EZH1 and EZH2 cogovern histone H3K27 trimethylation and are essential for hair follicle homeostasis and wound repair
EZH1 and EZH2 cogovern histone H3K27 trimethylation and are essential for hair follicle homeostasis and wound repair
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DOI：
10.1101/gad.2019811
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发表时间：
2011-03-01
影响因子：
10.5
通讯作者：
Fuchs, Elaine
中科院分区：
文献类型：
--
作者：
Ezhkova, Elena;Lien, Wen-Hui;Fuchs, Elaine
H3K27 (H3K27me3) 上的多梳蛋白组 (PcG) 依赖性三甲基化调节胚胎干细胞 (ESC) 的身份。 H3K27me3 如何控制成人 SC 和组织发育尚不清楚。在这里，我们有条件地靶向 H3K27 甲基转移酶 Ezh2 和 Ezh1，以解决它们在小鼠皮肤稳态中的作用。出生后表型仅出现在双靶向皮肤中，其中 H3K27me3 被废除，揭示了 EZH1/2 蛋白的功能冗余。令人惊讶的是，虽然 Ezh1/2 缺失的毛囊 (HF) 由于增殖缺陷和细胞凋亡增加而阻碍形态发生并退化，但表皮却过度增殖并在植入后存活。 mRNA 微阵列研究表明，尽管存在这些显着的表型差异，但相似的基因在 HF 和表皮 Ezh1/2 缺失祖细胞中上调。突出的特点是 (1) PcG 控制的非皮肤谱系基因，其表达仍显着低于天然组织，以及 (2) PcG 调节的 Ink4a/Inkb/Arf 基因座。有趣的是，当 EZH1/2 缺失时，即使 Ink4a/Arf/Ink4b 基因在 HF 细胞中完全激活，但在表皮祖细胞中仅部分激活。重要的是，Ink4b/Ink4a/Arf shRNA 的转导可在体外恢复 Ezh1/2-null HF 祖细胞的增殖/存活，表明该位点与观察到的 HF 表型的相关性。我们的研究结果揭示了对 Polycomb 依赖性组织控制的新见解，并为一个组织内的不同祖细胞如何响应 H3K27me3 的丢失提供了新的思路。
Polycomb protein group (PcG)-dependent trimethylation on H3K27 (H3K27me3) regulates identity of embryonic stem cells (ESCs). How H3K27me3 governs adult SCs and tissue development is unclear. Here, we conditionally target H3K27 methyltransferases Ezh2 and Ezh1 to address their roles in mouse skin homeostasis. Postnatal phenotypes appear only in doubly targeted skin, where H3K27me3 is abolished, revealing functional redundancy in EZH1/2 proteins. Surprisingly, while Ezh1/2-null hair follicles (HFs) arrest morphogenesis and degenerate due to defective proliferation and increased apoptosis, epidermis hyperproliferates and survives engraftment. mRNA microarray studies reveal that, despite these striking phenotypic differences, similar genes are up-regulated in HF and epidermal Ezh1/2-null progenitors. Featured prominently are (1) PcG-controlled nonskin lineage genes, whose expression is still significantly lower than in native tissues, and (2) the PcG-regulated Ink4a/Inkb/Arf locus. Interestingly, when EZH1/2 are absent, even though Ink4a/Arf/Ink4b genes are fully activated in HF cells, they are only partially so in epidermal progenitors. Importantly, transduction of Ink4b/Ink4a/Arf shRNAs restores proliferation/survival of Ezh1/2-null HF progenitors in vitro, pointing toward the relevance of this locus to the observed HF phenotypes. Our findings reveal new insights into Polycomb-dependent tissue control, and provide a new twist to how different progenitors within one tissue respond to loss of H3K27me3.