A New Histone H3 Modification Regulates Epigenetic Programming and Gene Expression in Breast Cancer

项目摘要 不同的组蛋白修饰，在N或C-末端的尾巴，作为一个“组蛋白代码”，以引起下游事件。 组蛋白亚基翻译后修饰（PTM），如甲基化、乙酰化和磷酸化 调节疾病如癌症中的表观遗传调节和基因表达。在这里，我们确定了一个新的PTM 在H3上，称为在脯氨酸16上的羟基化，其由脯氨酸羟化酶EglN 2催化。我们的初步数据 显示EglN 2介导的H3 Pro 16-OH导致赖氨酸（K）特异性脱甲基酶5A（KDM 5A）增加 结合对应于乳腺癌中H3 K4 me 3的减少。我们假设H3脯氨酰羟基化 由EglN 2介导的KDM 5A募集，因此控制在乳腺癌中重要的基因表达。 这是首次报道H3脯氨酰羟基化及其在表观遗传调控和基因调控中的潜在作用的研究。 在癌症中的表达。在具体目标1中，我们将确定H3脯氨酰羟基化对表观遗传的影响。 乳腺癌细胞中基因组范围内的调控和基因表达。在第二阶段，我们将 阐明H3脯氨酰羟基化调节表观遗传重编程的分子机制， 招募KDM 5A在具体目标3中，我们将阐明H3脯氨酰羟基化 调节乳腺癌细胞中的Wnt/b-Catenin信号传导。成功完成本提案将体现 一种新的H3翻译后修饰在乳腺表观遗传调节和基因表达中很重要 癌

Project Summary Distinct histone modifications, on N or C-terminal tails, act as a “histone code” to elicit downstream events. Histone subunit post-translational modification (PTM), such as methylation, acetylation and phosphorylation regulates epigenetic regulation and gene expression in diseases such as cancer. Here we identified a new PTM on H3 called hydroxylation on proline 16, which is catalyzed by proline hydroxylase EglN2. Our preliminary data show that EglN2-mediated H3 Pro16-OH leads to increased Lysine (K)-Specific Demethylase 5A (KDM5A) binding corresponding with decreased H3K4me3 in breast cancer. We hypothesize that H3 prolyl hydroxylation mediated by EglN2 recruits KDM5A therefore controlling gene expression important in breast cancer. This is the first study reporting H3 Prolyl hydroxylation and its potential role in epigenetic regulation and gene expression in cancer. In Specific Aim 1, we will determine the effet of H3 prolyl hydroxylation on epigenetic regulation and gene expression on a genome wide scale in breast cancer cells. In Specific Aim 2, we will elucidate the molecular mechanism by which H3 prolyl hydroxylation regulates epigenetic reprogramming by recruiting KDM5A. In Specific Aim 3, we will elucidate the molecular mechanism by which H3 prolyl hydroxylation regulates Wnt/b-Catenin signaling in breast cancer cells. Successful completion of this proposal will characterize a new H3 post-translational modification in its epigenetic regulation and gene expression important in breast cancer.