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：
10246904
负责人：
Uhn-Soo Cho
金额：
$ 59.92万
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/10246904
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重要的新兴领域。它导致了小说的认同治疗靶点和生物标志物。在染色质重塑复合物中， MLL家族组蛋白甲基转移酶通常在癌症中发现。它们会导致表观遗传癌症发生、发展和转移的基础畸变。了解活动是如何染色质上的MLL家族酶受到调节，其失调如何导致恶性肿瘤，阐明疾病机制。我们之前重组了一个功能活跃的MLL1核心， MLL1复合物在体外的表达，并确定了四个MLL1核心复合物组分，即ASH2L，RbBP 5，WDR 5和 DPY 30，其对于MLL1酶活性是必需的。在这里，我们表明，一个新的功能的ASH2L MLL1调节和以前未表征的作用模式。我们将使用生化，结构和表观基因组方法来描述ASH2L如何赋予新的复杂性， H3K4甲基化和基因表达。我们希望建立一个新的范式，非均质性是由一个定义明确的MLL1核心复合体建立的，它也具有一般意义其他染色质修饰酶。我们的研究将最终有利于发现新的治疗方法，用于癌症诊断和治疗的靶标或生物标志物。该项目符合国家的使命癌症研究所（NCI）。