Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Epigenetic control of adult stem cell function

Nature Reviews Molecular Cell Biology volume 17, pages 643–658 (2016)Cite this article

Subjects

Key Points

  • Distinct cellular differentiation programmes are facilitated by tight transcriptional and epigenetic regulation in adult stem cells.

  • The consequences of epigenetic deregulation in adult stem cells can be negligible, or they can lead to stem cell malfunction and disrupted tissue homeostasis, depending on the epigenetic factor and tissue under study.

  • Deregulation of epigenetic factors in adult stem cells often affects stem cell maintenance, self-renewal and differentiation.

  • However, deregulation of epigenetic factors in adult stem cells does not change the germ-layer fate (mesoderm, endoderm or ectoderm) of the cell.

  • Perturbation of epigenetic regulation can lead to stem cell dysfunction, which may cause diseases such as cancer; therapeutic intervention aiming at restoring correct epigenetic regulation may be clinically beneficial.

Abstract

Mammalian embryonic development is a tightly regulated process that, from a single zygote, produces a large number of cell types with hugely divergent functions. Distinct cellular differentiation programmes are facilitated by tight transcriptional and epigenetic regulation. However, the contribution of epigenetic regulation to tissue homeostasis after the completion of development is less well understood. In this Review, we explore the effects of epigenetic dysregulation on adult stem cell function. We conclude that, depending on the tissue type and the epigenetic regulator affected, the consequences range from negligible to stem cell malfunction and disruption of tissue homeostasis, which may predispose to diseases such as cancer.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Epigenetic regulation of haematopoietic stem cell function.
Figure 2: Epigenetic regulation of epidermal stem cell homeostasis.
Figure 3: Epigenetic regulation of myogenic differentiation and satellite cell function.
Figure 4: Epigenetic regulation of mesenchymal stem cell differentiation along the adipogenic and osteogenic lineages.

Similar content being viewed by others

References

  1. Blanpain, C. & Fuchs, E. Plasticity of epithelial stem cells in tissue regeneration. Science 344, 1242281 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Signer, R. A. & Morrison, S. J. Mechanisms that regulate stem cell aging and life span. Cell Stem Cell 12, 152–165 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Luis, N. M., Morey, L., Di Croce, L. & Benitah, S. A. Polycomb in stem cells: PRC1 branches out. Cell Stem Cell 11, 16–21 (2012).

    Article  CAS  PubMed  Google Scholar 

  4. Morey, L., Santanach, A. & Di Croce, L. Pluripotency and epigenetic factors in mouse embryonic stem cell fate regulation. Mol. Cell. Biol. 35, 2716–2728 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Wang, L. D. & Wagers, A. J. Dynamic niches in the origination and differentiation of haematopoietic stem cells. Nat. Rev. Mol. Cell Biol. 12, 643–655 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Rossi, L. et al. Less is more: unveiling the functional core of hematopoietic stem cells through knockout mice. Cell Stem Cell 11, 302–317 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Busch, K. et al. Fundamental properties of unperturbed haematopoiesis from stem cells in vivo. Nature 518, 542–546 (2015).

    Article  CAS  PubMed  Google Scholar 

  8. Sun, J. et al. Clonal dynamics of native haematopoiesis. Nature 514, 322–327 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Notta, F. et al. Distinct routes of lineage development reshape the human blood hierarchy across ontogeny. Science http://dx.doi.org/10.1126/science.aab2116 (2015).

  10. Hodges, E. et al. Directional DNA methylation changes and complex intermediate states accompany lineage specificity in the adult hematopoietic compartment. Mol. Cell 44, 17–28 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ji, H. et al. Comprehensive methylome map of lineage commitment from haematopoietic progenitors. Nature 467, 338–342 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kulis, M. et al. Whole-genome fingerprint of the DNA methylome during human B cell differentiation. Nat. Genet. 47, 746–756 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Meissner, A. et al. Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature 454, 766–770 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Cedar, H. & Bergman, Y. Epigenetics of haematopoietic cell development. Nat. Rev. Immunol. 11, 478–488 (2011).

    Article  CAS  PubMed  Google Scholar 

  15. Borgel, J. et al. Targets and dynamics of promoter DNA methylation during early mouse development. Nat. Genet. 42, 1093–1100 (2010).

    Article  CAS  PubMed  Google Scholar 

  16. Broske, A. M. et al. DNA methylation protects hematopoietic stem cell multipotency from myeloerythroid restriction. Nat. Genet. 41, 1207–1215 (2009).

    Article  CAS  PubMed  Google Scholar 

  17. Trowbridge, J. J., Snow, J. W., Kim, J. & Orkin, S. H. DNA methyltransferase 1 is essential for and uniquely regulates hematopoietic stem and progenitor cells. Cell Stem Cell 5, 442–449 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Tadokoro, Y., Ema, H., Okano, M., Li, E. & Nakauchi, H. De novo DNA methyltransferase is essential for self-renewal, but not for differentiation, in hematopoietic stem cells. J. Exp. Med. 204, 715–722 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Challen, G. A. et al. Dnmt3a is essential for hematopoietic stem cell differentiation. Nat. Genet. 44, 23–31 (2012).This study shows a progressive impairment of HSC differentiation following DNMT3A ablation, which demonstrates the necessity for intricate and long-term in vivo models to investigate adult stem cell function.

    Article  CAS  Google Scholar 

  20. Mayle, A. et al. Dnmt3a loss predisposes murine hematopoietic stem cells to malignant transformation. Blood 125, 629–638 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Yang, L., Rau, R. & Goodell, M. A. DNMT3A in haematological malignancies. Nat. Rev. Cancer 15, 152–165 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Challen, G. A. et al. Dnmt3a and Dnmt3b have overlapping and distinct functions in hematopoietic stem cells. Cell Stem Cell 15, 350–364 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Moran-Crusio, K. et al. Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell 20, 11–24 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Quivoron, C. et al. TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis. Cancer Cell 20, 25–38 (2011).

    Article  CAS  PubMed  Google Scholar 

  25. Li, Z. et al. Deletion of Tet2 in mice leads to dysregulated hematopoietic stem cells and subsequent development of myeloid malignancies. Blood 118, 4509–4518 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ko, M. et al. Ten-Eleven-Translocation 2 (TET2) negatively regulates homeostasis and differentiation of hematopoietic stem cells in mice. Proc. Natl Acad. Sci. USA 108, 14566–14571 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Dawlaty, M. M. et al. Tet1 is dispensable for maintaining pluripotency and its loss is compatible with embryonic and postnatal development. Cell Stem Cell 9, 166–175 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Huang, H. et al. TET1 plays an essential oncogenic role in MLL-rearranged leukemia. Proc. Natl Acad. Sci. USA 110, 11994–11999 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lessard, J., Baban, S. & Sauvageau, G. Stage-specific expression of polycomb group genes in human bone marrow cells. Blood 91, 1216–1224 (1998).

    CAS  PubMed  Google Scholar 

  30. van der Lugt, N. M. et al. Posterior transformation, neurological abnormalities, and severe hematopoietic defects in mice with a targeted deletion of the bmi-1 proto-oncogene. Genes Dev. 8, 757–769 (1994).

    Article  CAS  PubMed  Google Scholar 

  31. Lessard, J. & Sauvageau, G. Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature 423, 255–260 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. Park, I. K. et al. Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 423, 302–305 (2003).

    Article  CAS  PubMed  Google Scholar 

  33. Iwama, A. et al. Enhanced self-renewal of hematopoietic stem cells mediated by the polycomb gene product Bmi-1. Immunity 21, 843–851 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. Oguro, H. et al. Poised lineage specification in multipotential hematopoietic stem and progenitor cells by the polycomb protein Bmi1. Cell Stem Cell 6, 279–286 (2010).

    Article  CAS  PubMed  Google Scholar 

  35. Jacobs, J. J., Kieboom, K., Marino, S., DePinho, R. A. & van Lohuizen, M. The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature 397, 164–168 (1999).One of the first reports of BMI1 repressing the INK4A locus, thereby preventing cellular senescence. This molecular interaction has since been reported to operate in multiple tissue stem cells.

    Article  CAS  PubMed  Google Scholar 

  36. Oguro, H. et al. Differential impact of Ink4a and Arf on hematopoietic stem cells and their bone marrow microenvironment in Bmi1-deficient mice. J. Exp. Med. 203, 2247–2253 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Klauke, K. et al. Polycomb Cbx family members mediate the balance between haematopoietic stem cell self-renewal and differentiation. Nat. Cell Biol. 15, 353–362 (2013).

    Article  CAS  PubMed  Google Scholar 

  38. Majewski, I. J. et al. Opposing roles of polycomb repressive complexes in hematopoietic stem and progenitor cells. Blood 116, 731–739 (2010).

    Article  CAS  PubMed  Google Scholar 

  39. Lessard, J. et al. Functional antagonism of the Polycomb-Group genes eed and Bmi1 in hemopoietic cell proliferation. Genes Dev. 13, 2691–2703 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Xie, H. et al. Polycomb repressive complex 2 regulates normal hematopoietic stem cell function in a developmental-stage-specific manner. Cell Stem Cell 14, 68–80 (2014).This study circumvents the redundancy observed between EZH1 and EZH2 in some knockout mouse models by ablating the PRC2 core member EED. EED-deficient fetal liver HSCs are largely functional, whereas EED depletion in the adult HSC compartment impairs self-renewal, which highlights the distinct roles of this epigenetic regulator in developmental and adult tissue stem cells.

    Article  CAS  PubMed  Google Scholar 

  41. Richie, E. R. et al. The Polycomb-group gene eed regulates thymocyte differentiation and suppresses the development of carcinogen-induced T-cell lymphomas. Oncogene 21, 299–306 (2002).

    Article  CAS  PubMed  Google Scholar 

  42. Majewski, I. J. et al. Polycomb repressive complex 2 (PRC2) restricts hematopoietic stem cell activity. PLoS Biol. 6, e93 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kamminga, L. M. et al. The Polycomb group gene Ezh2 prevents hematopoietic stem cell exhaustion. Blood 107, 2170–2179 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Su, I. H. et al. Ezh2 controls B cell development through histone H3 methylation and Igh rearrangement. Nat. Immunol. 4, 124–131 (2003).

    Article  CAS  PubMed  Google Scholar 

  45. Mochizuki-Kashio, M. et al. Dependency on the polycomb gene Ezh2 distinguishes fetal from adult hematopoietic stem cells. Blood 118, 6553–6561 (2011).

    Article  CAS  PubMed  Google Scholar 

  46. Yin, J. et al. Ezh2 regulates differentiation and function of natural killer cells through histone methyltransferase activity. Proc. Natl Acad. Sci. USA 112, 15988–15993 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Hidalgo, I. et al. Ezh1 is required for hematopoietic stem cell maintenance and prevents senescence-like cell cycle arrest. Cell Stem Cell 11, 649–662 (2012).EZH1 prevents cellular senescence by repressing p16INK4A expression. This process is required to maintain HSC self-renewal.

    Article  CAS  PubMed  Google Scholar 

  48. McCabe, M. T. et al. Mutation of A677 in histone methyltransferase EZH2 in human B-cell lymphoma promotes hypertrimethylation of histone H3 on lysine 27 (H3K27). Proc. Natl Acad. Sci. USA 109, 2989–2994 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Morin, R. D. et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat. Genet. 42, 181–185 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Ntziachristos, P. et al. Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia. Nat. Med. 18, 298–301 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Puda, A. et al. Frequent deletions of JARID2 in leukemic transformation of chronic myeloid malignancies. Am. J. Hematol. 87, 245–250 (2012).

    Article  CAS  PubMed  Google Scholar 

  52. Ueda, T. et al. EED mutants impair polycomb repressive complex 2 in myelodysplastic syndrome and related neoplasms. Leukemia 26, 2557–2560 (2012).

    Article  CAS  PubMed  Google Scholar 

  53. Zhang, J. et al. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature 481, 157–163 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Loizou, J. I. et al. Histone acetyltransferase cofactor Trrap is essential for maintaining the hematopoietic stem/progenitor cell pool. J. Immunol. 183, 6422–6431 (2009).

    Article  CAS  PubMed  Google Scholar 

  55. Katsumoto, T. et al. MOZ is essential for maintenance of hematopoietic stem cells. Genes Dev. 20, 1321–1330 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Thomas, T. et al. Monocytic leukemia zinc finger protein is essential for the development of long-term reconstituting hematopoietic stem cells. Genes Dev. 20, 1175–1186 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Katsumoto, T., Yoshida, N. & Kitabayashi, I. Roles of the histone acetyltransferase monocytic leukemia zinc finger protein in normal and malignant hematopoiesis. Cancer Sci. 99, 1523–1527 (2008).

    Article  CAS  PubMed  Google Scholar 

  58. Wilting, R. H. et al. Overlapping functions of Hdac1 and Hdac2 in cell cycle regulation and haematopoiesis. EMBO J. 29, 2586–2597 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Heideman, M. R. et al. Sin3a-associated Hdac1 and Hdac2 are essential for hematopoietic stem cell homeostasis and contribute differentially to hematopoiesis. Haematologica 99, 1292–1303 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Rimmele, P. et al. Aging-like phenotype and defective lineage specification in SIRT1-deleted hematopoietic stem and progenitor cells. Stem Cell Rep. 3, 44–59 (2014).

    Article  CAS  Google Scholar 

  61. Matsui, K. et al. NAD-dependent histone deacetylase, SIRT1, plays essential roles in the maintenance of hematopoietic stem cells. Biochem. Biophys. Res. Commun. 418, 811–817 (2012).

    Article  CAS  PubMed  Google Scholar 

  62. Singh, S. K. et al. Sirt1 ablation promotes stress-induced loss of epigenetic and genomic hematopoietic stem and progenitor cell maintenance. J. Exp. Med. 210, 987–1001 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Jude, C. D. et al. Unique and independent roles for MLL in adult hematopoietic stem cells and progenitors. Cell Stem Cell 1, 324–337 (2007).In HSCs, MLL1 loss leads to loss of self-renewal and rapid bone marrow failure. However, MLL1 is dispensable in the differentiated haematopoietic lineages, which shows that chromatin modifiers can have specific roles depending on the differentiation stage.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. McMahon, K. A. et al. Mll has a critical role in fetal and adult hematopoietic stem cell self-renewal. Cell Stem Cell 1, 338–345 (2007).

    Article  CAS  PubMed  Google Scholar 

  65. Artinger, E. L. et al. An MLL-dependent network sustains hematopoiesis. Proc. Natl Acad. Sci. USA 110, 12000–12005 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Li, B. E., Gan, T., Meyerson, M., Rabbitts, T. H. & Ernst, P. Distinct pathways regulated by menin and by MLL1 in hematopoietic stem cells and developing B cells. Blood 122, 2039–2046 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Mishra, B. P. et al. The histone methyltransferase activity of MLL1 is dispensable for hematopoiesis and leukemogenesis. Cell Rep. 7, 1239–1247 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Maillard, I. et al. Menin regulates the function of hematopoietic stem cells and lymphoid progenitors. Blood 113, 1661–1669 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Heuser, M. et al. Loss of MLL5 results in pleiotropic hematopoietic defects, reduced neutrophil immune function, and extreme sensitivity to DNA demethylation. Blood 113, 1432–1443 (2009).

    Article  CAS  PubMed  Google Scholar 

  70. Jones, M. et al. Ash1l controls quiescence and self-renewal potential in hematopoietic stem cells. J. Clin. Invest. 125, 2007–2020 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Chen, X. et al. G9a/GLP-dependent histone H3K9me2 patterning during human hematopoietic stem cell lineage commitment. Genes Dev. 26, 2499–2511 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Lehnertz, B. et al. Activating and inhibitory functions for the histone lysine methyltransferase G9a in T helper cell differentiation and function. J. Exp. Med. 207, 915–922 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Lehnertz, B. et al. The methyltransferase G9a regulates HoxA9-dependent transcription in AML. Genes Dev. 28, 317–327 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Solanas, G. & Benitah, S. A. Regenerating the skin: a task for the heterogeneous stem cell pool and surrounding niche. Nat. Rev. Mol. Cell. Biol. 14, 737–748 (2013).

    Article  CAS  PubMed  Google Scholar 

  75. Ito, M. et al. Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis. Nat. Med. 11, 1351–1354 (2005).

    Article  CAS  PubMed  Google Scholar 

  76. Bock, C. et al. DNA methylation dynamics during in vivo differentiation of blood and skin stem cells. Mol. Cell 47, 633–647 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Sen, G. L., Reuter, J. A., Webster, D. E., Zhu, L. & Khavari, P. A. DNMT1 maintains progenitor function in self-renewing somatic tissue. Nature 463, 563–567 (2010).The authors elegantly demonstrate that DNMT1 and the associated DNA-methylation-driven repression of differentiation genes maintain the undifferentiated state of epidermal stem cells. Indeed, altering DNA methylation levels perturbs tissue homeostasis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Li, J. et al. Progressive alopecia reveals decreasing stem cell activation probability during aging of mice with epidermal deletion of DNA methyltransferase 1. J. Invest. Dermatol. 132, 2681–2690 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Vandiver, A. R. et al. Age and sun exposure-related widespread genomic blocks of hypomethylation in nonmalignant skin. Genome Biol. 16, 80 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Lee, K. et al. Expression of Bmi-1 in epidermis enhances cell survival by altering cell cycle regulatory protein expression and inhibiting apoptosis. J. Invest. Dermatol. 128, 9–17 (2008).

    Article  CAS  PubMed  Google Scholar 

  81. Mardaryev, A. N. et al. Cbx4 maintains the epithelial lineage identity and cell proliferation in the developing stratified epithelium. J. Cell Biol. 212, 77–89 (2015).

    Article  CAS  PubMed  Google Scholar 

  82. Luis, N. M. et al. Regulation of human epidermal stem cell proliferation and senescence requires polycomb- dependent and -independent functions of Cbx4. Cell Stem Cell 9, 233–246 (2011).Here we show that the PRC1 member CBX4 has a crucial role in epidermal stem cell function by promoting a quiescent state as opposed to an activated state, and at the same time repressing cellular senescence.

    Article  CAS  PubMed  Google Scholar 

  83. Sen, G. L., Webster, D. E., Barragan, D. I., Chang, H. Y. & Khavari, P. A. Control of differentiation in a self-renewing mammalian tissue by the histone demethylase JMJD3. Genes Dev. 22, 1865–1870 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Ezhkova, E. et al. Ezh2 orchestrates gene expression for the stepwise differentiation of tissue-specific stem cells. Cell 136, 1122–1135 (2009).In this study, EZH2 is shown to repress p16INK4A, thereby maintaining epidermal progenitors in a proliferative state. Surprisingly, the temporal intricacies of embryonic epidermal development are perturbed in EZH2-deficient mice, whereas postnatal development is unaffected.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Ezhkova, E. et al. EZH1 and EZH2 cogovern histone H3K27 trimethylation and are essential for hair follicle homeostasis and wound repair. Genes Dev. 25, 485–498 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Lien, W. H. et al. Genome-wide maps of histone modifications unwind in vivo chromatin states of the hair follicle lineage. Cell Stem Cell 9, 219–232 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Shaw, T. & Martin, P. Epigenetic reprogramming during wound healing: loss of polycomb-mediated silencing may enable upregulation of repair genes. EMBO Rep. 10, 881–886 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Dauber, K. L. et al. Dissecting the roles of polycomb repressive complex 2 subunits in the control of skin development. J. Invest. Dermatol. http://dx.doi.org/10.1016/j.jid.2016.02.809 (2016).

  89. Bardot, E. S. et al. Polycomb subunits Ezh1 and Ezh2 regulate the Merkel cell differentiation program in skin stem cells. EMBO J. 32, 1990–2000 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Wurm, S. et al. Terminal epidermal differentiation is regulated by the interaction of Fra-2/AP-1 with Ezh2 and ERK1/2. Genes Dev. 29, 144–156 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Xu, K. et al. EZH2 oncogenic activity in castration-resistant prostate cancer cells is Polycomb-independent. Science 338, 1465–1469 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Lee, S. T. et al. Context-specific regulation of NF-κB target gene expression by EZH2 in breast cancers. Mol. Cell 43, 798–810 (2011).

    Article  CAS  PubMed  Google Scholar 

  93. Mejetta, S. et al. Jarid2 regulates mouse epidermal stem cell activation and differentiation. EMBO J. 30, 3635–3646 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Connelly, J. T., Mishra, A., Gautrot, J. E. & Watt, F. M. Shape-induced terminal differentiation of human epidermal stem cells requires p38 and is regulated by histone acetylation. PLoS ONE 6, e27259 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. LeBoeuf, M. et al. Hdac1 and Hdac2 act redundantly to control p63 and p53 functions in epidermal progenitor cells. Dev. Cell 19, 807–818 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Winter, M. et al. Divergent roles of HDAC1 and HDAC2 in the regulation of epidermal development and tumorigenesis. EMBO J. 32, 3176–3191 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Koster, M. I. et al. p63 induces key target genes required for epidermal morphogenesis. Proc. Natl Acad. Sci. USA 104, 3255–3260 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Hopkin, A. S. et al. GRHL3/GET1 and trithorax group members collaborate to activate the epidermal progenitor differentiation program. PLoS Genet. 8, e1002829 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Driskell, I. et al. The histone methyltransferase Setd8 acts in concert with c-Myc and is required to maintain skin. EMBO J. 31, 616–629 (2012).

    Article  CAS  PubMed  Google Scholar 

  100. Rinaldi, L. & Benitah, S. A. Epigenetic regulation of adult stem cell function. FEBS J. 282, 1589–1604 (2015).

    Article  CAS  PubMed  Google Scholar 

  101. Keyes, W. M. et al. ΔNp63α is an oncogene that targets chromatin remodeler Lsh to drive skin stem cell proliferation and tumorigenesis. Cell Stem Cell 8, 164–176 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Mardaryev, A. N. et al. p63 and Brg1 control developmentally regulated higher-order chromatin remodelling at the epidermal differentiation complex locus in epidermal progenitor cells. Development 141, 101–111 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Fessing, M. Y. et al. p63 regulates Satb1 to control tissue-specific chromatin remodeling during development of the epidermis. J. Cell Biol. 194, 825–839 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Xiong, Y. et al. Brg1 governs a positive feedback circuit in the hair follicle for tissue regeneration and repair. Dev. Cell 25, 169–181 (2013).

    Article  CAS  PubMed  Google Scholar 

  105. Bao, X. et al. ACTL6a enforces the epidermal progenitor state by suppressing SWI/SNF-dependent induction of KLF4. Cell Stem Cell 12, 193–203 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Tsumagari, K. et al. Early de novo DNA methylation and prolonged demethylation in the muscle lineage. Epigenetics 8, 317–332 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Carrio, E. et al. Deconstruction of DNA methylation patterns during myogenesis reveals specific epigenetic events in the establishment of the skeletal muscle lineage. Stem Cells 33, 2025–2036 (2015).

    Article  CAS  PubMed  Google Scholar 

  108. Robson, L. G. et al. Bmi1 is expressed in postnatal myogenic satellite cells, controls their maintenance and plays an essential role in repeated muscle regeneration. PLoS ONE 6, e27116 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Sousa-Victor, P. et al. Geriatric muscle stem cells switch reversible quiescence into senescence. Nature 506, 316–321 (2014).Loss of BMI1 results in de-repression of p16INK4A, shifting muscle satellite stem cells to an irreversible senescent state in which they are refractory to injury-induced proliferative activation. The authors show strong parallels between this state and geriatric muscle satellite cells, in which the response to injury is also impaired, implicating PRC1 in stem cell ageing.

    Article  CAS  PubMed  Google Scholar 

  110. Juan, A. H. et al. Polycomb EZH2 controls self-renewal and safeguards the transcriptional identity of skeletal muscle stem cells. Genes Dev. 25, 789–794 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Woodhouse, S., Pugazhendhi, D., Brien, P. & Pell, J. M. Ezh2 maintains a key phase of muscle satellite cell expansion but does not regulate terminal differentiation. J. Cell Sci. 126, 565–579 (2013).

    Article  CAS  PubMed  Google Scholar 

  112. Juan, A. H., Kumar, R. M., Marx, J. G., Young, R. A. & Sartorelli, V. Mir-214-dependent regulation of the polycomb protein Ezh2 in skeletal muscle and embryonic stem cells. Mol. Cell 36, 61–74 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Asp, P. et al. Genome-wide remodeling of the epigenetic landscape during myogenic differentiation. Proc. Natl Acad. Sci. USA 108, E149–E158 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Caretti, G., Di Padova, M., Micales, B., Lyons, G. E. & Sartorelli, V. The Polycomb Ezh2 methyltransferase regulates muscle gene expression and skeletal muscle differentiation. Genes Dev. 18, 2627–2638 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Palacios, D. et al. TNF/p38α/polycomb signaling to Pax7 locus in satellite cells links inflammation to the epigenetic control of muscle regeneration. Cell Stem Cell 7, 455–469 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Stojic, L. et al. Chromatin regulated interchange between polycomb repressive complex 2 (PRC2)-Ezh2 and PRC2-Ezh1 complexes controls myogenin activation in skeletal muscle cells. Epigenetics Chromatin 4, 16 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Kawabe, Y., Wang, Y. X., McKinnell, I. W., Bedford, M. T. & Rudnicki, M. A. Carm1 regulates Pax7 transcriptional activity through MLL1/2 recruitment during asymmetric satellite stem cell divisions. Cell Stem Cell 11, 333–345 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Boonsanay, V. et al. Regulation of Skeletal muscle stem cell quiescence by Suv4-20h1-dependent facultative heterochromatin formation. Cell Stem Cell 18, 229–242 (2016).The authors show that SUV420H1 is crucial for muscle stem cell quiescence through repression of MYOD expression, and its ablation results in aberrant stem cell activation and ultimately depletion.

    Article  CAS  PubMed  Google Scholar 

  119. Ling, B. M. et al. Lysine methyltransferase G9a methylates the transcription factor MyoD and regulates skeletal muscle differentiation. Proc. Natl Acad. Sci. USA 109, 841–846 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Ryall, J. G. et al. The NAD+-dependent SIRT1 deacetylase translates a metabolic switch into regulatory epigenetics in skeletal muscle stem cells. Cell Stem Cell 16, 171–183 (2015).This study links metabolic reprogramming during muscle stem cell activation with changes in the chromatin landscape. During the metabolic switch from fatty acid oxidation to glycolysis, intracellular NAD+ levels are depleted, accompanied by a decrease of SIRT1 activity and concomitant increase in H3K16 acetylation and related transcriptional activation at muscle differentiation loci.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Cerletti, M., Jang, Y. C., Finley, L. W., Haigis, M. C. & Wagers, A. J. Short-term calorie restriction enhances skeletal muscle stem cell function. Cell Stem Cell 10, 515–519 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Mercken, E. M. et al. SRT2104 extends survival of male mice on a standard diet and preserves bone and muscle mass. Aging Cell 13, 787–796 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Zhang, T. et al. Prmt5 is a regulator of muscle stem cell expansion in adult mice. Nat. Commun. 6, 7140 (2015).

    Article  CAS  PubMed  Google Scholar 

  124. Rosen, E. D. & Spiegelman, B. M. PPARγ: a nuclear regulator of metabolism, differentiation, and cell growth. J. Biol. Chem. 276, 37731–37734 (2001).

    Article  CAS  PubMed  Google Scholar 

  125. Rosen, E. D. & MacDougald, O. A. Adipocyte differentiation from the inside out. Nat. Rev. Mol. Cell Biol. 7, 885–896 (2006).

    Article  CAS  PubMed  Google Scholar 

  126. Wang, L. et al. Histone H3K9 methyltransferase G9a represses PPARγ expression and adipogenesis. EMBO J. 32, 45–59 (2013).

    Article  CAS  PubMed  Google Scholar 

  127. Mikkelsen, T. S. et al. Comparative epigenomic analysis of murine and human adipogenesis. Cell 143, 156–169 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Hemming, S. et al. EZH2 and KDM6A act as an epigenetic switch to regulate mesenchymal stem cell lineage specification. Stem Cells 32, 802–815 (2014).

    Article  CAS  PubMed  Google Scholar 

  129. Ye, L. et al. Histone demethylases KDM4B and KDM6B promotes osteogenic differentiation of human MSCs. Cell Stem Cell 11, 50–61 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Lee, J. et al. Targeted inactivation of MLL3 histone H3-Lys-4 methyltransferase activity in the mouse reveals vital roles for MLL3 in adipogenesis. Proc. Natl Acad. Sci. USA 105, 19229–19234 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Lee, J. E. et al. H3K4 mono- and di-methyltransferase MLL4 is required for enhancer activation during cell differentiation. eLife 2, e01503 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Chatterjee, T. K. et al. HDAC9 knockout mice are protected from adipose tissue dysfunction and systemic metabolic disease during high-fat feeding. Diabetes 63, 176–187 (2014).

    Article  CAS  PubMed  Google Scholar 

  133. Barker, N. & Clevers, H. Lineage tracing in the intestinal epithelium. Curr. Protoc. Stem Cell Biol. http://dx.doi.org/10.1002/9780470151808.sc05a04s13 (2010).

  134. Barker, N., van de Wetering, M. & Clevers, H. The intestinal stem cell. Genes Dev. 22, 1856–1864 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Kaaij, L. T. et al. DNA methylation dynamics during intestinal stem cell differentiation reveals enhancers driving gene expression in the villus. Genome Biol. 14, R50 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Sheaffer, K. L. et al. DNA methylation is required for the control of stem cell differentiation in the small intestine. Genes Dev. 28, 652–664 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Yu, D. H. et al. Postnatal epigenetic regulation of intestinal stem cells requires DNA methylation and is guided by the microbiome. Genome Biol. 16, 211 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Chiacchiera, F. et al. Polycomb complex PRC1 preserves intestinal stem cell identity by sustaining Wnt/β-catenin transcriptional activity. Cell Stem Cell 18, 91–103 (2015).This study shows the role of PRC1 in maintaining intestinal identity by repressing non-intestinal lineages and promoting intestinal stem cell self-renewal.

    Article  CAS  PubMed  Google Scholar 

  139. Benoit, Y. D. et al. Polycomb repressive complex 2 impedes intestinal cell terminal differentiation. J. Cell Sci. 125, 3454–3463 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Visvader, J. E. & Stingl, J. Mammary stem cells and the differentiation hierarchy: current status and perspectives. Genes Dev. 28, 1143–1158 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Rios, A. C., Fu, N. Y., Lindeman, G. J. & Visvader, J. E. In situ identification of bipotent stem cells in the mammary gland. Nature 506, 322–327 (2014).

    Article  CAS  PubMed  Google Scholar 

  142. Van Keymeulen, A. et al. Distinct stem cells contribute to mammary gland development and maintenance. Nature 479, 189–193 (2011).

    Article  CAS  PubMed  Google Scholar 

  143. Stingl, J. et al. Purification and unique properties of mammary epithelial stem cells. Nature 439, 993–997 (2006).

    Article  CAS  PubMed  Google Scholar 

  144. Shackleton, M. et al. Generation of a functional mammary gland from a single stem cell. Nature 439, 84–88 (2006).

    Article  CAS  PubMed  Google Scholar 

  145. Maruyama, R. et al. Epigenetic regulation of cell type-specific expression patterns in the human mammary epithelium. PLoS Genet. 7, e1001369 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Bloushtain-Qimron, N. et al. Cell type-specific DNA methylation patterns in the human breast. Proc. Natl Acad. Sci. USA 105, 14076–14081 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Pathania, R. et al. DNMT1 is essential for mammary and cancer stem cell maintenance and tumorigenesis. Nat. Commun. 6, 6910 (2015).

    Article  CAS  PubMed  Google Scholar 

  148. Song, S. J. et al. MicroRNA-antagonism regulates breast cancer stemness and metastasis via TET-family-dependent chromatin remodeling. Cell 154, 311–324 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Pietersen, A. M. et al. Bmi1 regulates stem cells and proliferation and differentiation of committed cells in mammary epithelium. Curr. Biol. 18, 1094–1099 (2008).

    Article  CAS  PubMed  Google Scholar 

  150. Gu, B. et al. Pygo2 expands mammary progenitor cells by facilitating histone H3 K4 methylation. J. Cell Biol. 185, 811–826 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Gu, B., Watanabe, K., Sun, P., Fallahi, M. & Dai, X. Chromatin effector Pygo2 mediates Wnt-Notch crosstalk to suppress luminal/alveolar potential of mammary stem and basal cells. Cell Stem Cell 13, 48–61 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Li, X. et al. Targeted overexpression of EZH2 in the mammary gland disrupts ductal morphogenesis and causes epithelial hyperplasia. Am. J. Pathol. 175, 1246–1254 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Michalak, E. M. et al. Polycomb group gene Ezh2 regulates mammary gland morphogenesis and maintains the luminal progenitor pool. Stem Cells 31, 1910–1920 (2013).

    Article  CAS  PubMed  Google Scholar 

  154. Pal, B. et al. Global changes in the mammary epigenome are induced by hormonal cues and coordinated by Ezh2. Cell Rep. 3, 411–426 (2013).

    Article  CAS  PubMed  Google Scholar 

  155. Shore, A. N. et al. Pregnancy-induced noncoding RNA (PINC) associates with polycomb repressive complex 2 and regulates mammary epithelial differentiation. PLoS Genet. 8, e1002840 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Tough, D. F., Lewis, H. D., Rioja, I., Lindon, M. J. & Prinjha, R. K. Epigenetic pathway targets for the treatment of disease: accelerating progress in the development of pharmacological tools: IUPHAR Review 11. Br. J. Pharmacol. 171, 4981–5010 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Ahuja, N., Sharma, A. R. & Baylin, S. B. Epigenetic therapeutics: a new weapon in the war against cancer. Annu. Rev. Med. 67, 73–89 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Avgustinova, A. & Benitah, S. A. The epigenetics of tumour initiation: cancer stem cells and their chromatin. Curr. Opin. Genet. Dev. 36, 8–15 (2016).

    Article  CAS  PubMed  Google Scholar 

  159. van Galen, P. et al. A multiplexed system for quantitative comparisons of chromatin landscapes. Mol. Cell 61, 170–180 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Rotem, A. et al. Single-cell ChIP–seq reveals cell subpopulations defined by chromatin state. Nat. Biotechnol. 33, 1165–1172 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Lavin, Y. et al. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 159, 1312–1326 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Lara-Astiaso, D. et al. Chromatin state dynamics during blood formation. Science 345, 943–949 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Lepper, C., Conway, S. J. & Fan, C. M. Adult satellite cells and embryonic muscle progenitors have distinct genetic requirements. Nature 460, 627–631 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Barker, N. et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003–1007 (2007).

    Article  CAS  PubMed  Google Scholar 

  165. van der Flier, L. G., Haegebarth, A., Stange, D. E., van de Wetering, M. & Clevers, H. OLFM4 is a robust marker for stem cells in human intestine and marks a subset of colorectal cancer cells. Gastroenterology 137, 15–17 (2009).

    Article  PubMed  Google Scholar 

  166. Jensen, K. B. et al. Lrig1 expression defines a distinct multipotent stem cell population in mammalian epidermis. Cell Stem Cell 4, 427–439 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Horsley, V. et al. Blimp1 defines a progenitor population that governs cellular input to the sebaceous gland. Cell 126, 597–609 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Means, A. L., Xu, Y., Zhao, A., Ray, K. C. & Gu, G. A. CK19CreERT knockin mouse line allows for conditional DNA recombination in epithelial cells in multiple endodermal organs. Genesis 46, 318–323 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Liu, Y., Lyle, S., Yang, Z. & Cotsarelis, G. Keratin 15 promoter targets putative epithelial stem cells in the hair follicle bulge. J. Invest. Dermatol. 121, 963–968 (2003).

    Article  CAS  PubMed  Google Scholar 

  170. Di Croce, L. & Helin, K. Transcriptional regulation by Polycomb group proteins. Nat. Struct. Mol. Biol. 20, 1147–1155 (2013).

    Article  CAS  PubMed  Google Scholar 

  171. Tavares, L. et al. RYBP-PRC1 complexes mediate H2A ubiquitylation at polycomb target sites independently of PRC2 and H3K27me3. Cell 148, 664–678 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Morey, L., Aloia, L., Cozzuto, L., Benitah, S. A. & Di Croce, L. RYBP and Cbx7 define specific biological functions of polycomb complexes in mouse embryonic stem cells. Cell Rep. 3, 60–69 (2013).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Research in the laboratory of S.A.B. is supported by the European Research Council (ERC), the Worldwide Cancer Research Association, the Foundation La Marató, the Spanish Ministry of Economy and Development, the Foundation Vencer el Cancer (Beat Cancer), the Government of Cataluña (SGR and Mario Salviá grants), the Foundation Botín and the Institute for Research in Biomedicine (IRB-Barcelona). A.A. is supported by a Marie Curie EU COFUND postdoctoral fellowship. The Institute for Research in Biomedicine (IRB) Barcelona is the recipient of a Severo Ochoa Award of Excellence from MINECO (Government of Spain).

Author information

Author notes

  1. Alexandra Avgustinova and Salvador Aznar Benitah: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute for Research in Biomedicine (IRB) Barcelona, Barcelona Institute of Science and Technology, Barcelona, 08028, Spain

    Alexandra Avgustinova & Salvador Aznar Benitah

  2. ICREA, Catalan Institution for Research and Advanced Studies, Barcelona, 08010, Spain

    Salvador Aznar Benitah

Authors
  1. Alexandra Avgustinova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Salvador Aznar Benitah
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Alexandra Avgustinova or Salvador Aznar Benitah.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information S1 (table)

Supplementary Information (PDF 254 kb)

PowerPoint slides

Glossary

DNA methyltransferase 1

(DNMT1). The DNA methyltransferase that is responsible for maintaining the pattern of DNA methylation after replication, by depositing 5-methylcytosine on hemi-methylated DNA.

DNMT3A and DNMT3B

(DNA methyltransferases 3A and 3B). These DNA methyltransferases are responsible for establishing the de novo pattern of DNA methylation on unmethylated cytosines during cell fate determination in embryonic development and adult homeostasis.

TET2

(Ten-eleven translocation 2). This enzyme converts 5-methylcytosine to 5-hydroxymethylcytosine, which can function as a first step towards DNA demethylation or can have a stable functional role in gene regulation.

PRC1

(Polycomb repressive complex 1). This complex is involved in stabilizing gene repression during development and adult homeostasis by marking genes with histone 2A Lys119 monoubiquitylation (H2AK119Ub1).

PRC2

(Polycomb repressive complex 2). This complex is involved in stabilizing gene repression during development and adult homeostasis by marking genes with histone H3 Lys27 trimethylation (H3K27me3).

Trithorax group

(TrxG). The Trithorax group complex counteracts the activity of Polycomb group proteins to drive gene expression, mainly by marking genes with histone 3 Lys4 (H3K4) methylation.

Chromatin remodeller

A protein that makes chromatin accessible (open) or inaccessible (closed) to the transcriptional machinery by catalysing specific histone or DNA modifications.

SWI/SNF chromatin remodelling complex

An ATP-dependent nucleosome-remodelling complex that destabilizes the interaction between histones and DNA to enhance the accessibility of the transcriptional machinery to DNA.

Super enhancer

Enhancers are intergenic regulatory elements that are distal to the promoter and bound by transcription factors. Enhancers physically interact in a 3D loop with promoters to stabilize RNA polymerase II and activate transcription. Super enhancers are large enhancers that span approximately 20 kb and are bound simultaneously by several transcription factors. They typically regulate the expression of genes that are involved in pluripotency and fate choices during embryonic development.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Avgustinova, A., Benitah, S. Epigenetic control of adult stem cell function. Nat Rev Mol Cell Biol 17, 643–658 (2016). https://doi.org/10.1038/nrm.2016.76

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm.2016.76

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing