Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas.
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
Am J Pathol. 2019 Jun;189(6):1212-1225. doi: 10.1016/j.ajpath.2019.02.016. Epub 2019 Apr 5.
Normal proliferation and differentiation of uterine epithelial cells are critical for uterine development and function. Enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2), a core component of polycomb repressive complexes 2, possesses histone methyltransferase activity that catalyzes the trimethylation of lysine 27 of histone H3. EZH2 has been involved in epithelial-mesenchymal transition, a key event in development and carcinogenesis. However, its role in uterine epithelial cell function remains unknown. To determine the role of uterine EZH2, Ezh2 was conditionally deleted using progesterone receptor Cre recombinase, which is expressed in both epithelial and mesenchymal compartments of the uterus. Loss of EZH2 promoted stratification of uterine epithelium, an uncommon and detrimental event in the uterus. The abnormal epithelium expressed basal cell markers, including tumor protein 63, cytokeratin 5 (KRT5), KRT6A, and KRT14. These results suggest that EZH2 serves as a guardian of uterine epithelial integrity, partially via inhibiting the differentiation of basal-like cells and preventing epithelial stratification. The observed epithelial abnormality was accompanied by fertility defects, altered uterine growth and function, and the development of endometrial hyperplasia. Thus, the Ezh2 conditional knockout mouse model may be useful to explore mechanisms that regulate endometrial homeostasis and uterine function.
正常的子宫上皮细胞增殖和分化对于子宫的发育和功能至关重要。EZH2 是多梳抑制复合物 2 的核心组成部分，具有组蛋白甲基转移酶活性，可催化组蛋白 H3 赖氨酸 27 的三甲基化。EZH2 参与上皮-间充质转化，这是发育和癌变中的关键事件。然而，其在子宫上皮细胞功能中的作用尚不清楚。为了确定子宫 EZH2 的作用，我们使用孕激素受体 Cre 重组酶条件性删除 Ezh2，该酶在子宫的上皮和间充质区室中均有表达。EZH2 的缺失促进了子宫上皮的分层，这是子宫中罕见且有害的事件。异常的上皮细胞表达基底细胞标志物，包括肿瘤蛋白 63、细胞角蛋白 5（KRT5）、KRT6A 和 KRT14。这些结果表明，EZH2 作为子宫上皮完整性的守护者，部分通过抑制基底样细胞的分化和防止上皮分层来发挥作用。观察到的上皮异常伴随着生育缺陷、子宫生长和功能改变以及子宫内膜增生的发展。因此，Ezh2 条件性敲除小鼠模型可能有助于探索调节子宫内膜稳态和子宫功能的机制。
