Epidermal Stem Cells Are Defined by Global Histone Modifications that Are Altered by Myc-Induced Dif.pdf
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Epidermal Stem Cells Are Defined by Global Histone Modifications that Are Altered by Myc-Induced Dif
Epidermal Stem Cells Are Defined by Global Histone
Modifications that Are Altered by Myc-Induced
Differentiation
Michaela Frye1, Amanda G. Fisher2, Fiona M. Watt1,3*
1 Wellcome Trust Centre for Stem Cell Research, University of Cambridge, Cambridge, United Kingdom, 2 Lymphocyte Development Group, Imperial
College School of Medicine, London, United Kingdom, 3 Cancer Research UK Cambridge Research Institute, University of Cambridge, Cambridge,
United Kingdom
Activation of Myc induces epidermal stem cells to exit their niche and differentiate into sebocytes and interfollicular epidermis,
a process that is associated with widespread changes in gene transcription. We have identified chromatin modifications that
are characteristic of epidermal stem cells and investigated the effects of Myc activation. Quiescent stem cells in the
interfollicular epidermis and the hair follicle bulge had high levels of tri-methylated histone H3 at lysine 9 and H4 at lysine 20.
Chromatin in both stem cell populations was hypoacteylated at histone H4 and lacked mono-methylation of histone H4 at
lysine 20. Myc-induced exit from the stem cell niche correlated with increased acetylation at histone H4 and transiently
increased mono-methylation at lysine 20. The latter was replaced by epigenetic modifications that are largely associated with
chromatin silencing: di-methylation at histone H3 lysine 9 and histone H4 lysine 20. These modifications correlated with
changes in the specific histone methyltransferases Set8 and Ash-1. The Myc-induced switch from mono- to di-methylated
H4K20 required HDAC activity and was blocked by the HDAC inhibitor trichostatin A (TSA). TSA treatment induced a similar
epidermal phenotype to activation of Myc, and activation of Myc in the presence of TSA resulted in massive stimulation of
terminal differentiation. We conclude that Myc-induced chromatin modifications play a major role in Myc-induced exit from
the stem cell compartment.
Citation: Frye M, Fisher AG, Watt FM
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