Ezh2 Orchestrates Gene Expression for the Stepwise Differentiation of Tissue-Specific Stem Cells

Although in vitro studies of embryonic stem cells have identified polycomb repressor complexes (PRCs) as key regulators of differentiation, it remains unclear as to how PRC-mediated mechanisms control fates of multipotent progenitors in developing tissues. Here, we show that an essential PRC compone...

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Bibliographic Details
Published in:Cell 2009-03, Vol.136 (6), p.1122-1135
Main Authors: Ezhkova, Elena, Pasolli, H. Amalia, Parker, Joel S., Stokes, Nicole, Su, I-hsin, Hannon, Gregory, Tarakhovsky, Alexander, Fuchs, Elaine
Format: Article
Language:English
Subjects:
Animals
Cell Differentiation
Cell Nucleus - metabolism
Cyclin-Dependent Kinase Inhibitor p15 - metabolism
Cyclin-Dependent Kinase Inhibitor p16 - metabolism
DNA
Enhancer of Zeste Homolog 2 Protein
Epidermis - cytology
Epidermis - metabolism
Gene Expression Regulation, Developmental
Histone-Lysine N-Methyltransferase - metabolism
Histones - metabolism
Humans
Methylation
Mice
Polycomb Repressive Complex 2
Polycomb-Group Proteins
Repressor Proteins - metabolism
SIGNALING
Stem Cells - metabolism
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Summary:Although in vitro studies of embryonic stem cells have identified polycomb repressor complexes (PRCs) as key regulators of differentiation, it remains unclear as to how PRC-mediated mechanisms control fates of multipotent progenitors in developing tissues. Here, we show that an essential PRC component, Ezh2, is expressed in epidermal progenitors but diminishes concomitant with embryonic differentiation and with postnatal decline in proliferative activity. We show that Ezh2 controls proliferative potential of basal progenitors by repressing the Ink4A-Ink4B locus and tempers the developmental rate of differentiation by preventing premature recruitment of AP1 transcriptional activator to the structural genes that are required for epidermal differentiation. Together, our studies reveal that PRCs control epigenetic modifications temporally and spatially in tissue-restricted stem cells. They maintain their proliferative potential and globally repressing undesirable differentiation programs while selectively establishing a specific terminal differentiation program in a stepwise fashion.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2008.12.043