Knocking off their Sox: lineage-specific repression by Polycomb in epidermal stem cells.

A recent publication in The EMBO Journal (Bardot et al, 2013) provides novel insights into lineage specification during the development of the mouse skin. Ezhkova and colleagues demonstrate that Ezh1 and Ezh2, core enzymes of the Polycomb Repressive Complex (PRC), restrict differentiation of Merkel cells, a specialized population of mechanosensory cells by directly repressing the cell fate determinant transcription factor (TF) Sox2 in epidermal progenitors. Generally, lineage determination starts with morphogenetic gradients, triggering signalling events that converge on specific TFs, which in turn remodel one cellular state into another. With the exception of a few cases, such as Oct4 and Nanog in embryonic stem cells (ESCs) and MyoD in muscle cells, lineage determinant TFs are not cell type specific. Instead, unique combinations confer certain differentiation states (Boyer et al, 2006). Given the right combination of TFs, many cells to work with, and sufficient time, it might actually be possible to convert any cell type into another. Examples range from transdifferention of fibroblasts into muscle cells or neurons (Pournasr et al, 2011) to turning terminally differentiated cells into pluripotent stem cells (Yamanaka and Blau, 2010). However, such dramatic fate conversions occur with low efficiency, which might be due to the requirement to change the epigenetic landscape that determines the transcriptional potential of each cell. Studies using cultured ESCs investigated the interplay between the chromatin context, often defined as the status of covalent modifications of histone proteins, and TFs. These studies demonstrated that Ezh1/2, the enzymes that catalyse trimethylation of lysine 27 on histone H3 (H3K27Me3), play an essential role in repressing lineage determinant TFs, while ensuring maintenance of the pluripotent stem cell state. Upon differentiation of ESCs, lineage-specific genes lose H3K27Me3 marks and are activated, while genes not required for lineage commitment remain repressed (Boyer et al, 2006; Shen et al, 2008). However, the role of Polycomb-mediated gene repression in tissue stem/progenitor cell differentiation during morphogenesis and homeostasis in vivo is not well understood. Perturbing H3K27Me3 patterns during development was