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Genome-wide mechanisms and dynamics of ATP-dependent chromatin remodeling complexes

ATP依赖性染色质重塑复合物的全基因组机制和动力学

基本信息

批准号：
10799754
负责人：
Sandipan Brahma
金额：
$ 24.9万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10799754
关键词：
ARID1A gene Acute Address Affect Automobile Driving Binding Biochemical Bioinformatics Biological Process British Columbia Catalytic Domain Cell physiology Cells Chromatin Chromatin Remodeling Factor Chromatin Structure Complex DNA DNA Packaging Data Defect Development Disease Enhancers Environment Family Foundations Fred Hutchinson Cancer Research Center Frequencies Future Gene Activation Gene Expression Genes Genetic Transcription Genome Genomic Segment Genomics Goals Heterogeneity Histones Human Genome Individual Kinetics Knowledge Label Lead Link Malignant Neoplasms Maps Mentors Modeling Molecular Molecular Machines Mus Mutation Nucleosomes Phase Polycomb Positioning Attribute Process Protein Complex Subunit Protein Subunits Proteins Regulation Regulator Genes Regulatory Element Repression Research Research Personnel Residual state Resolution Role SMARCA4 gene SMARCB1 gene SWI/SNF Family Complex Saccharomycetales Scientist Site Specificity Structure Supervision Techniques Testing Time Tissues Training Transcriptional Regulation Universities Variant cell type chromatin remodeling chromosomal location design developmental disease embryonic stem cell epigenomics exome sequencing genome sequencing genome-wide in vivo insight molecular imaging nervous system disorder novel novel strategies polybromo preference promoter recruit single molecule stem cell differentiation stem cells superresolution microscopy targeted treatment transcription factor

项目摘要

PROJECT SUMMARY/ABSTRACT The SWI/SNF family ATP-dependent chromatin remodelers are multi-subunit protein complexes that dynamically position chromosomal nucleosomes to modulate DNA accessibility, transcription-factor binding, and cell-type-specific gene expression. SWI/SNF function is crucial at several stages of mammalian development, and recent human whole-genome and exome sequencing studies revealed striking mutational frequencies in genes encoding SWI/SNF subunits across a range of diseases - from neurologic disorders to over 20% of all cancers. Disease-associated SWI/SNF mutations often cause the loss of a protein subunit that further destabilizes the complex and results in altered subunit composition and functions. Of note, heterogeneity in SWI/SNF subunit composition is also observed naturally within and across cell types, hypothesized to result in complex- and tissue-specific SWI/SNF functions. Despite their importance, how these subunits determine the substrate preference and mechanistic functions of SWI/SNF complexes are not well understood, largely due to the lack of robust approaches to characterize where they bind within the genome and how they interact with chromatin genome-wide. Thus, the main goal of this proposal is to address this key knowledge gap. Since chromatin remodelers directly interact with nucleosomes, it is important to clarify remodeler-bound nucleosome compositions and structures. Standard biochemical characterization of soluble components purified from cellular extracts cannot determine the nucleosome structures associated with chromatin-bound complexes. It is also important to understand the kinetic parameters of remodeler-chromatin interactions, such as how fast a remodeler is recruited to its target sites, and how long does it remain bound at its genomic sites. The candidate proposes to address these questions by using structural and functional epigenomics approaches and live-cell single-molecule imaging, to characterize remodeler-chromatin interactions in the context of the complex and dynamic chromatin environment inside cells. Aim 1 is to determine the genome-wide occupancy of SWI/SNF complexes with distinct subunit compositions. Aim 2 is to determine a) the structures and histone composition of remodeler-bound nucleosomes genome-wide, and b) the kinetic parameters of remodeler-chromatin interactions in live cells. Aim 3 is to study the interaction of SWI/SNF with repressive chromatin. The mentored phase of this project will be completed under the sponsorship of Dr. Steven Henikoff at the Fred Hutchinson Cancer Research Center. The candidate will acquire training in live-cell single-molecule imaging under the supervision of Dr. Sheila Teves at the University of British Columbia. The proposed research and training will provide a strong foundation for the candidate to develop as an independent investigator, studying chromatin remodeling mechanisms and dynamics in the regulation of fundamental cellular processes.

项目总结/文摘