Colón-Caraballo Mariano, Monteiro Janice B, Flores Idhaliz
Department of Microbiology, Ponce Health Sciences University-School of Medicine and Ponce Research Institute, Ponce, PR, USA.
Department of Biochemistry, Ponce Health Sciences University-School of Medicine and Ponce Research Institute, Ponce, PR, USA.
Reprod Sci. 2015 Sep;22(9):1134-42. doi: 10.1177/1933719115578924. Epub 2015 Mar 27.
Epigenetic mechanisms may play an important role in the etiology of endometriosis. The modification of histones by methylation of lysine residues has been shown to regulate gene expression by changing chromatin structure. We have previously shown that endometriotic lesions had aberrant levels of histone acetylation (lower) and methylation (higher) than control tissues. We aimed to determine the levels of trimethylated histone 3 at lysine residue 27 (H3K27me3), a well-known repressive mark, by immunoassay of fresh tissues and immunohistochemistry (IHC) of an endometriosis-focused tissue microarray. Also, we aimed to determine levels of expression of enhancer of zeste homolog 2 (EZH2), the enzyme responsible for trimethylation of H3K27me3, in cell lines. Average levels of H3K27me3 measured by immunoassay were not significantly different in lesions compared to endometrium from patients and controls. However, there was a trend of higher levels of H3K27me3 in secretory versus proliferative endometrium. The results of IHC showed that lesions (ovarian, fallopian, and peritoneal) and secretory endometrium from controls have higher percentage of H3K27me3-positive nuclei than eutopic endometrium from patients. Endometriotic epithelial cells express high levels of EZH2, which is upregulated by progesterone. This study provides evidence in support of a role of H3K27me3 in the pathogenesis of endometriosis and for EZH2 as a potential therapeutic target for this disease, but more studies are necessary to understand the molecular mechanisms at play.
表观遗传机制可能在子宫内膜异位症的病因学中发挥重要作用。赖氨酸残基甲基化对组蛋白的修饰已被证明可通过改变染色质结构来调节基因表达。我们之前已经表明，子宫内膜异位症病变组织中组蛋白乙酰化水平（较低）和甲基化水平（较高）与对照组织相比存在异常。我们旨在通过对新鲜组织进行免疫测定以及对聚焦于子宫内膜异位症的组织芯片进行免疫组织化学（IHC）来确定赖氨酸残基27处三甲基化组蛋白3（H3K27me3）的水平，H3K27me3是一种众所周知的抑制性标记。此外，我们旨在确定在细胞系中负责H3K27me3三甲基化的酶——zeste同源物2增强子（EZH2）的表达水平。通过免疫测定测得的病变组织中H3K27me3的平均水平与患者和对照的子宫内膜相比无显著差异。然而，分泌期子宫内膜与增殖期子宫内膜相比，H3K27me3水平有升高趋势。免疫组织化学结果显示，病变组织（卵巢、输卵管和腹膜）以及对照的分泌期子宫内膜中H3K27me3阳性细胞核的百分比高于患者的在位内膜。子宫内膜异位症上皮细胞表达高水平的EZH2，且其表达受孕酮上调。本研究为H3K27me3在子宫内膜异位症发病机制中的作用以及EZH2作为该疾病潜在治疗靶点提供了证据支持，但仍需更多研究来了解其中的分子机制。
