Bacterial Gene Regulation and Transcriptional Networks
Caister Academic Press
M. Madan Babu
MRC Laboratory of Molecular Biology, Cambridge, UK
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Gene regulation at the transcriptional level is central to the process by which organisms convert the constant sensing of environmental changes and intracellular fluxes of metabolites to homeostatic responses. In recent years a wealth of data from structural studies, sequence analysis and comparative genomics has led to a greater understanding of bacterial gene regulation and transcriptional networks.
Along with the strategic guidance of M. Madan Babu (Cambridge, UK) authors from around the world have joined forces to review and discuss the latest research observations and current theories in this highly topical and important area of microbiology. The first few chapters describe the components required for transcriptional regulation, elucidate their complexity and discuss the genome-scale theories that currently prevail by investigating a large number of completely sequenced microbial genomes. Other chapters discuss how transcriptional regulation and gene circuits can be used by bacteria to sense signals and generate phenotypic variation. The next chapters introduce experimental and computational methods for investigating transcriptional regulatory networks on a genomic scale. Later chapters explore the transcriptional complexity of specific organisms, discuss current understanding of the genome-scale regulatory networks and the importance of key transcription factors. Specific organisms covered include Escherichia coli, Bacillus subtilis, Helicobacter pylori, Mycobacterium tuberculosis, Pseudomonas aeruginosa and Cyanobacteria.
This book constitutes a major work on bacterial gene regulation and is a recommended purchase for all institutions and organisations interested in microbiology.
Table of contents
1. The Bacterial Transcription Apparatus
L. Aravind and Lakshminarayan M. Iyer
We provide a portrait of the bacterial transcription apparatus in light of recent structural studies, sequence analysis and comparative genomics to bring out several key underappreciated features. Comparisons of cellular RNA polymerase subunits with the RNA-dependent RNA polymerase involved in RNAi in eukaryotes and their homologs from newly identified bacterial selfish elements have helped in the identification of novel domains and the possible evolutionary stages leading to the RNA polymerases of extant life forms. We present the case for the ancient orthology of the basal transcription factors, the sigma factor and TFIIB, in the bacterial and the archaeo-eukaryotic lineages. Further, we furnish a synopsis of the structural and architectural taxonomy of specific transcription factors and their genome-scale demography. Although the proteome-wide trends in transcription factor distribution are generally invariant, there are certain notable deviations in firmicutes like Paenibacillus and Geobacillus due to unusual lineage-specifically expanded two-component signaling systems that might have a special biological significance. We then discuss the intersection between functional properties of transcription factors and the organization of transcriptional networks. Finally, we bring attention to some puzzling questions raised by our new understanding of the bacterial transcription apparatus and potential areas for future explorations.
2. DNA Structure and Bacterial Nucleoid-associated Proteins
Georgi Muskhelishvili and Andrew Travers
In the bacterial nucleoid different configurations of negatively supercoiled DNA are constrained by different NAPs. Thus while H-NS can constrain, by bridging, the interwindings of plectonemic structure, HU induces a left-handed coiled configuration while FIS can bind within DNA loops. The topological and dynamic interconvertibility of these structures contributes substantially to the regulation of gene expression in bacteria. We review here some of the mechanisms involved and argue that they form the basis for a coordination of gene transcription which results in the establishment of a single interconnected heterarchical control system that is responsible both for maintaining, when appropriate, a homoeostatic control of growth and also for mediating transitions between different cellular physiological states.
3. Structure and Evolution of Prokaryotic Transcription Factor Binding Sites
With the ever-increasing number of available sequenced bacterial genomes and the availability of high throughput experimental approaches such as chromatine immuno-precipitation sequencing (ChIP-seq), it has become possible to extend our knowledge about the transcriptional regulation from model organisms to other bacteria. Recent research has focused especially on the comparison of closely related species, allowing us to get insight into the different regulatory evolutionary events creating phenotypic diversity and involved in the evolution of bacterial gene regulatory networks.
4. Operons and Prokaryotic Genome Organization
Sarath Chandra Janga and Gabriel Moreno-Hagelsieb
An average of 60% of prokaryotic genes are organized into operons-polycistronic transcription units, making them a very important feature of their genomic organization. Operons most commonly contain genes whose products have functional associations and are abundant because they constitute an easy means for coregulation and the associated genes can act as a functional unit with a higher success rate in horizontal gene transfer events than single genes. Operons are transcribed from a single promoter, thus rarely needing genomic features between their constituting genes, naturally resulting in shorter distances between genes in operons than between adjacent genes in different transcription units. Thus, operons can be predicted based on distances between adjacent genes in the same DNA strand. This feature, intergenic distance, is the most informative criterion for predicting operons. However, predictions based on conservation of gene order followed by phylogenetic profiles, provide cleaner predictions, albeit with much lower coverage. Transcriptional terminators and other sequence features might add quality to operon predictions, but the gain is minimal for most prokaryotes. Operon organization is not well conserved with evolutionary divergence. However, operons rearrange in a functionally coherent manner. Thus, the combination of operon predictions with operon rearrangements constitutes the most powerful source for the prediction of functional associations by genomic context in prokaryotes.
5. Small-molecule-mediated Signalling in Bacteria
Aswin Sai Narain Seshasayee and Nicholas M. Luscombe
The ability to sense and respond to environmental cues is critical to the survival of unicellular organisms like bacteria. An important type of signals is represented by small molecules. In this review, following a general description of the prevalence of small-molecule-binding proteins in the prokaryotic kingdom, we discuss the following aspects of bacterial signalling mediated by small molecules: (a) the interplay between small-molecule signalling and metabolism, which involves local regulation of specific metabolic pathways, in addition to a more global integration of metabolic and other cellular functions; and (b) signal transduction via two second messenger small molecules - ppGpp and c-di-GMP - which initiate stringent response following nutrient starvation, and control switching between motile and adhesive states respectively. In conclusion, we briefly mention two other dimensions of small-molecule signalling: (a) the role of antibiotics in triggering transcriptional responses at sub-inhibitory concentrations; and (b) inter-kingdom signalling between bacteria and their mammalian hosts through hormones and quorum sensing signals.
6. Transcriptional Circuits and Phenotypic Variation
Ákos T. Kovács and Oscar P. Kuipers
By developing various survival strategies simultaneously, bacterial populations are well-prepared to meet harsh conditions. The Gram-positive model organism B. subtilis presents a superb example how noise, positive- and negative feedback loops and epigenetic inheritance influence developmental pathways. Noise in combination with a fast positive autoregulatory pathway creates the possibility to initiate natural competence in a subpopulation, followed by a slow negative feedback loop to escape from the competent state when needed. In contrast, sporulation is a one-way differentiation process that is accurately timed and regulated by a gradual increase of phosphorylated Spo0A levels in conjunction with a fine-tuned autoactivation through the phosphorelay in specific activated cells. Intertwinement of regulatory pathways depending on defined levels and activities of regulators can result in genetic logic AND gates, which ensure that appropriate pathways are only activated under specific conditions in a given subpopulation of cells. Finally, communication between subpopulations of cells within an isogenic culture aids and determines the development of complex microbial communities.
7. Genomic Approaches to Reconstructing Transcriptional Networks
Stephen J. W. Busby and Stephen D. Minchin
The traditional methods for discovering transcriptional regulatory networks in bacteria, based on genetics and biochemistry, are now being replaced by high throughput pan-genome methods. Experimental approaches include methods involving RNA or methods based on the direct observation of transcription factors. This chapter places the new methods in context and discusses their potential benefits and drawbacks.
8. Structure and Evolution of Transcriptional Regulatory Networks
Guilhem Chalancon and M. Madan Babu
Regulation of gene expression is primarily mediated by proteins called transcription factors (TFs), which recognize and bind specific nucleotide sequences and affect transcription of nearby genes. Over the last years, considerable information has been accumulated on regulatory interactions between the TFs and their regulated target genes (TGs) in various model prokaryotic systems such as Escherichia coli and Bacillus subtilis. This has permitted researchers to model the transcriptional regulatory system of an organism as a network, wherein TFs or TGs are represented as nodes and regulatory interactions are denoted as directed links. Representation of this information as a network has provided us with a robust conceptual framework to investigate this system, and work in the last decade has uncovered several fundamental general principles pertaining to its structure and evolution. In this chapter, we first introduce the concept of transcriptional regulatory networks. We then discuss our current understanding of the structure of transcriptional regulatory networks. Specifically, we discuss the local and global structure of such networks. We then discuss the various forces that influence network evolution such as gene duplication, horizontal gene transfer, and gene loss. In particular, we discuss how the transcriptional regulatory network evolves across organisms that live in different environments. Finally, we conclude by discussing major challenges for future research and highlighting how the new understanding can have implications for biotechnology and medicine and can be exploited in applications such as microbial engineering and synthetic biology.
9. Operation of the Gene Regulatory Network in Escherichia coli
Transcription factors function as sensory systems acting at the core of genetic regulatory switches. The transcriptional regulatory network in Escherichia coli can be studied as the integration of the whole of these genetic sensory systems. The operation of this regulatory system affect the expression of genes by interacting with the DNA at the promoter regions of transcription units. In this chapter I present the advances of what we know about the mechanistic logic for the operation of the regulatory program in E. coli. It is proposed that for a better understanding on the operation of the regulatory network it should be considered the globalism of transcription factors, the signal perceived by each, their co-regulating activity, the genome position of regulatory and target genes, and cellular concentration of the regulatory proteins, among others.
10. Bacillus subtilis Transcriptional Network
Yuko Makita and Kenta Nakai
Bacillus subtilis is a soil living bacterium, long known as a representative of the low G+C group of Gram-positive bacteria in contrast to Escherichia coli, a representative of Gram-negative bacteria. Its genome contains about 4,176 protein-coding genes and 178 RNA genes. The number of sigma factors is 18, which is much larger than 7 in E. coli. Although there are very few theoretical studies of its global transcriptional network, our preliminary analysis based on experimentally validated data stored in the DBTBS database suggests that it is a typical scale-free network largely governed by a small number of hub transcription factors like that of many other model organisms. However, some of the results of the network motif analysis in E. coli were not confirmed in B. subtilis. Although this is likely to be due to the small sample size in B. subtilis, a more cautious approach might be necessary to perform network motif analyses of bacterial gene regulatory networks, which are not so large, in general. As a specific sub-network, the gene regulatory network for sporulation, which is regarded as a model of eukaryotic differentiation process, is described. In the description of the network, not only transcriptional regulation but also post-translational regulation as well as genome recombination are necessary.
11. Helicobacter pylori Transcriptional Network
Alberto Danielli and Vincenzo Scarlato
The human gastric pathogen Helicobacter pylori appears to enroll only 17 transcriptional regulators to transduce environmental signals into coordinated output expression of the genome. We show that the low number of transcriptional regulators, together with the large body of molecular tools, set H. pylori as appealing model organism to characterize transcriptional network structures involved in virulence regulation and host-pathogen interactions. In particular we provide evidence that the regulators are wired in a shallow transcriptional regulatory network (TRN), which orchestrates the key physiological responses needed to colonize the gastric niche: heat and stress response, motility and chemotaxis, acid acclimation and metal ion homeostasis. Interestingly, long regulatory cascades are absent, and rather than having a plethora of specialized regulators, the TRN of H. pylori appears to transduce separate environmental inputs by using different combinations of a small set of regulators. It is not tailored to adapt to many environmental stimuli, and apparently not flexible to react to metabolic signals encountered outside of the gastric niche. On the other hand, the predominance of negative regulatory interactions suggests that this architecture of the TRN evolved to quickly respond to changing conditions in the gastric niche in order to maintain homeostasis. Metal-responsive regulators such as NikR and Fur appear to have a very important role in this TRN, forming a central regulatory hub, with regulatory interaction feeding into all other sub-network circuits.
12. The Transcriptional Regulatory Network of Mycobacterium tuberculosis
Gábor Balázsi, Oleg A. Igoshin, and Maria Laura Gennaro
Approximately one third of the world's human population is infected with Mycobacterium tuberculosis. Most infected individuals have latent infection: they do not show symptoms and carry bacteria that survived the immune response and are mostly dormant. When the immune response weakens, dormant bacteria can reactivate and cause a life-threatening disease. If the mechanisms of dormancy were better understood, disease reactivation and spreading could be prevented. Here we review our recent work on two mycobacterial survival strategies that are probably related to dormancy: environmental sensing followed by stress response and stochastically delayed switching into dormancy. We discuss the use of large-scale regulatory networks to infer how hypoxia affects the mycobacterial transcriptome at the genomic scale. We also show how sigma factor sequestration by the corresponding anti-sigma factor may generate a nonlinear response, which results in bistability when combined with positive feedback.
13. Transcriptional Regulatory Network in Pseudomonas aeruginosa
Deepak Balasubramanian, Senthil Kumar Murugapiran, Eugenia Silva-Herzog, Lisa Schneper, Xing Yang, Gorakh Tatke, Giri Narasimhan and Kalai Mathee
Pseudomonas aeruginosa is found in a wide range of habitats, primarily in soil and water and is the epitome of opportunistic human pathogens. A myriad of virulence factors produced by the bacterium ensure its success as a pathogen. P. aeruginosa has one of the largest genomes among eubacteria and transcriptional regulators comprise about 8% of the genome. Sequence analysis of the regulators belonging to different families shows clustering while network analysis shows extensive crosstalk, and reveals empirically identified and novel interactions between regulators. Gene expression in P. aeruginosa is an intricately interlinked process and is exemplified in the regulation of virulence factor expression. Major regulatory processes such as quorum sensing involving multiple regulators translate external signals perceived by the bacterium into gene expression/repression via regulatory cascades. Many global regulators have been identified that serve to link different virulence systems. Understanding the role of the as yet uncharacterized transcriptional regulatory proteins will provide important insights into the physiology of this important human pathogen and has potential therapeutic implications.
14. Transcriptional Regulation Network in Cyanobacteria: a Comparative Genomic View
Xizeng Mao, Fenglou Mao, Zhengchang Su, Yi Li and Ying Xu
Cyanobacteria are the oldest and most diverse organisms of autotrophic photosynthesis on Earth. Compared to the most studied bacteria such as E. coli, the overall knowledge about the transcriptional regulation system of cyanobacteria is still limited and fragmented. The availability of a large number of fully sequenced cyanobacterial genomes, along with genome-scale transcriptomic data, provided unprecedented opportunities for researchers to elucidate the transcriptional regulation system in this group of organisms in a systematic manner. In this chapter, we first provide a brief introduction to the basics of cyanobacteria, including their diverse living habits and phylogenetic classification, and then describe the basic components of their transcription regulation system. We then proceed to describe in details the regulatory machinery of three key pathways, namely photosynthesis, nitrogen assimilation and osmoregulation, along with their cross-talk networks. To demonstrate how comparative genomics can help to elucidate the complexity of transcriptional regulation systems under diverse living environments, we will use six cyanobacteria to demonstrate what information can be derived through genome comparisons and how. The chapter ends with a list of available Internet resources along with a list of challenging problems in full elucidation of cyanobacterial transcription regulation systems
How to buy this book
(EAN: 9781908230140 9781908230799 Subjects: [microbiology] [bacteriology] [molecular microbiology] [genomics] [bacterial regulation] )