Global Changes in the Mammary Epigenome Are Induced by Hormonal Cues and Coordinated by Ezh2
Global Changes in the Mammary Epigenome Are Induced by Hormonal Cues and Coordinated by Ezh2
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DOI：
10.1016/j.celrep.2012.12.020
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发表时间：
2013-02-01
期刊：
影响因子：
8.8
通讯作者：
Visvader, Jane E.
中科院分区：
文献类型：
--
作者：
Pal, Bhupinder;Bouras, Toula;Visvader, Jane E.
乳腺上皮是一个动态的、对激素高度敏感的组织。为了探索染色质修饰在其谱系规范和激素反应中的潜在作用，我们测定了不同状态下乳腺上皮亚群的全基因组组蛋白甲基化图谱。成体腺体亚群之间H3K27三甲基化的显著差异表明，上皮细胞命运的决定是由多梳复合体介导的抑制所协调的。值得注意的是，乳腺表观基因组在不同的激素环境中经历了高度特异性的变化，在怀孕期间腔细胞的全球H3K27me3图谱中观察到了深刻的变化。因此，我们研究了关键的H3K27甲基转移酶Ezh2在乳腺生理学中的作用。它的表达和磷酸化与H3K27me3的修饰一致，并在怀孕期间达到顶峰，部分是由孕酮驱动的。靶向缺失Ezh2会损害怀孕期间的肺泡发育，阻止哺乳，并显著减少干细胞/祖细胞的数量。综上所述，这些发现揭示了Ezh2将激素刺激与表观遗传学变化结合在一起，这些变化支撑着乳腺中的祖细胞活性、谱系特异性和肺泡扩张。
The mammary epithelium is a dynamic, highly hormone-responsive tissue. To explore chromatin modifications underlying its lineage specification and hormone responsiveness, we determined genomewide histone methylation profiles of mammary epithelial subpopulations in different states. The marked differences in H3K27 trimethylation between subpopulations in the adult gland suggest that epithelial cell-fate decisions are orchestrated by polycomb-complex-mediated repression. Remarkably, the mammary epigenome underwent highly specific changes in different hormonal contexts, with a profound change being observed in the global H3K27me3 map of luminal cells during pregnancy. We therefore examined the role of the key H3K27 methyltransferase Ezh2 in mammary physiology. Its expression and phosphorylation coincided with H3K27me3 modifications and peaked during pregnancy, driven in part by progesterone. Targeted deletion of Ezh2 impaired alveologenesis during pregnancy, preventing lactation, and drastically reduced stem/progenitor cell numbers. Taken together, these findings reveal that Ezh2 couples hormonal stimuli to epigenetic changes that underpin progenitor activity, lineage specificity, and alveolar expansion in the mammary gland.