Epigenetic mechanisms of regulation of histone lysine methyltransferases involved in leukemia

白血病中组蛋白赖氨酸甲基转移酶调控的表观遗传机制

基本信息

批准号：
10736549
负责人：
Karim Jean Armache
金额：
$ 45.2万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10736549
关键词：
Acetylation African Trypanosomiasis Amino Acids Binding Biochemical Biological Assay Biological Models Biological Process Biology Biophysics Cell Culture Techniques Cell Cycle Regulation Cells Cellular biology Chagas Disease Chemicals Chromatin Chromatin Structure Complex Coupled Cryoelectron Microscopy DNA Repair Data Dependence Deposition Development Disease Ensure Enzymes Epigenetic Process Family Gene Expression Gene Expression Regulation Genetic Recombination Genetic Transcription Histone Acetylation Histone H3 Histone H4 Histone-Lysine N-Methyltransferase Histones Homologous Gene Human Immune system Libraries Link Lysine MLL gene Malignant Neoplasms Mammals Mediating Methods Methylation Methyltransferase Modeling Modification Molecular Conformation Mutate Mutation Analysis Nucleosomes Organism Output Play Post-Translational Protein Processing Post-Translational Regulation Process Proliferating Property RNA Polymerase II Regulation Resolution Role Saccharomycetales Science Specificity Structure System Testing Therapeutic Transcription Elongation Trypanosoma Ubiquitination Variant Work Yeasts chemical group comparative effective therapy epigenetic regulation fighting histone acetyltransferase histone methyltransferase histone modification human pathogen improved in vivo inhibitor insight leukemia novel novel strategies novel therapeutics reconstitution repaired

项目摘要

Chromatin conformation underlies accessibility of enzymes that participate in transcription, replication, recombination, and repair. Many chromatin-regulatory mechanisms ensure that enzymes such as RNA polymerase II gain access to and efficiently transcribe chromatin. One of the mechanisms of chromatin regulation is based on the posttranslational modification of histones. Chemical groups are deposited, read and removed by specific families of enzymes to regulate chromatin structure. These modifications rarely function in isolation, and there is often crosstalk between them that results in a coordinated transcriptional output. One of the prime examples of such crosstalk is seen in transcription elongation, in which histones H3 and H4 are acetylated, H2B is ubiquitinated, and histone H3 is methylated at lysine 4 and 79 (H3K4 and H3K79). COMPASS/MLL and Dot1 are the enzymes that catalyze methylation of H3K4 and H3K79 respectively and are evolutionarily conserved. They play essential roles in processes such as transcription elongation, cell cycle control, and DNA repair. Homologs are found, among others, in yeast, and mammals. Deregulation of Dot1L and MLL1, has been found in several cancers, especially in leukemias, and Dot1L and MLL1 inhibition has emerged as a promising therapeutic strategy. Trypanosome Dot1 is involved in evasion of the human immune system contributing to devastating diseases such as African sleeping sickness. Understanding the mechanisms underlying Dot1 and COMPASS/MLL1 functions is critical to discovery of novel strategies to fight diseases associated with their deregulation. This proposal centers on finding and characterizing novel mechanisms of Dot1 and COMPASS/MLL1 regulation. We will use biochemical, biophysical and structural methods to study these histone methyltransferases. We will validate our mechanistic hypotheses in cells and in vivo. Using this integrative structural and functional approach and different model systems will allow us to determine evolutionarily conserved and organism-specific biological functions and modes of regulation of Dot1 and COMPASS/MLL1 which can be applied to therapeutic strategies for a variety of diseases.

染色质构象基于参与转录，复制的酶的可及性重组和修复。许多染色质调节机制确保酶（例如RNA）聚合酶II获得并有效转录染色质。染色质调节的机制之一基于组蛋白的翻译后修饰。化学组被沉积，阅读和去除酶的特定家族调节染色质结构。这些修饰很少在孤立地发挥作用，并且它们之间通常会串扰，从而导致协调的转录输出。素数之一在转录伸长中可以看到这种串扰的例子，其中组蛋白H3和H4是乙酰化的，H2B 是泛素化的，组蛋白H3在赖氨酸4和79（H3K4和H3K79）处甲基化。指南针/MLL和DOT1 是分别催化H3K4和H3K79甲基化并在进化上保守的酶。它们在转录伸长，细胞周期控制和DNA修复等过程中起着至关重要的作用。在酵母和哺乳动物中发现同源物。已经发现DOT1L和MLL1的放松管制在几种癌症中，尤其是在白血病中，dot1l和mll1抑制已成为有前途的治疗策略。锥体DOT1参与逃避人类免疫系统的促成毁灭性疾病，例如非洲昏睡病。了解点1和 Compass/Mll1功能对于发现与其相关疾病的新型策略至关重要放松管制。该提议旨在查找和表征DOT1和指南针/MLL1法规。我们将使用生化，生物物理和结构方法研究这些组蛋白甲基转移酶。我们将验证细胞和体内的机械假设。使用此综合结构和功能方法以及不同的模型系统将使我们能够在进化上确定保守和有机体特异性的生物学功能以及DOT1和Compass/Mll1的调节模式可以应用于各种疾病的治疗策略。