. doi:10.1371/journal.pgen.1000242

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Tavares L, Dimitrova E, Oxley D, Webster J, Poot R, Demmers J, Bezstarosti K, Taylor S, Ura H, Koide H, Wutz A, Vidal M, Elderkin S, Brockdorff N (2012) RYBP-PRC1 complexes mediate H2A ubiquitylation at polycomb target sites independently of PRC2 and H3K27me3. Cell 148:664–678. doi:10.1016/j.cell.2011.12.029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Qin J, Whyte WA, Anderssen E, Apostolou E, Chen HH, Akbarian S, Bronson RT, Hochedlinger K, Ramaswamy S, Young RA, Hock H (2012) The polycomb group protein L3mbtl2 assembles an atypical PRC1-family complex that is essential in pluripotent stem cells and early development. Cell Stem Cell 11:319–332. doi:10.1016/j.stem.2012.06.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Zhao XD, Han X, Chew JL, Liu J, Chiu KP, Choo A, Orlov YL, Sung WK, Shahab A, Kuznetsov VA, Bourque G, Oh S, Ruan Y, Ng HH, Wei CL (2007) Whole-genome mapping of histone H3 Lys4 and 27 trimethylations reveals distinct genomic compartments in human embryonic stem cells. Cell Stem Cell 1:286–298. doi:10.1016/j.stem.2007.08.004

    Article  CAS  PubMed  Google Scholar 

  112. Mikkelsen TS, Ku M, Jaffe DB, Issac B, Lieberman E, Giannoukos G, Alvarez P, Brockman W, Kim TK, Koche RP, Lee W, Mendenhall E, O’Donovan A, Presser A, Russ C, Xie X, Meissner A, Wernig M, Jaenisch R, Nusbaum C, Lander ES, Bernstein BE (2007) Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448:553–560. doi:10.1038/nature06008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Krivtsov AV, Armstrong SA (2007) MLL translocations, histone modifications and leukaemia stem-cell development. Nat Rev Cancer 7:823–833. doi:10.1038/nrc2253

    Article  CAS  PubMed  Google Scholar 

  114. Ang YS, Tsai SY, Lee DF, Monk J, Su J, Ratnakumar K, Ding J, Ge Y, Darr H, Chang B, Wang J, Rendl M, Bernstein E, Schaniel C, Lemischka IR (2011) Wdr5 mediates self-renewal and reprogramming via the embryonic stem cell core transcriptional network. Cell 145:183–197. doi:10.1016/j.cell.2011.03.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Ho L, Ronan JL, Wu J, Staahl BT, Chen L, Kuo A, Lessard J, Nesvizhskii AI, Ranish J, Crabtree GR (2009) An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency. Proc Natl Acad Sci U S A 106:5181–5186. doi:10.1073/pnas.0812889106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Ho L, Jothi R, Ronan JL, Cui K, Zhao K, Crabtree GR (2009) An embryonic stem cell chromatin remodeling complex, esBAF, is an essential component of the core pluripotency transcriptional network. Proc Natl Acad Sci U S A 106:5187–5191. doi:10.1073/pnas.0812888106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Gaspar-Maia A, Alajem A, Polesso F, Sridharan R, Mason MJ, Heidersbach A, Ramalho-Santos J, McManus MT, Plath K, Meshorer E, Ramalho-Santos M (2009) Chd1 regulates open chromatin and pluripotency of embryonic stem cells. Nature 460:863–868. doi:10.1038/nature08212

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Wang L, Du Y, Ward JM, Shimbo T, Lackford B, Zheng X, Miao YL, Zhou B, Han L, Fargo DC, Jothi R, Williams CJ, Wade PA, Hu G (2014) INO80 facilitates pluripotency gene activation in embryonic stem cell self-renewal, reprogramming, and blastocyst development. Cell Stem Cell 14:575–591. doi:10.1016/j.stem.2014.02.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. 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. doi:10.1016/j.cell.2008.05.031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Bannister AJ, Kouzarides T (2011) Regulation of chromatin by histone modifications. Cell Res 21:381–395. doi:10.1038/cr.2011.22

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Tessarz P, Kouzarides T (2014) Histone core modifications regulating nucleosome structure and dynamics. Nat Rev Mol Cell Biol 15:703–708. doi:10.1038/nrm3890

    Article  CAS  PubMed  Google Scholar 

  122. Voigt P, Tee WW, Reinberg D (2013) A double take on bivalent promoters. Genes Dev 27:1318–1338. doi:10.1101/gad.219626.113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Christman JK, Price P, Pedrinan L, Acs G (1977) Correlation between hypomethylation of DNA and expression of globin genes in Friend erythroleukemia cells. Eur J Biochem 81:53–61

    Article  CAS  PubMed  Google Scholar 

  124. McGhee JD, Ginder GD (1979) Specific DNA methylation sites in the vicinity of the chicken beta-globin genes. Nature 280:419–420

    Article  CAS  PubMed  Google Scholar 

  125. Jones PA, Taylor SM (1980) Cellular differentiation, cytidine analogs and DNA methylation. Cell 20:85–93

    Article  CAS  PubMed  Google Scholar 

  126. Klose RJ, Bird AP (2006) Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci 31:89–97. doi:10.1016/j.tibs.2005.12.008

    Article  CAS  PubMed  Google Scholar 

  127. Lei H, Oh SP, Okano M, Juttermann R, Goss KA, Jaenisch R, Li E (1996) De novo DNA cytosine methyltransferase activities in mouse embryonic stem cells. Development 122:3195–3205

    CAS  PubMed  Google Scholar 

  128. Ng RK, Dean W, Dawson C, Lucifero D, Madeja Z, Reik W, Hemberger M (2008) Epigenetic restriction of embryonic cell lineage fate by methylation of Elf5. Nat Cell Biol 10(11):1280–1290. doi:10.1038/ncb1786

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Tsumura A, Hayakawa T, Kumaki Y, Takebayashi S, Sakaue M, Matsuoka C, Shimotohno K, Ishikawa F, Li E, Ueda HR, Nakayama J, Okano M (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. doi:10.1111/j.1365-2443.2006.00984.x

    Article  CAS  PubMed  Google Scholar 

  130. Oda M, Kumaki Y, Shigeta M, Jakt LM, Matsuoka C, Yamagiwa A, Niwa H, Okano M (2013) DNA methylation restricts lineage-specific functions of transcription factor Gata4 during embryonic stem cell differentiation. PLoS Genet 9(6):e1003574. doi:10.1371/journal.pgen.1003574

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Pastor WA, Aravind L, Rao A (2013) TETonic shift: biological roles of TET proteins in DNA demethylation and transcription. Nat Rev Mol Cell Biol 14:341–356. doi:10.1038/nrm3589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Koh KP, Rao A (2013) DNA methylation and methylcytosine oxidation in cell fate decisions. Curr Opin Cell Biol 25:152–161. doi:10.1016/j.ceb.2013.02.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. 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 (2011) Tet1 and Tet2 regulate 5-hydroxymethylcytosine production and cell lineage specification in mouse embryonic stem cells. Cell Stem Cell 8:200–213. doi:10.1016/j.stem.2011.01.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. 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 (2013) Combined deficiency of Tet1 and Tet2 causes epigenetic abnormalities but is compatible with postnatal development. Dev Cell 24:310–323. doi:10.1016/j.devcel.2012.12.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Wang J, Qiao M, He Q, Shi R, Loh SJ, Stanton LW, Wu M (2015) Pluripotency activity of nanog requires biochemical stabilization by variant histone protein H2A.Z. Stem Cells 33:2126–2134. doi:10.1002/stem.2011

    Article  CAS  PubMed  Google Scholar 

  136. Pijnappel WW, Esch D, Baltissen MP, Wu G, Mischerikow N, Bergsma AJ, van der Wal E, Han DW, Bruch H, Moritz S, Lijnzaad P, Altelaar AF, Sameith K, Zaehres H, Heck AJ, Holstege FC, Scholer HR, Timmers HT (2013) A central role for TFIID in the pluripotent transcription circuitry. Nature 495:516–519. doi:10.1038/nature11970

    Article  PubMed  CAS  Google Scholar 

  137. Yang VS, Carter SA, Hyland SJ, Tachibana-Konwalski K, Laskey RA, Gonzalez MA (2011) Geminin escapes degradation in G1 of mouse pluripotent cells and mediates the expression of Oct4, Sox2, and Nanog. Curr Biol 21:692–699. doi:10.1016/j.cub.2011.03.026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Caronna EA, Patterson ES, Hummert PM, Kroll KL (2013) Geminin restrains mesendodermal fate acquisition of embryonic stem cells and is associated with antagonism of Wnt signaling and enhanced polycomb-mediated repression. Stem Cells 31:1477–1487. doi:10.1002/stem.1410

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Wang L, Miao YL, Zheng X, Lackford B, Zhou B, Han L, Yao C, Ward JM, Burkholder A, Lipchina I, Fargo DC, Hochedlinger K, Shi Y, Williams CJ, Hu G (2013) The THO complex regulates pluripotency gene mRNA export and controls embryonic stem cell self-renewal and somatic cell reprogramming. Cell Stem Cell 13:676–690. doi:10.1016/j.stem.2013.10.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Smith AG, Hooper ML (1987) Buffalo rat liver cells produce a diffusible activity which inhibits the differentiation of murine embryonal carcinoma and embryonic stem cells. Dev Biol 121:1–9

    Article  CAS  PubMed  Google Scholar 

  141. Smith AG, Heath JK, Donaldson DD, Wong GG, Moreau J, Stahl M, Rogers D (1988) Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides. Nature 336:688–690. doi:10.1038/336688a0

    Article  CAS  PubMed  Google Scholar 

  142. Silva J, Smith A (2008) Capturing pluripotency. Cell 132:532–536. doi:10.1016/j.cell.2008.02.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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    Authors and Affiliations

    1. Institute of Biomedical Sciences, Academia Sinica, IBMS Rm.417, 128 Academia Road, Section 2, Nankang, Taipei, 115, Taiwan

      Chen-Yun Chen, Yuan-Yuan Cheng, Christopher Y. T. Yen & Patrick C. H. Hsieh

    2. Institute of Life Sciences, National Defense Medical Center, Taipei, 114, Taiwan

      Yuan-Yuan Cheng & Patrick C. H. Hsieh

    3. Institute of Medical Genomics and Proteomics, Institute of Clinical Medicine and Department of Surgery, National Taiwan University and Hospital, Taipei, 100, Taiwan

      Patrick C. H. Hsieh

    4. Institute of Clinical Medicine, National Cheng Kung University, Tainan, 701, Taiwan

      Patrick C. H. Hsieh

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    This review was supported by the Ministry of Science and Technology (MOST 104-2811-B-001-036 and 105-2325-B-001-009), and the Academia Sinica Translational Medicine Program.

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    C.-Y. Chen and Y.-Y. Cheng contributed equally to this work.

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    Chen, CY., Cheng, YY., Yen, C.Y.T. et al. Mechanisms of pluripotency maintenance in mouse embryonic stem cells. Cell. Mol. Life Sci. 74, 1805–1817 (2017). https://doi.org/10.1007/s00018-016-2438-0

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