GATA6 expression promoted by an active enhancer may become a molecular marker in endometriosis lesions
GATA6 expression promoted by an active enhancer may become a molecular marker in endometriosis lesions
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DOI：
10.1111/aji.13078
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发表时间：
2019-02-01
影响因子：
3.6
通讯作者：
Harada, Tasuku
中科院分区：
文献类型：
--
作者：
Izawa, Masao;Taniguchi, Fuminori;Harada, Tasuku
子宫内膜异位症细胞DNA甲基化的全基因组分析显示了表观遗传背景的不同方面;然而，子宫内膜异位症中负责异常基因表达的特定DNA甲基化位点尚不清楚。是否有特定的子宫内膜异位症相关DNA甲基化可以作为子宫内膜异位症病变的分子标志物？研究方法本研究使用子宫内膜异位症患者卵巢巧克力囊肿衬里的子宫内膜组织和无病患者的子宫内膜组织。为了分析，从子宫内膜和子宫内膜异位组织收集基质细胞。以子宫内膜细胞为对照，提取子宫内膜异位症细胞中的差异甲基化胞嘧啶-磷酸-鸟嘌呤（CpG）特征。在这些CpG中，我们集中在GATA 6基因内的一段低甲基化的CpG，并检查其在细胞和组织中作为增强子的潜在作用。结果：我们鉴定出了一段低甲基化的CpG序列，位于肿瘤细胞的GATA 6基因体中。由于GATA 6 mRNA在子宫内膜异位细胞中高度表达，而在子宫内膜细胞中不表达，因此我们假设低甲基化序列可能在GATA 6基因表达中起增强子的作用。染色质免疫沉淀分析预测的活性增强子内的基因体序列中的癌变细胞的存在。免疫组化结果显示，GATA 6在卵巢巧克力囊肿中呈阳性染色，而在子宫内膜组织和子宫内膜异位症的一些腹膜组织中，GATA 6染色处于边缘水平。结论子宫内膜异位症中顺式元件的异常甲基化与基因表达有关。GATA 6表达可能成为诊断子宫内膜异位症病变的分子标志物。
Problem Genome-wide profiling of DNA methylation in endometriotic cells has shown a distinct facet of epigenetic backgrounds; however, specific DNA methylation sites responsible for aberrant gene expression in endometriosis were unknown. Are there specific endometriosis-associated DNA methylations that can be used as molecular markers in endometriosis lesions? Method of study This study used endometriotic tissues from the chocolate cyst lining of the ovaries of patients with endometriosis, and endometrial tissues from disease-free patients. For analysis, stromal cells were collected from endometrial and endometriotic tissues. Using endometrial cells as control, differentially methylated cytosine-phosphate-guanine (CpG) characteristic in endometriotic cells was extracted. Among these CpGs, we focused on a stretch of hypomethylated CpGs within GATA6 gene and examined the potential role as enhancer in endometriotic cells and tissues. Result(s) We identified a stretch of hypomethylated CpGs within the GATA6 gene body in endometriotic cells. Because GATA6 mRNA was highly expressed in endometriotic cells but not in endometrial cells, we then hypothesized that the hypomethylated sequence may function as an enhancer in GATA6 gene expression. Chromatin immunoprecipitation analysis predicted the presence of active enhancer within the gene body sequence in endometriotic cells. Immunohistochemistry showed a positive staining of GATA6 in ovarian chocolate cysts, while in endometrial tissues and in some peritoneal tissues with endometriosis, GATA6 staining was at a marginal level. Conclusion This is the first implication showing a link between an aberrant DNA methylation of cis element and gene expression in endometriosis. GATA6 expression may become a molecular marker to diagnose endometriosis lesions.