YBX1识别KMT2D介导的组蛋白H3K4me1促进乳腺癌发生发展的机制研究

组蛋白甲基化是由组蛋白甲基转移酶（HMTs）介导的一种重要的表观遗传修饰，KMT2D作为HMTs家族成员之一，催化哺乳动物H3K4单甲基化（H3K4me1）。H3K4me1修饰通常发生在增强子区域，参与基因的激活。YBX1作为Y-box结合蛋白，在人类多种肿瘤的发生发展中起重要作用。我们前期研究发现：YBX1能够识别KMT2D催化的H3K4me1修饰；敲低KMT2D和YBX1均显著抑制乳腺癌细胞的增殖和迁移。本项目拟通过细胞和动物实验系统分析KMT2D和YBX1在乳腺癌发生发展中的作用，并深入解析KMT2D催化H3K4me1修饰通过招募YBX1而发挥作用这一表观遗传机制。在此基础上，结合临床病例分析进一步验证KMT2D和YBX1在乳腺癌发生发展中的作用。该项目不仅有助于阐明KMT2D和YBX1调控基因表达的新机制，也将为乳腺癌的预防和治疗提供新的靶点。

Histone lysine methylation is a key epigenetic modification mediated by histone methyltransferases (HMTs). Histone lysine methyltransferase 2D (KMT2D) is one of the members of HMTs family which catalyzes mammalian H3K4 monomethylation (H3K4me1). This histone modification is mainly distributed in the enhancer region and related with activation of gene expression. As a Y-box binding protein, YBX1 plays key roles in the progression of various kinds of tumors. Our preliminary date showed that YBX1 recognized histone H3K4me1 modification catalyzed by KMT2D; knockdown the expression of KMT2D and YBX1 significantly inhibited breast cancer cells proliferation and migration, respectively. We will systematically study the roles of KMT2D and YBX1 in the progression of breast cancer through cellular and animal experiments in this project. And the epigenetic mechanism by which KMT2D catalyzes the modification of histone H3K4me1 to recruit YBX1, thereby regulating gene expression, will be elucidated. After that, the role of KMT2D and YBX1 in breast cancer progression will be further verified by clinical cases analysis. Results of this project will not only reveal a novel mechanism of KMT2D and YBX1 regulating gene expression, but also provide novel targets for the prevention and treatment of breast cancer.