权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Structural insights into the MLL core complexes

MLL 核心复合体的结构见解

基本信息

批准号：
10414123
负责人：
Uhn-Soo Cho
金额：
$ 58.82万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-25 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10414123
关键词：
ASH2L gene Affect Biochemical Biological Cells Chromatin Chromatin Remodeling Factor Complex Cryoelectron Microscopy DNA biosynthesis Data Deposition Disease Elements Enzymes Epigenetic Process Event Evolution Family Gene Expression Genetic Transcription Heterogeneity Histones Human In Vitro Lead Light MLL gene Malignant Neoplasms Mediating Methylation Mission Mixed-Lineage Leukemia Molecular Molecular Conformation Mutation National Cancer Institute Neoplasm Metastasis Nucleosome Core Particle Nucleosomes Pathogenesis Play Post-Translational Protein Processing Proteins Recombinants Regulation Resolution Role Shapes Structural Models Structure Tail Testing Transcriptional Activation Transcriptional Regulation cancer diagnosis cancer initiation cancer therapy driver mutation epigenetic regulation epigenomics histone methyltransferase insight multidisciplinary new therapeutic target novel particle protein protein interaction reconstitution targeted biomarker therapeutic biomarker

项目摘要

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).

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)。