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 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.
Ezhkova
Elena
E
Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY 10065, USA.
Pasolli
H Amalia
HA
Parker
Joel S
JS
Stokes
Nicole
N
Su
I-hsin
IH
Hannon
Gregory
G
Tarakhovsky
Alexander
A
Fuchs
Elaine
E
D000818:Animals; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008745:Methylation; D051379:Mice; D063151:Polycomb Repressive Complex 2; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism*
D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D006657:Histones; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2