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Building a unified framework for understanding bacterial gene regulation and chromosomal architecture

建立理解细菌基因调控和染色体结构的统一框架

基本信息

批准号：
10622670
负责人：
Lydia Freddolino
金额：
$ 40.7万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10622670
关键词：
3-Dimensional Architecture Area Automobile Driving Bacteria Bacterial Antibiotic Resistance Bacterial Chromosomes Bacterial Genes Bacteriophage mu Behavior Binding ChIP-seq Chromosome Structures DNA DNA-Binding Proteins DNA-Protein Interaction Dissociation Epigenetic Process Escherichia coli Gene Expression Regulation Genes Genetic Genetic Transcription Genome Growth Heterochromatin Impairment Investigation Laboratories Logic Maps Measurement Metabolic Methods Modification Molecular Nutrient Organism Physiological Play Post-Translational Protein Processing Process Prophages Proteins Regulation Research Role Sigma Factor Structure Study models Technology Therapeutic Transcriptional Regulation Virulence Work bacterial genetics cell motility clinically relevant crosslink design experimental study genome-wide global health innovation innovative technologies interest prevent protein profiling rapid technique response synthetic biology targeted treatment three dimensional structure tool transcription factor transcription regulatory network virulence gene

项目摘要

ABSTRACT Transcriptional regulation via protein-DNA interactions plays an important role in the regulatory networks of all known organisms. Bacterial regulatory networks are now an especially fruitful target for detailed investigation: as antibiotic- resistant bacteria continue to emerge as a global health threat, new and innovative approaches to either preventing virulence or impairing bacterial growth are required. As our ability to predict and exploit bacterial behavior for therapeutic purposes hinges on our understanding of the logic behind their regulatory networks, it is of great utility to fully map those networks and the molecular mechanisms underlying them. Several challenges, both old and newly recognized, stand in the way of a comprehensive understanding of regulatory logic even in well-studied models such as Escherichia coli. In additional to classical cis-regulatory logic by transcription factors and sigma factors, recent work by our laboratory and others has revealed contributions due to chromosomal context, large heterochromatin-like regions of repressive occupancy of nucleoid-associated proteins, overall three-dimensional chromosomal structure, and epigenetic modifications of both DNA-binding proteins and the DNA itself that further modulate transcriptional regulation. In addition, for non-model bacteria even the fundamental logic of classical transcriptional regulation is often poorly characterized. Thus, the fundamental regulatory logic behind cellular decisions such as metabolic switches, motility, and induction of virulence is often under-characterized. We have developed several innovative technologies to assist in rapid characterization of bacterial transcriptional regulatory logic, including: IPOD-HR, which allows overall profiling of protein occupancy on bacterial; transposon based methods for rapidly profiling genome-wide effects of genetic context on transcription; and a method based on the transposable phage Mu for crosslinking-free measurement of the 3D structure of the genome. Using these methods alongside classical approaches such as bacterial genetics and ChIP-seq, we are pursuing several avenues of research to investigate bacterial transcriptional regulatory networks. Key areas of interest include: Rapid elucidation of new transcriptional regulatory networks: Leveraging the IPOD-HR technology, which we have shown can be readily applied to new bacterial species, we are mapping the set of cis regulatory interactions driving important environmental responses in several clinically relevant bacterial species. Dynamics and composition of extended protein occupancy domains (EPODs): We have shown that highly protein occupied, heterochromatin like EPODs are present in a broad range of bacterial species, and play key roles in regulating prophages, virulence genes, and metabolic genes. We will continue to investigate the regulatory roles of EPODs, the proteins that comprise them, and the factors dictating their formation/dissociation across a range of bacterial taxa. Interplay of bacterial epigenetic marks with TF binding and EPODs: By interfacing our IPOD-HR and ChIP-seq experiments with tracking of covalent DNA and DNA-binding protein modifications, we will elucidate how these modifications modulate both local and large-scale protein occupancy and transcription in bacteria.

摘要

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Uncovering Transcriptional Regulators and Targets of sRNAs Using an Integrative Data-Mining Approach: H-NS-Regulated RseX as a Case Study.

DOI：
10.3389/fcimb.2021.696533
发表时间：
2021
期刊：
Frontiers in cellular and infection microbiology
影响因子：
5.7
作者：
Mihailovic MK;Ekdahl AM;Chen A;Leistra AN;Li B;González Martínez J;Law M;Ejindu C;Massé É;Freddolino PL;Contreras LM
通讯作者：
Contreras LM

Applications of molecular modeling to flavoproteins: Insights and challenges.

分子建模在黄素蛋白中的应用：见解和挑战。