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Structure and Mechanism of the SET1/COMPASS H3K4 Methyltransferase Complex

SET1/COMPASS H3K4 甲基转移酶复合物的结构和机制

基本信息

批准号：
10047581
负责人：
Champak Chatterjee
金额：
$ 38.66万
依托单位：
UNIVERSITY OF WASHINGTON
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：
2020-09-08 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10047581
关键词：
ASH2L gene Active Sites Address Animals Binding Biochemical Biological Biological Assay Biological Models Biology Cells Chemicals Chromatin Structure Complex Congenital Heart Defects Cryoelectron Microscopy Crystallization Data Defect Disease Elements Enhancers Enzyme Kinetics Enzymes Epigenetic Process Etiology Eukaryota Eukaryotic Cell Family Family member Gene Expression Gene Expression Regulation Genes Genetic Genetic Transcription HRX protein Health Histone H3 Histone-Lysine N-Methyltransferase Histones Human In Vitro Intellectual functioning disability Light Link Lysine MLL gene MLL2 gene Malignant Neoplasms Mammals Measures Mental disorders Methods Methylation Methyltransferase Mixed-Lineage Leukemia Molecular Monoubiquitination Motion Mutation Names Nucleosomes Orthologous Gene Outcome Post-Translational Protein Processing Protein Subunits Recombinants Regulation Reporting Residual state Role Saccharomyces cerevisiae Schizophrenia Side Signal Transduction Specificity Structure Structure-Activity Relationship Testing Transcriptional Activation Transcriptional Regulation Work Yeast Model System Yeasts autism spectrum disorder base clinically relevant congenital heart disorder enzyme substrate epigenetic regulation histone methylation human disease in vivo interest leukemia member methyl group nervous system disorder neuropsychiatric disorder novel paralogous gene protein complex prototype reconstitution response

项目摘要

Project Summary The post-translational modification of histone H3 lysine 4 (H3K4) by methyl groups is an evolutionarily conserved epigenetic mark that is generally associated with transcription activation in all eukaryotic cells. Early studies of the yeast model system, S. cerevisiae, have not only identified the prototype of the SET1/MLL family of methyltransferases as the enzyme responsible for H3K4 mono-, di-, and trimethylation, but also revealed a yeast Set1-centric protein complex, known as COMPASS, that stabilizes and confers catalytic activity to the enzyme. The SET1/MLL family of H3K4 methyltransferases has undergone a significant expansion in animals. Mammals have evolved a total of six distinct and functionally non-redundant family members, each of which also functions within a COMPASS or COMPASS-like complex. Remarkably, recent studies have shown that mutations or dysregulation of the six human SET1/MLL methyltransferases are associated with a spectrum of mental illnesses, including schizophrenia, autism, and intellectual disability disorders. Malfunctions of some of these family members are further linked to other human diseases such as mixed lineage leukemia and congenital heart disease. Despite their important biological roles and their high relevance to human health, a molecular and mechanistic understanding of the SET1/MLL H3K4 methyltransferases is largely lacking due to the large sizes of most SET1/MLL enzymes and the complexity associated with their assemblies and regulation. To date, most structural and biochemical studies have been focused on single domains and small fragments of the yeast and human SET1/MLL enzymes and COMPASS subunits. Many questions, such as how the SET1/MLL enzymes bind and become regulated by four common catalytic module subunits, namely RBBP5/Swd1, WDR5/Swd3, ASH2L/Bre2, and DPY30/Sdc1 (human/yeast ortholog), how the resulting complexes recognize H3K4 in the context of nucleosome and differentially catalyze mono- vs. multi-H3K4 methylation, and how the activities of COMPASS and COMPASS-like complexes are regulated by upstream signals such as H2B mono-ubiquitination remain unclear. Using a combination of structural, chemical and biochemical approaches, as well as yeast cell- based functional assays, we propose to dissect the structure and function relationship of the yeast Set1 COMPASS complex as a model system and extend this work to the clinically relevant human SET1/MLL complexes. Our proposed studies hold the promise to establish the missing framework for understanding the structural basis of the SET1/MLL H3K4 methyltransferase function and regulation in eukaryotic biology and unmasking the molecular mechanisms of various human diseases associated with their malfunction.

项目总结