Dissecting the Roles of Polycomb Repressive Complex 2 Subunits in the Control of Skin Development

Abstract

Polycomb repressive complex 2 (PRC2) is an essential regulator of cell physiology. While there have been numerous studies on PRC2 function in somatic tissue development and stem cell control, these have focused on the loss of a single PRC2 subunit. Recent studies, however, have shown that PRC2 subunits may function independently of the PRC2 complex. To investigate the function of PRC2 in the control of skin development, we generated and analysed three conditional knockout mouse lines, in which the essential PRC2 subunits EED, Suz12, or Ezh1/2 are conditionally ablated in the embryonic epidermal progenitors that give rise to the epidermis, hair follicles, and Merkel cells. Our studies showed that the observed loss-of-function phenotypes are shared between the three knockouts, indicating that in the skin epithelium, EED, Suz12, and Ezh1/2 function largely as subunits of the PRC2 complex. Interestingly, the absence of PRC2 results in dramatically different phenotypes across the different skin lineages: premature acquisition of a functional epidermal barrier, formation of ectopic Merkel cells, and defective postnatal development of hair follicles. The strikingly different roles of PRC2 in the formation of three lineages exemplify the complex outcomes that the lack of PRC2 can have in a somatic stem cell system.

Epigenetic control in skin development, homeostasis and injury repair

“…Using quantitative‐ChIP experiments, wound‐induced genes Myc and EGFR were found de‐repressed by loss of H3K27me3 and EED occupancy . These data correlated with PRC2 complex gene ablation studies where epidermal hyperproliferation was observed, which could explain how BL cells lose H3K27me3 marks during wound repair . Also, Ezh1/2 double‐knockout split‐thickness engraftment demonstrated delayed re‐epithelization from the HF after wounding, suggesting that knockout bulge‐SCs have less re‐epithelization potential .…”

“…Specifically, loss of Ezh1/2 resulted in hyperproliferative IFE, whereas the follicular region showed proliferative arrest. Similarly, loss of other PRC2 components, Eed and Suz12, showed IFE hyperproliferation and HFs morphogenesis arrests due to proliferation defects and increased apoptosis . In addition, loss of these PRC2 genes showed an ectopic formation of Merkel cells in the epidermis, which are essential for sensory function of the skin by activation of the Merkel cell‐specific genes, Isl1 and Sox2 .…”

“…Similarly, loss of other PRC2 components, Eed and Suz12, showed IFE hyperproliferation and HFs morphogenesis arrests due to proliferation defects and increased apoptosis . In addition, loss of these PRC2 genes showed an ectopic formation of Merkel cells in the epidermis, which are essential for sensory function of the skin by activation of the Merkel cell‐specific genes, Isl1 and Sox2 . Using ChIP‐Seq and microarray analysis, it was found that Ezh1/2 null mice failed to repress cell cycle inhibitor gene locus Ink4a/Arf/Ink4b .…”

Dissection of Merkel cell formation in hairy and glabrous skin reveals a common requirement for FGFR2‐mediated signalling

“…However, in the glabrous paw skin, loss of Shh or Smo had much less of an effect on Merkel cell formation as these cells were still formed, and their total count was only slightly reduced, compared to control (Table ). This lesser effect on Merkel cell formation was also found in the glabrous paw skin when coupling the loss of Smo with the loss of EED , a component of the Polycomb repressive complex (PRC) 2 that temporally restricts Merkel cell formation . Loss of EED leads to an ectopic expansion of Merkel cells in both the back and glabrous paw skin .…”

“…This lesser effect on Merkel cell formation was also found in the glabrous paw skin when coupling the loss of Smo with the loss of EED , a component of the Polycomb repressive complex (PRC) 2 that temporally restricts Merkel cell formation . Loss of EED leads to an ectopic expansion of Merkel cells in both the back and glabrous paw skin . Concurrent loss of EED and Smo in the skin epithelium depleted Merkel cells in the back skin; however, it leads to a slight increase in the number of Merkel cells in the glabrous paw skin (Table ).…”