Polycomb subunits Ezh1 and Ezh2 regulate the Merkel cell differentiation program in skin stem cells
Polycomb subunits Ezh1 and Ezh2 regulate the Merkel cell differentiation program in skin stem cells
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DOI：
10.1038/emboj.2013.110
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发表时间：
2013-07-17
期刊：
影响因子：
11.4
通讯作者：
Ezhkova, Elena
中科院分区：
文献类型：
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作者：
Bardot, Evan S.;Valdes, Victor J.;Ezhkova, Elena
虽然已知Polycomb复合物调节ES细胞中的细胞身份，但其在控制组织特异性干细胞中的作用尚未得到很好的理解。在这里，我们表明，Ezh 1和Ezh 2，关键Polycomb亚基，从小鼠皮肤中的结果在表皮祖细胞的命运决定的显着变化，导致谱系承诺的默克尔细胞，一个专门的皮肤细胞亚型参与mechanotransduction的数量增加。通过剖析遗传机制，我们发现Polycomb复合体通过抑制转录因子Sox 2来限制表皮祖细胞的分化。Sox 2的消融导致默克尔细胞的急剧损失，表明Sox 2是默克尔细胞特化的关键调节剂。我们表明，Sox 2直接激活Atoh 1，专性调节默克尔细胞分化。一致地，消融Sox 2减弱了Ezh 1/2-null表型，证实了Polycomb介导的Sox 2抑制在维持表皮祖细胞状态中的重要性。总之，这些发现定义了一种新的调节网络，通过该网络Polycomb复合物维持祖细胞状态并支配体内分化。
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.