Molecular analysis of ASH1L

ASH1L 的分子分析

• 批准号: 10202533
• 负责人: TATIANA G KUTATELADZE
• 金额: --
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 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/10202533
• 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; Molecular Structure; 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

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.

项目概要 人类 ASH1L（缺失、小或同源异型盘，如 1）介导增殖和存活 造血干细胞，并且在白血病中经常上调。是造血所必需的 发育基因的发育和表达，包括 HOX 基因家族。 在混合谱系白血病 (MLL) 重排急性白血病中发现 ASH1L 活性上调 淋巴细胞白血病（ALL）通常与不良预后相关。 ASH1L 是一个主要 甲基化组蛋白 H3 的甲基转移酶，产生表观遗传标记 H3K36me2 与转录激活和延伸有关。 ASH1L 包含独特的组合 催化甲基转移酶 SET 结构域和相邻的溴结构域 (BD)，PHD 指， 和一个生物学作用尚不清楚的 BAH 结构域。我们最近的研究表明，BD、PHD 和 ASH1L 的 BAH 结构域是能够识别组蛋白独特状态的表观遗传读取器 H3。 ASH1L 这些新功能背后的分子机制尚不清楚， 在拟议的研究中得到阐明。我们假设不同的伴随识别 PHD、BD 和 BAH 结构域的组蛋白状态可招募或稳定 ASH1L 的启动子 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。我们试图了解 BD、PHD 和 BAH 领域之间的串扰 ASH1L并确定多价分子机制和功能意义 ASH1L 与染色质的结合。我们将采用互补的体外和体内 建立分子和结构基础并定义生物学重要性的方法 ASH1L 阅读器的组蛋白结合。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的新靶标 增强我们对表观遗传驱动基因基本原理的了解 转录。它还将有助于更好地了解与异常相关的人类癌症 ASH1L 的活性，包括急性白血病。