Molecular analysis of ASH1L

ASH1L 的分子分析

• 批准号: 10044132
• 负责人: TATIANA G KUTATELADZE
• 金额: $ 38.01万
• 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 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10044132
• 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; 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; outcome forecast; 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.

项目摘要 人ASH1L（缺失、小或同源异型盘样1）介导细胞增殖和存活， 在造血干细胞中，它通常被上调，并且在白血病中经常被上调。它是造血所必需的 发育基因的发育和表达，包括HOX基因家族。 在混合系白血病（MLL）重排的急性白血病中发现ASH1L活性上调 淋巴母细胞白血病（ALL）通常与不良预后相关。ASH1L是一个主要的 甲基化组蛋白H3的甲基转移酶，产生表观遗传标记H3K36me2 与转录激活和延伸相关。ASH1L包含一个独特的组合 催化甲基转移酶SET结构域和相邻的布罗莫结构域（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不同状态的表观遗传阅读器 H3. ASH1L这些新功能的分子机制尚不清楚， 在拟议的研究中予以阐明。我们假设，伴随的识别不同的 组蛋白状态的PHD，BD和BAH结构域招募或稳定ASH1L的启动子， ASH1L靶基因，并且是ASH1L的催化活性和H3K36的甲基化所必需的 这些基因。我们试图理解的BD，PHD和BAH域之间的串扰， 并确定了ASH1L多价体的分子机制和功能意义 ASH1L与染色质的接合。我们将在体外和体内采用互补的 建立分子和结构基础并确定生物学重要性的方法 ASH1L读者的组蛋白结合。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点， 增强我们对表观遗传驱动基因的基本原理的了解 转录。它也将导致更好地了解人类癌症相关的异常 ASH1L活性，包括急性白血病。