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Biophysical Determinants of the Nucleosome as an Activity Center for Chromatin Regulators

核小体作为染色质调节剂活动中心的生物物理决定因素

基本信息

批准号：
10638494
负责人：
Shixin Liu
金额：
$ 33.9万
依托单位：
ROCKEFELLER UNIVERSITY
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：
2023-09-22 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10638494
关键词：
ATP phosphohydrolase Architecture Atomic Force Microscopy Base Pairing Binding Biological Assay Biophysics Cell Nucleus Characteristics Chemicals Chromatin Complex DNA DNA Binding DNA Packaging Data Detection Disease Energy consumption Enzymes Exhibits Fluorescence Fluorescence Microscopy Gene Expression Genetic Transcription Genome Genomic DNA Genomics Geometry Heterochromatin Histone H1 Histone H2A Histone H3 Histones Human Individual Intervention Investigation Kinetics Laboratories Length Licensing Link Linker DNA Lysine Measures Methods Methylation Modification Molecular Machines Multienzyme Complexes Mutation Nucleosome Core Particle Nucleosomes ORC1L gene Oncogenic Pathogenesis Polycomb Positioning Attribute Preparation Proteins Replication Initiation Replication Origin Reporting Resolution Role Shapes Site Spectrum Analysis Technology Testing Therapeutic Time Variant Visualization biophysical properties chromatin protein helicase human disease mutant origin recognition complex protein function recruit single molecule transcription factor

项目摘要

PROJECT SUMMARY/ABSTRACT The fundamental unit of hierarchically organized eukaryotic chromatin is the nucleosome, which contains 147 base pairs of genomic DNA wrapped around an octamer of core histone proteins. Conventionally, nucleosomes have been viewed as DNA packaging units that inhibit gene expression by obstructing the accessibility of DNA to the transcriptional machinery. However, we and others have shown that nucleosomes also serve as potent hotspots which recruit, modulate, and stimulate the activity of various essential chromatin regulators, indicating a new role for nucleosomes in furnishing the genome with a multitude of physical features and interactions which direct protein function. As such, I hypothesize that the physical characteristics and topology of nucleosomes modulate the activity of chromatin regulators, constituting an underappreciated layer of physical parameters encoded within chromatin architecture that govern genomic transactions in the nucleus. These parameters include the shape and composition of the nucleosome core particle as well as the spacing and geometry of contiguous nucleosomes in an array. To test this hypothesis, I propose to use single-molecule fluorescence detection and force manipulation technologies established in my laboratory, which uniquely track real-time transient and heterogeneous molecular interactions, to investigate the physical characteristics of nucleosome topology that determine its capacity to tune the activity of several important classes of chromatin regulators at multiple scales. We will first investigate how the topology of individual nucleosomes directs the DNA targeting activity and cooperation of essential pioneer transcription factors (Aim 1). We will then probe how the geometry of local nucleosomes in an array modulates the engagement, recruitment, and propagation of chromatin- modifying enzymes on chromatin (Aim 2). Finally, we will investigate the biophysical basis of global nucleosome localization and functionalization by energy-consuming molecular machines (Aim 3). Together, these studies will zoom in on the topology of nucleosomes comprising a layer of biophysical parameters encoded within chromatin architecture that regulate genomic transactions in the nucleus. They will contribute evidence towards a new perspective that views nucleosomes as genomic regulators which harness their unique physical features to actively modulate, recruit, and stimulate the activity of chromatin-associated factors, rather than passive DNA packaging units. The proposed investigations will shed light on a nucleosome-focused angle for tackling several long-standing questions about the interplay between chromatin and its regulators and promise to mechanistically inform how disease-associated mutations perturb essential genomic activities, potentially revealing mutation- selective protein-chromatin interfaces that may be therapeutically exploited to treat human disease.

项目总结/文摘