Polycomb subunits Ezh1 and Ezh2 regulate the Merkel cell differentiation program in skin stem cells

Abstract

While the Polycomb complex is known to regulate cell identity in ES cells, its role in controlling tissue-specific stem cells is not well understood. Here we show that removal of Ezh1 and Ezh2, key Polycomb subunits, from mouse skin results in a marked change in fate determination in epidermal progenitor cells, leading to an increase in the number of lineage-committed Merkel cells, a specialized subtype of skin cells involved in mechanotransduction. By dissecting the genetic mechanism, we showed that the Polycomb complex restricts differentiation of epidermal progenitor cells by repressing the transcription factor Sox2. Ablation of Sox2 results in a dramatic loss of Merkel cells, indicating that Sox2 is a critical regulator of Merkel cell specification. We show that Sox2 directly activates Atoh1, the obligate regulator of Merkel cell differentiation. Concordantly, ablation of Sox2 attenuated the Ezh1/2-null phenotype, confirming the importance of Polycomb-mediated repression of Sox2 in maintaining the epidermal progenitor cell state. Together, these findings define a novel regulatory network by which the Polycomb complex maintains the progenitor cell state and governs differentiation in vivo.

Histone Lysine Methyltransferase Ezh1 Promotes TLR-Triggered Inflammatory Cytokine Production by Suppressing Tollip

“…Ezh1 in embryonic stem cells has been linked to the maintenance of stem cell identity and pluripotency (27). Ezh1 is involved in the maintenance of proliferation and survival of hematopoietic stem cells (31) and is responsible for the development of skin stem cells (28,32). Ezh1 has been functionally linked to H3K27 methylation-dependent gene repression, but an understanding of Ezh1's function in innate immunity and inflammation has been limited.…”

The Sox2: GFP+/− knock‐in mouse model does not faithfully recapitulate Sox2 expression in skin

“…[2,7] However, we detected aberrant GFP expression in the infundibulum of keratinocytes (Figures 2E and S1A,B) in neonatal hair follicles that lacked endogenous Sox2 expression ( Figure 2C, E, G white arrow) (n=5 biological replicates).…”

“…To provide context for the discrepancy between GFP expression and endogenous Sox2 expression, we generated a map of the Sox2 locus on chromosome 3 of the mouse and included the newly identified epigenetic regulatory elements that have been suggested to repress Sox2 expression in the epidermis ( Figure 1A). [7][8][9] We also mapped the cloning strategy utilized to generate the recombination vector for GFP insertion into the Sox2 locus ( Figure 2B). [6] Upon recombination with the cloning vector within embryonic stem (ES) cells, regions that have been identified to epigenetically silence Sox2 in the epidermis are ablated in Sox2:…”

“…[7] To investigate GFP expression in the dermis of Sox2: GFP+/− skin, we quantified and compared endogenous Sox2 expression to transgenic GFP expression in DPs (Figure 2A, C, F). We found that endogenous Sox2 overlapped with GFP expression in 51% of GFP+ DPs ( Figure 2A, C, F, H).…”

Epigenetic Regulation of Epidermal Differentiation

“…A new study of the embryonic epidermal progenitor cells shows that Ezh1 and Ezh2 also play a critical role in the differentiation program of the Merkel cells ), a specialized cell type of epithelial origin responsible for mechanotransduction of sensory stimuli (Haeberle and Lumpkin 2008;Maricich et al 2009;Bardot et al 2013). Recent work has proposed Sox2 as a master regulator of Merkel cell differentiation (Driskell et al 2009;Bardot et al 2013;Lesko et al 2013), and loss of both Ezh1 and Ezh2 from epidermal progenitors leads to a dramatic increase in the number of fully differentiated Merkel cells, which is a direct result of loss H3K27me3 repression at Sox2 (Driskell et al 2009;Bardot et al 2013;Lesko et al 2013). Together these studies show evidence for the role of polycomb-mediated repression in maintenance of epidermal progenitor cells by repressing both suprabasal and Merkel cell lineages.…”