ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville VIC 3052, Australia.
Cell Rep. 2013 Feb 21;3(2):411-26. doi: 10.1016/j.celrep.2012.12.020. Epub 2013 Jan 31.
The mammary epithelium is a dynamic, highly hormone-responsive tissue. To explore chromatin modifications underlying its lineage specification and hormone responsiveness, we determined genome-wide 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.
乳腺上皮组织是一种动态的、高度受激素影响的组织。为了探索其谱系特化和激素反应的染色质修饰基础，我们确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。成年腺体中亚群之间 H3K27 三甲基化的显著差异表明上皮细胞命运决定是由多梳复合物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发生了高度特异性的变化，在怀孕期间，腔细胞的全局 H3K27me3 图谱发生了深刻的变化。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。其表达和磷酸化与 H3K27me3 修饰相吻合，并在怀孕期间达到峰值，部分受孕酮驱动。Ezh2 的靶向缺失会在怀孕期间损害肺泡发生，阻止泌乳，并大大减少干细胞/祖细胞数量。总之，这些发现表明，Ezh2 将激素刺激与表观遗传变化联系起来，这些变化是乳腺中祖细胞活性、谱系特异性和肺泡扩张的基础。
