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

Abstract

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.

Ezh2, the histone methyltransferase of PRC2, regulates the balance between self-renewal and differentiation in the cerebral cortex

“…Loss of polycomb function in a variety of cell types leads to upregulated transcription of the negative regulators of the cell cycle encoded by the Ink4/Arf locus (Cdkn2a/Cdkn2b) (11,33,34). Cdkn2a and Cdkn2b are not normally expressed in the developing cerebral cortex (35)(36)(37), and we found the H3K27me3 modification present on the Cdkn2a and Cdkn2b promoters in the wild-type E12 cortex (Fig.…”

“…Studies in ES cells have found that loss of function of polycomb components compromises pluripotency and the ability of ES cells to generate differentiated progeny (8)(9)(10). Loss of polycomb function in the developing skin alters epithelial stem cell proliferation and accelerates the timing of skin development (11).…”

Yes-associated protein (YAP) transcriptional coactivator functions in balancing growth and differentiation in skin

“…Microarray analyses detected Yap transcripts in embryonic epidermis (14). Using a pan-antibody (Ab) that recognizes all forms of YAP, we confirmed YAP protein expression as early as embryo day 12 (E12), when epidermis exists as a single layer.…”

“…5E). This was accompanied by an elevation in expression of AP1 family members known to govern the expression of these latedifferentiation genes (14) (Fig. S5).…”

Development and Homeostasis of the Skin Epidermis

“…Small interfering RNA-mediated deletion of JMJD3, an H3K27me3 demethylase in organotypic human epidermal cultures, prevented epidermal differentiation, whereas conversely, JMJD3 overexpression led to premature differentiation (Sen et al 2008). Whereas conditional deletion in the epidermis of the polycomb complex protein Ezh2 alone leads to rather mild phenotype (Ezhkova et al 2009), conditional deletion of both EZH1/2 differentially affects HF and IFE. HF morphogenesis and maintenance are compromised, exhibiting low proliferation and increased apoptosis that is at least partially mediated by ectopic activation of the Ink4a/Inkb/Arf locus.…”