Molecular analysis of ASH1L

ASH1L 的分子分析

基本信息

批准号：
10457926
负责人：
TATIANA G KUTATELADZE
金额：
$ 37.25万
依托单位：
UNIVERSITY OF COLORADO DENVER
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：
2020-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10457926
关键词：
ASH1L gene Acute Lymphocytic Leukemia Acute leukemia Affinity Binding Biochemical Biological Biological Assay Bromodomain Calorimetry Cell physiology Chromatin Complex Data Development Developmental Gene EMSA Epigenetic Process Fluorescence Resonance Energy Transfer Fluorescence Spectroscopy Gene Family Genes Genetic Transcription Hematopoietic Hematopoietic stem cells Histone H3 Histones Homeobox Genes Human Impairment In Vitro Knowledge Lead Length Ligands Light Link Malignant Neoplasms Measures Mediating Methylation Methyltransferase Mixed-Lineage Leukemia Modeling Molecular Molecular Analysis Mutagenesis Mutate NMR Spectroscopy Nucleosomes PHD Finger Pathogenicity Peptides Physiological Post-Translational Protein Processing Prognosis Reader Regulation Research Resolution Role SET Domain Signal Pathway Signal Transduction Structure Therapeutic Therapeutic Intervention Titrations Transcription Elongation Transcriptional Activation Transcriptional Regulation Western Blotting X-Ray Crystallography chromatin immunoprecipitation design in vivo insight leukemia loss of function mutant new therapeutic target novel prevent promoter recruit screening

项目摘要

Project Summary Human ASH1L (absent, small, or homeotic discs like 1) mediates proliferation and survival of hematopoietic stem cells and is often upregulated in leukemias. It is required for hematopoietic development and expression of developmental genes, including the HOX gene family. Upregulated activity of ASH1L, found in mixed lineage leukemia (MLL)-rearranged acute lymphoblastic leukemia (ALL), is generally associated with a poor prognosis. ASH1L is a major methyltransferase that methylates histone H3, generating the epigenetic mark H3K36me2 associated with transcriptional activation and elongation. ASH1L contains a unique combination of the catalytic methyltransferase SET domain and adjacent bromodomain (BD), a PHD finger, and a BAH domain with unclear biological roles. Our recent studies reveal that the BD, PHD and BAH domains of ASH1L are epigenetic readers capable of recognizing distinctive states of histone H3. The molecular mechanisms underlying these novel functions of ASH1L are unknown and will be elucidated in the proposed studies. We hypothesize that the concomitant recognition of distinct histone states by the PHD, BD and BAH domains recruits or stabilizes ASH1L at promoters of ASH1L target genes and is necessary for the catalytic activity of ASH1L and methylation of H3K36 at these genes. We seek to understand a crosstalk between the BD, PHD and BAH domains of ASH1L and determine the molecular mechanism and functional significance of the multivalent engagement of ASH1L with chromatin. We will employ complementary in vitro and in vivo approaches to establish the molecular and structural basis and define the biological importance of histone binding by ASH1L readers. This research will provide atomic-resolution insights into ASH1L signaling pathways that may constitute new targets for therapeutic interventions and enhance our knowledge of fundamental principles underlying the epigenetic-driven gene transcription. It will also lead to a better understanding of human cancers associated with aberrant activity of ASH1L, including acute leukemias.

项目摘要人Ash1l（不存在，小或同源碟片（如1））介导造血干细胞，通常在白血病中上调。造血需要发育基因的发展和表达，包括HOX基因家族。在混合谱系白血病（MLL）急性中发现的ASH1L的上调活性淋巴细胞白血病（ALL）通常与预后不良有关。 ASH1L是主要的甲基转移酶甲基甲基甲基H3，产生表观遗传标记H3K36me2 与转录激活和伸长相关。 ASH1L包含独特的组合催化甲基转移酶套件域和邻近溴化域（BD）的博士学位，博士指的手指，以及具有不清楚的生物学作用的BAH领域。我们最近的研究表明，BD，博士和 ASH1L的BAH域是能够识别组蛋白独特状态的表观遗传学读者 H3。这些新型ASH1L功能的分子机制是未知的，将会在拟议的研究中阐明。我们假设对独特的伴随认可组蛋白通过博士，BD和BAH领域招募或稳定ASH1L在 ASH1L靶基因，对于ASH1L的催化活性和H3K36的甲基化是必需的在这些基因上。我们试图理解BD，PhD和BAH领域之间的串扰 ASH1L并确定多价的分子机制和功能意义 ASH1L与染色质的互动。我们将在体外和体内使用互补建立分子和结构基础并定义生物学重要性的方法 ASH1L读取器的组蛋白结合。这项研究将提供原子分辨率的见解 ASH1L信号通路可能构成治疗干预措施的新目标增强我们对表观遗传驱动基因的基本原理的了解转录。这也将使人们对与异常相关的人类癌症有更好的了解 ASH1L的活性，包括急性白血病。