Showing papers on "Gene expression published in 2012"

Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq

Abstract: An extensive repertoire of modifications is known to underlie the versatile coding, structural and catalytic functions of RNA, but it remains largely uncharted territory. Although biochemical studies indicate that N(6)-methyladenosine (m(6)A) is the most prevalent internal modification in messenger RNA, an in-depth study of its distribution and functions has been impeded by a lack of robust analytical methods. Here we present the human and mouse m(6)A modification landscape in a transcriptome-wide manner, using a novel approach, m(6)A-seq, based on antibody-mediated capture and massively parallel sequencing. We identify over 12,000 m(6)A sites characterized by a typical consensus in the transcripts of more than 7,000 human genes. Sites preferentially appear in two distinct landmarks--around stop codons and within long internal exons--and are highly conserved between human and mouse. Although most sites are well preserved across normal and cancerous tissues and in response to various stimuli, a subset of stimulus-dependent, dynamically modulated sites is identified. Silencing the m(6)A methyltransferase significantly affects gene expression and alternative splicing patterns, resulting in modulation of the p53 (also known as TP53) signalling pathway and apoptosis. Our findings therefore suggest that RNA decoration by m(6)A has a fundamental role in regulation of gene expression.

Transcription factors: from enhancer binding to developmental control.

Abstract: Developmental progression is driven by specific spatiotemporal domains of gene expression, which give rise to stereotypically patterned embryos even in the presence of environmental and genetic variation. Views of how transcription factors regulate gene expression are changing owing to recent genome-wide studies of transcription factor binding and RNA expression. Such studies reveal patterns that, at first glance, seem to contrast with the robustness of the developmental processes they encode. Here, we review our current knowledge of transcription factor function from genomic and genetic studies and discuss how different strategies, including extensive cooperative regulation (both direct and indirect), progressive priming of regulatory elements, and the integration of activities from multiple enhancers, confer specificity and robustness to transcriptional regulation during development.

Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages

Abstract: We assessed gene expression in tissue macrophages from various mouse organs The diversity in gene expression among different populations of macrophages was considerable Only a few hundred mRNA transcripts were selectively expressed by macrophages rather than dendritic cells, and many of these were not present in all macrophages Nonetheless, well-characterized surface markers, including MerTK and FcγR1 (CD64), along with a cluster of previously unidentified transcripts, were distinctly and universally associated with mature tissue macrophages TCEF3, C/EBP-α, Bach1 and CREG-1 were among the transcriptional regulators predicted to regulate these core macrophage-associated genes The mRNA encoding other transcription factors, such as Gata6, was associated with single macrophage populations We further identified how these transcripts and the proteins they encode facilitated distinguishing macrophages from dendritic cells

Atheroprotective communication between endothelial cells and smooth muscle cells through miRNAs.

Abstract: The shear-responsive transcription factor Kruppel-like factor 2 (KLF2) is a critical regulator of endothelial gene expression patterns induced by atheroprotective flow. As microRNAs (miRNAs) post-transcriptionally control gene expression in many pathogenic and physiological processes, we investigated the regulation of miRNAs by KLF2 in endothelial cells. KLF2 binds to the promoter and induces a significant upregulation of the miR-143/145 cluster. Interestingly, miR-143/145 has been shown to control smooth muscle cell (SMC) phenotypes; therefore, we investigated the possibility of transport of these miRNAs between endothelial cells and SMCs. Indeed, extracellular vesicles secreted by KLF2-transduced or shear-stress-stimulated HUVECs are enriched in miR-143/145 and control target gene expression in co-cultured SMCs. Extracellular vesicles derived from KLF2-expressing endothelial cells also reduced atherosclerotic lesion formation in the aorta of ApoE(-/-) mice. Combined, our results show that atheroprotective stimuli induce communication between endothelial cells and SMCs through an miRNA- and extracellular-vesicle-mediated mechanism and that this may comprise a promising strategy to combat atherosclerosis.

RNA therapeutics: beyond RNA interference and antisense oligonucleotides

Abstract: Here, we discuss three RNA-based therapeutic technologies exploiting various oligonucleotides that bind to RNA by base pairing in a sequence-specific manner yet have different mechanisms of action and effects. RNA interference and antisense oligonucleotides downregulate gene expression by inducing enzyme-dependent degradation of targeted mRNA. Steric-blocking oligonucleotides block the access of cellular machinery to pre-mRNA and mRNA without degrading the RNA. Through this mechanism, steric-blocking oligonucleotides can redirect alternative splicing, repair defective RNA, restore protein production or downregulate gene expression. Moreover, they can be extensively chemically modified to acquire more drug-like properties. The ability of RNA-blocking oligonucleotides to restore gene function makes them best suited for the treatment of genetic disorders. Positive results from clinical trials for the treatment of Duchenne muscular dystrophy show that this technology is close to achieving its clinical potential.

Long non-coding antisense RNA controls Uchl1 translation through an embedded SINEB2 repeat

Abstract: Most of the mammalian genome is transcribed. This generates a vast repertoire of transcripts that includes protein-coding messenger RNAs, long non-coding RNAs (lncRNAs) and repetitive sequences, such as SINEs (short interspersed nuclear elements). A large percentage of ncRNAs are nuclear-enriched with unknown function. Antisense lncRNAs may form sense-antisense pairs by pairing with a protein-coding gene on the opposite strand to regulate epigenetic silencing, transcription and mRNA stability. Here we identify a nuclear-enriched lncRNA antisense to mouse ubiquitin carboxy-terminal hydrolase L1 (Uchl1), a gene involved in brain function and neurodegenerative diseases. Antisense Uchl1 increases UCHL1 protein synthesis at a post-transcriptional level, hereby identifying a new functional class of lncRNAs. Antisense Uchl1 activity depends on the presence of a 5' overlapping sequence and an embedded inverted SINEB2 element. These features are shared by other natural antisense transcripts and can confer regulatory activity to an artificial antisense to green fluorescent protein. Antisense Uchl1 function is under the control of stress signalling pathways, as mTORC1 inhibition by rapamycin causes an increase in UCHL1 protein that is associated to the shuttling of antisense Uchl1 RNA from the nucleus to the cytoplasm. Antisense Uchl1 RNA is then required for the association of the overlapping sense protein-coding mRNA to active polysomes for translation. These data reveal another layer of gene expression control at the post-transcriptional level.

miRNA-Mediated Gene Silencing by Translational Repression Followed by mRNA Deadenylation and Decay

Abstract: microRNAs (miRNAs) regulate gene expression through translational repression and/or messenger RNA (mRNA) deadenylation and decay. Because translation, deadenylation, and decay are closely linked processes, it is important to establish their ordering and thus to define the molecular mechanism of silencing. We have investigated the kinetics of these events in miRNA-mediated gene silencing by using a Drosophila S2 cell-based controllable expression system and show that mRNAs with both natural and engineered 3′ untranslated regions with miRNA target sites are first subject to translational inhibition, followed by effects on deadenylation and decay. We next used a natural translational elongation stall to show that miRNA-mediated silencing inhibits translation at an early step, potentially translation initiation.

Mapping cis - and trans -regulatory effects across multiple tissues in twins

Abstract: Sequence-based variation in gene expression is a key driver of disease risk. Common variants regulating expression in cis have been mapped in many expression quantitative trait locus (eQTL) studies, typically in single tissues from unrelated individuals. Here, we present a comprehensive analysis of gene expression across multiple tissues conducted in a large set of mono- and dizygotic twins that allows systematic dissection of genetic (cis and trans) and non-genetic effects on gene expression. Using identity-by-descent estimates, we show that at least 40% of the total heritable cis effect on expression cannot be accounted for by common cis variants, a finding that reveals the contribution of low-frequency and rare regulatory variants with respect to both transcriptional regulation and complex trait susceptibility. We show that a substantial proportion of gene expression heritability is trans to the structural gene, and we identify several replicating trans variants that act predominantly in a tissue-restricted manner and may regulate the transcription of many genes.

Using Gene Expression Noise to Understand Gene Regulation

Abstract: Phenotypic variation is ubiquitous in biology and is often traceable to underlying genetic and environmental variation. However, even genetically identical cells in identical environments display variable phenotypes. Stochastic gene expression, or gene expression "noise," has been suggested as a major source of this variability, and its physiological consequences have been topics of intense research for the last decade. Several recent studies have measured variability in protein and messenger RNA levels, and they have discovered strong connections between noise and gene regulation mechanisms. When integrated with discrete stochastic models, measurements of cell-to-cell variability provide a sensitive "fingerprint" with which to explore fundamental questions of gene regulation. In this review, we highlight several studies that used gene expression variability to develop a quantitative understanding of the mechanisms and dynamics of gene regulation.

A Molecular Taxonomy for Urothelial Carcinoma

Abstract: Purpose Even though urothelial cancer is the fourth most common tumor type among males, progress in treatment has been scarce. A problem in day-to-day clinical practice is that precise assessment of individual tumors is still fairly uncertain; consequently efforts have been undertaken to complement tumor evaluation with molecular biomarkers. An extension of this approach would be to base tumor classification primarily on molecular features. Here, we present a molecular taxonomy for urothelial carcinoma based on integrated genomics. Experimental design We use gene expression profiles from 308 tumor cases to define five major urothelial carcinoma subtypes: urobasal A, genomically unstable, urobasal B, squamous cell carcinoma like, and an infiltrated class of tumors. Tumor subtypes were validated in three independent publically available data sets. The expression of 11 key genes was validated at the protein level by immunohistochemistry. Results The subtypes show distinct clinical outcomes and differ with respect to expression of cell-cycle genes, receptor tyrosine kinases particularly FGFR3, ERBB2, and EGFR, cytokeratins, and cell adhesion genes, as well as with respect to FGFR3, PIK3CA, and TP53 mutation frequency. The molecular subtypes cut across pathologic classification, and class-defining gene signatures show coordinated expression irrespective of pathologic stage and grade, suggesting the molecular phenotypes as intrinsic properties of the tumors. Available data indicate that susceptibility to specific drugs is more likely to be associated with the molecular stratification than with pathologic classification. Conclusions We anticipate that the molecular taxonomy will be useful in future clinical investigations.

MEG3 noncoding RNA: a tumor suppressor

Abstract: Maternally expressed gene 3 (MEG3) is an imprinted gene belonging to the imprinted DLK1-MEG3 locus located at chromosome 14q32.3 in humans. Its mouse ortholog, Meg3, also known as gene trap locus 2 (Gtl2), is located at distal chromosome 12. The MEG3 gene encodes a long noncoding RNA (lncRNA) and is expressed in many normal tissues. MEG3 gene expression is lost in an expanding list of primary human tumors and tumor cell lines. Multiple mechanisms contribute to the loss of MEG3 expression in tumors, including gene deletion, promoter hypermethylation, and hypermethylation of the intergenic differentially methylated region. Re-expression of MEG3 inhibits tumor cell proliferation in culture and colony formation in soft agar. This growth inhibition is partly the result of apoptosis induced by MEG3. MEG3 induces accumulation of p53 (TP53) protein, stimulates transcription from a p53-dependent promoter, and selectively regulates p53 target gene expression. Maternal deletion of the Meg3 gene in mice results in skeletal muscle defects and perinatal death. Inactivation of Meg3 leads to a significant increase in expression of angiogenesis-promoting genes and microvessel formation in the brain. These lines of evidence strongly suggest that MEG3 functions as a novel lncRNA tumor suppressor.

Dual RNA-seq of pathogen and host

Abstract: A comprehensive understanding of host-pathogen interactions requires a knowledge of the associated gene expression changes in both the pathogen and the host. Traditional, probe-dependent approaches using microarrays or reverse transcription PCR typically require the pathogen and host cells to be physically separated before gene expression analysis. However, the development of the probe-independent RNA sequencing (RNA-seq) approach has begun to revolutionize transcriptomics. Here, we assess the feasibility of taking transcriptomics one step further by performing 'dual RNA-seq', in which gene expression changes in both the pathogen and the host are analysed simultaneously.

Inhibition of natural antisense transcripts in vivo results in gene-specific transcriptional upregulation

Abstract: The ability to specifically upregulate genes in vivo holds great therapeutic promise. Here we show that inhibition or degradation of natural antisense transcripts (NATs) by single-stranded oligonucleotides or siRNAs can transiently and reversibly upregulate locus-specific gene expression. Brain-derived neurotrophic factor (BDNF) is normally repressed by a conserved noncoding antisense RNA transcript, BDNF-AS. Inhibition of this transcript upregulates BDNF mRNA by two- to sevenfold, alters chromatin marks at the BDNF locus, leads to increased protein levels and induces neuronal outgrowth and differentiation both in vitro and in vivo. We also show that inhibition of NATs leads to increases in glial-derived neurotrophic factor (GDNF) and ephrin receptor B2 (EPHB2) mRNA. Our data suggest that pharmacological approaches targeting NATs can confer locus-specific gene upregulation effects.

Nutrition and epigenetics: An interplay of dietary methyl donors, one-carbon metabolism and DNA methylation

Abstract: DNA methylation is the most extensively studied mechanism of epigenetic gene regulation. Increasing evidence indicates that DNA methylation is labile in response to nutritional and environmental influences. Alterations in DNA methylation profiles can lead to changes in gene expression, resulting in diverse phenotypes with the potential for increased disease risk. The primary methyl donor for DNA methylation is S-adenosylmethionine (SAM), a species generated in the cyclical cellular process called one-carbon metabolism. One-carbon metabolism is catalyzed by several enzymes in the presence of dietary micronutrients, including folate, choline, betaine and other B vitamins. For this reason, nutrition status, particularly micronutrient intake, has been a focal point when investigating epigenetic mechanisms. Although animal evidence linking nutrition and DNA methylation is fairly extensive, epidemiological evidence is less comprehensive. This review serves to integrate studies of the animal in vivo with human epidemiological data pertaining to nutritional regulation of DNA methylation and to further identify areas in which current knowledge is limited.

Inhibition of miR-15 Protects Against Cardiac Ischemic Injury

Abstract: Rationale:Myocardial infarction (MI) is a leading cause of death worldwide. Because endogenous cardiac repair mechanisms are not sufficient for meaningful tissue regeneration, MI results in loss of cardiac tissue and detrimental remodeling events. MicroRNAs (miRNAs) are small, noncoding RNAs that regulate gene expression in a sequence dependent manner. Our previous data indicate that miRNAs are dysregulated in response to ischemic injury of the heart and actively contribute to cardiac remodeling after MI. Objective:This study was designed to determine whether miRNAs are dysregulated on ischemic damage in porcine cardiac tissues and whether locked nucleic acid (LNA)-modified anti-miR chemistries can target cardiac expressed miRNAs to therapeutically inhibit miR-15 on ischemic injury. Methods and Results:Our data indicate that the miR-15 family, which includes 6 closely related miRNAs, is regulated in the infarcted region of the heart in response to ischemia-reperfusion injury in mice and pigs. LNA-modified...

Posttranscriptional Upregulation by MicroRNAs

Abstract: MicroRNAs are small non-coding RNA guide molecules that regulate gene expression via association with effector complexes and sequence-specific recognition of target sites on other RNAs; misregulated microRNA expression and functions are linked to a variety of tumors, developmental disorders, and immune disease. MicroRNAs have primarily been demonstrated to mediate posttranscriptional downregulation of expression; translational repression, and deadenylation-dependent decay of messages through partially complementary microRNA target sites in mRNA untranslated regions (UTRs). However, an emerging assortment of studies, discussed in this review, reveal that microRNAs and their associated protein complexes (microribonucleoproteins or microRNPs) can additionally function to posttranscriptionally stimulate gene expression by direct and indirect mechanisms. These reports indicate that microRNA-mediated effects can be selective, regulated by the RNA sequence context, and associated with RNP factors and cellular conditions. Like repression, translation upregulation by microRNAs has been observed to range from fine-tuning effects to significant alterations in expression. These studies uncover remarkable, new abilities of microRNAs and associated microRNPs in gene expression control and underscore the importance of regulation, in cis and trans, in directing appropriate microRNP responses.

Transcriptional and Posttranscriptional Regulation of HIV-1 Gene Expression

Abstract: Control of HIV-1 gene expression depends on two viral regulatory proteins, Tat and Rev. Tat stimulates transcription elongation by directing the cellular transcriptional elongation factor P-TEFb to nascent RNA polymerases. Rev is required for the transport from the nucleus to the cytoplasm of the unspliced and incompletely spliced mRNAs that encode the structural proteins of the virus. Molecular studies of both proteins have revealed how they interact with the cellular machinery to control transcription from the viral LTR and regulate the levels of spliced and unspliced mRNAs. The regulatory feedback mechanisms driven by HIV-1 Tat and Rev ensure that HIV-1 transcription proceeds through distinct phases. In cells that are not fully activated, limiting levels of Tat and Rev act as potent blocks to premature virus production.

Nanoparticle hydrophobicity dictates immune response.

Abstract: Understanding the interactions of nanomaterials with the immune system is essential for the engineering of new macromolecular systems for in vivo applications. Systematic study of immune activation is challenging due to the complex structure of most macromolecular probes. We present here the use of engineered gold nanoparticles to determine the sole effect of hydrophobicity on the immune response of splenocytes. The gene expression profile of a range of cytokines (immunological reporters) was analyzed against the calculated log P of the nanoparticle headgroups, with an essentially linear increase in immune activity with the increase in hydrophobicity observed in vitro. Consistent behavior was observed with in vivo mouse models, demonstrating the importance of hydrophobicity in immune system activation.

Transcription factor Foxp3 and its protein partners form a complex regulatory network

Abstract: The transcription factor Foxp3 is indispensible for the differentiation and function of regulatory T cells (T(reg) cells). To gain insights into the molecular mechanisms of Foxp3-mediated gene expression, we purified Foxp3 complexes and explored their composition. Biochemical and mass-spectrometric analyses revealed that Foxp3 forms multiprotein complexes of 400-800 kDa or larger and identified 361 associated proteins, ∼30% of which were transcription related. Foxp3 directly regulated expression of a large proportion of the genes encoding its cofactors. Some transcription factor partners of Foxp3 facilitated its expression. Functional analysis of the cooperation of Foxp3 with one such partner, GATA-3, provided additional evidence for a network of transcriptional regulation afforded by Foxp3 and its associates to control distinct aspects of T(reg) cell biology.

Regulation of Gene Expression in Escherichia Coli

Abstract: 1. Introduction: From Physiology to DNA and Back.- 2. RNA Chain Initiation and Promoter Escape by RNA Polymerase.- Promoter Function is Regulated at Two Distinct Phases of Transcription: Promoter Binding and RNA Chain Initiation.- The Biochemistry of the RNA Chain Initiation Phase of Transcription.- Parameters That Describe the RNA Chain Initiation Reaction at Different Promoters.- Factors That Affect the Initiation Reaction: Intrinsic Factors.- Factors That Affect the Initiation Reaction: Extrinsic Factors.- Models for the Mechanism of RNA Chain Initiation: Some Simple Models Do Not Account for What Is Known.- Models for the Mechanism of RNA Chain Initiation-Models Based on Recent Models for RNA Chain Elongation.- 3. Transcription Termination and Its Control.- Termination.- Antitermination.- 4. Codon Context, Translational Step-Times and Attenuation.- Overview.- Attenuation.- Codon Context and Translational Efficiency.- Effects of Codon Pair Bias on Translational Step-Times.- Discussion.- 5. Control by Antisense RNA.- Antisense RNAs Control Diverse Biological Functions.- Antisense RNAs Control Gene Expression at Many Different Post-Transcriptional Levels.- Antisense RNAs Pair to Their Target RNAs by Defined Mechanisms.- Overview.- 6. Translational Control of Gene Expression in E. Coli and Bacteriophage.- Translation Initiation.- Translational Operators.- Translational Repressors.- Mechanisms of Control.- Translational Control and mRNA Processing and/or Degradation.- The Role of Translational Control in Growth Rate Regulation.- Conclusions and Perspectives.- 7. Effects of DNA Supercoiling on Gene Expression.- Synopsis.- The Dependence of Transcription on the Cellular Level of DNA Gyrase and DNA Topoisomerase I.- Mechanistic Considerations.- Supercoiling of the DNA Template by Transcription.- Concluding Remarks.- 8. The HU and IHF Proteins: Accessory Factors for Complex Protein-DNA Assemblies.- Perspective.- Structure.- Interaction with Nucleic Acids.- Control of Intracellular Concentration and Activity.- Participation of IHF and HU in Well-Characterized Biochemical Processes.- Unfinished Business.- 9. The lac and gal Operons Today.- The lac and gal Operons Encode Enzymes of a Continuous Biochemical Pathway.- The Regulatory Circuits and Their Components.- Modulation of Promoters by cAMP*CRP.- Control of P2 by UTP in gal.- Natural Polarity.- Negative Control by Repressor-Operator Interactions.- Epilogue.- 10. The Maltose System.- and Scope.- The Positive Transcriptional Activator MalT.- The Maltose/Maltodextrin Transport System.- The Enzymes of the Maltose System.- Nonclassical Regulatory Phenomena.- Perspectives.- 11. The Phosphoenolpyruvate-Dependent Carbohydrate: Phosphotransferase System (PTS) and Control of Carbon Source Utilization.- Regulatory Phenomena Related to Carbon Source Utilization.- Bacterial Transport Systems and Global Regulatory Networks Form a Unit.- The Bacterial PTS Is a Transport and Signal Transduction System.- IIAGlc of the PTS Is Central to Carbon Catabolite Repression.- IIAGlc, the Regulation of Adenylate Cyclase Activity and of Intracellular cAMP Levels.- Not Only cAMP Levels, but Also CRP Levels Are Essential in Catabolite Repression.- IIAGlc and Inducer Exclusion.- Catabolite Repression and Inducer Exclusion Act in Concert.- Carbon Catabolite Repression through PTS-Control Is Part of a Stimulon.- Concluding Remarks.- 12. The Cap Modulon.- The Long History of CAP.- Cyclic AMP and Gene Expression.- CAP as a Global Regulator: The CAP Modulon.- CAP Binding at Target Promoters and Structural Studies.- Activation by CAP at "Simple"CRP.- Control of P2 by UTP in gal.- Natural Polarity.- Negative Control by Repressor-Operator Interactions.- Epilogue.- 10. The Maltose System.- and Scope.- The Positive Transcriptional Activator MalT.- The Maltose/Maltodextrin Transport System.- The Enzymes of the Maltose System.- Nonclassical Regulatory Phenomena.- Perspectives.- 11. The Phosphoenolpyruvate-Dependent Carbohydrate: Phosphotransferase System (PTS) and Control of Carbon Source Utilization.- Regulatory Phenomena Related to Carbon Source Utilization.- Bacterial Transport Systems and Global Regulatory Networks Form a Unit.- The Bacterial PTS Is a Transport and Signal Transduction System.- IIAGlc of the PTS Is Central to Carbon Catabolite Repression.- IIAGlc, the Regulation of Adenylate Cyclase Activity and of Intracellular cAMP Levels.- Not Only cAMP Levels, but Also CRP Levels Are Essential in Catabolite Repression.- IIAGlc and Inducer Exclusion.- Catabolite Repression and Inducer Exclusion Act in Concert.- Carbon Catabolite Repression through PTS-Control Is Part of a Stimulon.- Concluding Remarks.- 12. The Cap Modulon.- The Long History of CAP.- Cyclic AMP and Gene Expression.- CAP as a Global Regulator: The CAP Modulon.- CAP Binding at Target Promoters and Structural Studies.- Activation by CAP at "Simple" Promoters.- Activation by CAP at Complex Promoters.- CAP as a Repressor and a Co-Repressor.- CAP: Paradigm or Artifact?.- 13. Regulation of Nitrogen Assimilation.- The glnALG(glnA ntrBC) Operon.- The ?54-Dependent Promoter.- Transcriptional Enhancers.- Phosphorylation of NRI.- NRI/NRII as Two-Component Paradigm.- Activation of Transcription.- Response to Nitrogen Availability.- 14. History of the Pho System.- 15. Are the Multiple Signal Transduction Pathways of the Pho Regulon Due to Cross Talk or Cross Regulation?.- Genes for Pi Control of the Pho Regulon.- Transmembrane Signaling by Environmental Pi.- Genes for Pi Independent Controls of the Pho Regulon.- Activation by CreC and Acetyl Phosphate.- Cross Talk, Cross Regulation and a Hypothesis.- Is There Evidence for Cross Regulation?.- Overview and Prospects for Future Studies.- 16. The FNR Modulon and FNR-Regulated Gene Expression.- The Metabolic Arena.- The FNR Modulon.- The FNR Protein and Relationships with CAP.- The DNA-Binding Specificity of FNR.- In Vitro Transcription Activation and Repression.- Transcriptional Organization of Representative Promoters.- Potential FNR Contacts with RNA Polymerase and DNA-Bending.- The Mystery of Redox-Sensing.- Structural and Functional Homologs of FNR.- Concluding Remarks.- 17. The NAR Modulon Systems: Nitrate and Nitrite Regulation of Anaerobic Gene Expression.- Anaerobic Respiration.- The Characterization of the Nar Regulatory System.- Dual Two-Component Regulatory Systems.- The Role of Nitrite in the Nar Regulatory System.- The Sensor Proteins.- The Response Regulators.- Indirect Nitrate Regulation of Gene Expression.- Concluding Remarks.- 18. Regulation of Aerobic and Anaerobic Metabolism by the Arc System.- Identification of the arc Genes.- In Vivo Studies of arc Mutants.- In Vitro Phosphorylation Studies.- The Arc Modulon.- ArcA DNA Binding.- The Arc Stimulus.- Future Studies.- 19. The Porin Regulon: A Paradigm for the Two-Component Regulatory Systems.- Background.- The History of Porin Regulation.- The Structure of the ompB Locus.- The Structure of the ompF and ompC Genes.- The Roles of OmpR and EnvZ.- Phosphorylation and Signal Transduction.- Summary and Conclusions.- 20. The Leucine\Lrp Regulon.- The Leucine-Responsive Regulatory Protein.- Regulation of Lrp Synthesis.- Target Operons of Lrp and Mutant Phenotypes.- Lrp as a Chromosome Organizer.- Molecular Aspects of Lrp Interactions at Individual Promoters.- 21. Adaptive responses to Oxidative Stress: The soxRS and oxyR Regulons.- Reactive Oxygen Species.- Antioxidant Defenses.- Oxidative Stress.- Global Responses to Oxidative Stress.- The soxRS Regulon.- The oxyR Regulon.- Control of Antibiotic Resistance Genes.- 22. The SOS Regulatory System.- and Current Regulatory Model.- Development of the SOS Model.- Recent Developments.- Behavior of the SOS Gene Regulatory Circuitry.- Future Prospects.- 23. Heat Shock Regulation.- Properties of Important Heat Shock Proteins.- Regulation of the ?32-Promoted Heat Shock Response.- A Second Heat Shock Regulon.- The ?54-Promoted Stress Response.- Heat Shock or Stress Responses in Other Eubacteria.- 24. Roles for Energy-Dependent Proteases in Regulatory Cascades.- The Proteases and Their Targets.- Summary and General Conclusions.- 25. Control of rRNA and Ribosome Synthesis.- rRNA Gene Organization.- High Activity of rRNA Synthesis Rates.- Stringent Control.- Growth Rate Dependent Control.- Additional Considerations.- Conclusion and Future Prospects.- 26. Cell Division.- The Cell Division Process.- Essential Cell Division Genes.- Transcriptional Regulation of Cell Division Genes.- Translational Control.- Division Inhibitors.- Cell Division Inhibition by Mutations in Genes That Do Not Code for Cell Division Proteins.- Past, Present and Future.- 27. Regulation of Gene Expression in Stationary Phase.- The ?s Regulon.- RpoS Regulation.

Widespread genetic switches and toxicity resistance proteins for fluoride.

Abstract: Most riboswitches are metabolite-binding RNA structures located in bacterial messenger RNAs where they control gene expression. We have discovered a riboswitch class in many bacterial and archaeal species whose members are selectively triggered by fluoride but reject other small anions, including chloride. These fluoride riboswitches activate expression of genes that encode putative fluoride transporters, enzymes that are known to be inhibited by fluoride, and additional proteins of unknown function. Our findings indicate that most organisms are naturally exposed to toxic levels of fluoride and that many species use fluoride-sensing RNAs to control the expression of proteins that alleviate the deleterious effects of this anion.