性别二态性在肝癌发生中的作用- DNA 甲基化修饰调控 X 染色体失活逃逸分子 XIST。
Gender dimorphism in hepatocarcinogenesis-DNA methylation modification regulated X-chromosome inactivation escape molecule XIST.
机构信息
Department of Medical Genetics, Naval Medical University, Shanghai, China.
School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, China.
出版信息
Clin Transl Med. 2023 Dec;13(12):e1518. doi: 10.1002/ctm2.1518.
BACKGROUND
Sex disparities constitute a significant issue in hepatocellular carcinoma (HCC). However, the mechanism of gender dimorphism in HCC is still not completely understood.
METHODS
5-Hydroxymethylcytosine (5hmC)-Seal technology was utilised to detect the global 5hmC levels from four female and four male HCC samples. Methylation of XIST was detected by Sequenom MassARRAY methylation profiling between HCC tissues (T) and adjacent normal liver tissues (L). The role of Tet methylcytosine dioxygenase 2 (TET2) was investigated using diethylnitrosamine (DEN)-administered Tet2 female mice, which regulated XIST in hepatocarcinogenesis. All statistical analyses were carried out by GraphPad Prism 9.0 and SPSS version 19.0 software.
RESULTS
The results demonstrated that the numbers of 5hmC reads in the first exon of XIST from female HCC tissues (T) were remarkably lower than that in female adjacent normal liver tissues (L). Correspondingly, DNA methylation level of XIST first exon region was significantly increased in female T than in L. By contrast, no significant change was observed in male HCC patients. Compared to L, the expression of XIST in T was also significantly downregulated. Female patients with higher XIST in HCC had a higher overall survival (OS) and more extended recurrence-free survival (RFS). Moreover, TET2 can interact with YY1 binding to the promoter region of XIST and maintain the hypomethylation state of XIST. In addition, DEN-administered Tet2 mice developed more tumours than controls in female mice.
CONCLUSIONS
Our study provided that YY1 and TET2 could interact to form protein complexes binding to the promoter region of XIST, regulating the methylation level of XIST and then affecting the expression of XIST. This research will provide a new clue for studying sex disparities in hepatocarcinogenesis.
HIGHLIGHTS
XIST was significantly downregulated in HCC tissues and had gender disparity. Methylation levels in the XIST first exon were higher in female HCC tissues, but no significant change in male HCC patients. The TET2-YY1 complex regulate XIST expression in female hepatocytes. Other ways regulate XIST expression in male hepatocytes.
背景
性别差异是肝细胞癌（HCC）中的一个重要问题。然而，HCC 中性别二态性的机制仍不完全清楚。
方法
利用 5-羟甲基胞嘧啶（5hmC）-Seal 技术检测来自 4 名女性和 4 名男性 HCC 样本的全基因组 5hmC 水平。通过 HCC 组织（T）和相邻正常肝组织（L）之间的 Sequenom MassARRAY 甲基化分析检测 XIST 的甲基化。使用二乙基亚硝胺（DEN）处理的 Tet2 雌性小鼠研究 Tet 甲基胞嘧啶双加氧酶 2（TET2）的作用，该小鼠调节了肝癌发生过程中的 XIST。所有统计分析均使用 GraphPad Prism 9.0 和 SPSS 版本 19.0 软件进行。
结果
结果表明，女性 HCC 组织（T）中 XIST 第一外显子的 5hmC 读数数量明显低于女性相邻正常肝组织（L）。相应地，XIST 第一外显子区域的 DNA 甲基化水平在女性 T 中明显高于 L。相比之下，在男性 HCC 患者中没有观察到显著变化。与 L 相比，T 中的 XIST 表达也显著下调。HCC 中 XIST 表达较高的女性患者总生存率（OS）更高，无复发生存期（RFS）更长。此外，TET2 可以与 YY1 相互作用，形成结合 XIST 启动子区域的蛋白质复合物，维持 XIST 的低甲基化状态。此外，DEN 处理的 Tet2 雌性小鼠比对照组在雌性小鼠中形成更多的肿瘤。
结论
我们的研究表明，YY1 和 TET2 可以相互作用形成蛋白质复合物，结合 XIST 的启动子区域，调节 XIST 的甲基化水平，进而影响 XIST 的表达。这项研究为研究肝癌发生中的性别差异提供了新的线索。
重点
XIST 在 HCC 组织中表达显著下调，并存在性别差异。女性 HCC 组织中 XIST 第一外显子的甲基化水平较高，但男性 HCC 患者无明显变化。TET2-YY1 复合物调节雌性肝细胞中 XIST 的表达。其他途径调节雄性肝细胞中 XIST 的表达。
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