Structural insights into the MLL core complexes

项目摘要 癌症表观遗传学是一个具有重要意义的新兴领域。它导致了对小说的认同 治疗靶点和生物标志物。在染色质重塑复合体中， MLL家族组蛋白甲基转移酶常见于癌症。它们导致表观遗传 导致癌症发生、发展和转移的基因突变。了解活动是如何 染色质上的MLL家族酶的调节及其失调如何导致恶性意志 阐明了疾病的机制。我们之前重组了一个功能活跃的MLL1核心 并鉴定了4个MLL1核心复合体成分，即ASH2L、RbBP5、WDR5和 DPY30，它们是MLL1酶活性所必需的。在这里，我们展示了ASH2 L的一个新功能 在MLL1调控和一种以前未知的作用模式中。我们将使用生物化学， 用结构和表观基因组学方法描述ASH_2L如何赋予调控新的复杂性 H3K4甲基化和基因表达。我们希望建立一个关于表观遗传学的新范式 异质性是由定义明确的MLL1核心复合体建立的，这也具有普遍意义 用于其他染色质修饰酶。我们的研究最终将有助于发现新的治疗方法 癌症诊断和治疗的靶点或生物标记物。这个项目符合国家的使命 癌症研究所(NCI)。

Project Summary Cancer epigenetics is an emerging field of high significance. It has led to the identification of novel therapeutic targets and biomarkers. Among chromatin remodeling complexes, driver mutations of the MLL family histone methyltransferases are commonly found in cancer. They lead to epigenetic aberrations that underlie cancer initiation, evolution, and metastasis. Understanding how the activity of the MLL family enzymes on chromatin is regulated and how its dysregulation leads to malignancy will shed light on disease mechanisms. We previously reconstituted a functionally active MLL1 core complex in vitro and identified four MLL1 core complex components, i.e. ASH2L, RbBP5, WDR5 and DPY30, which are essential for MLL1 enzymatic activity. Here we show that a novel function of ASH2L in MLL1 regulation and a previously uncharacterized mode of action. We will use biochemical, structural and epigenomic approaches to delineate how ASH2L confers new complexity to regulation of H3K4 methylation and gene expression. We expect to establish a new paradigm on how epigenetic heterogeneity is established by a well-defined MLL1 core complex, which also has general implications for other chromatin modifying enzymes. Our study will ultimately benefit discovery of novel therapeutic targets or biomarkers for cancer diagnosis and treatment. This project matches the mission of National Cancer Institute (NCI).