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1.
Cell ; 186(22): 4803-4817.e13, 2023 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-37683634

RESUMO

Patescibacteria, also known as the candidate phyla radiation (CPR), are a diverse group of bacteria that constitute a disproportionately large fraction of microbial dark matter. Its few cultivated members, belonging mostly to Saccharibacteria, grow as epibionts on host Actinobacteria. Due to a lack of suitable tools, the genetic basis of this lifestyle and other unique features of Patescibacteira remain unexplored. Here, we show that Saccharibacteria exhibit natural competence, and we exploit this property for their genetic manipulation. Imaging of fluorescent protein-labeled Saccharibacteria provides high spatiotemporal resolution of phenomena accompanying epibiotic growth, and a transposon-insertion sequencing (Tn-seq) genome-wide screen reveals the contribution of enigmatic Saccharibacterial genes to growth on their hosts. Finally, we leverage metagenomic data to provide cutting-edge protein structure-based bioinformatic resources that support the strain Southlakia epibionticum and its corresponding host, Actinomyces israelii, as a model system for unlocking the molecular underpinnings of the epibiotic lifestyle.


Assuntos
Bactérias , Bactérias/classificação , Bactérias/genética , Bactérias/crescimento & desenvolvimento , Metagenoma , Metagenômica , Filogenia , Actinobacteria/fisiologia
2.
Cell ; 153(7): 1427-9, 2013 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-23791172

RESUMO

The prediction and verification of adaptive trajectories on macroevolutionary timescales have rarely been achieved for complex biological systems. Employing a model linking biological information at multiple scales, Heckmann et al. simulate likely sequences of evolutionary changes from C3 to C4 photosynthesis biochemistry.


Assuntos
Evolução Biológica , Fotossíntese , Plantas/genética
3.
Proc Natl Acad Sci U S A ; 119(8)2022 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-35165190

RESUMO

Mycobacterium tuberculosis has a lipid-rich cell envelope that is remodeled throughout infection to enable adaptation within the host. Few transcriptional regulators have been characterized that coordinate synthesis of mycolic acids, the major cell wall lipids of mycobacteria. Here, we show that the mycolic acid desaturase regulator (MadR), a transcriptional repressor of the mycolate desaturase genes desA1 and desA2, controls mycolic acid desaturation and biosynthesis in response to cell envelope stress. A madR-null mutant of M. smegmatis exhibited traits of an impaired cell wall with an altered outer mycomembrane, accumulation of a desaturated α-mycolate, susceptibility to antimycobacterials, and cell surface disruption. Transcriptomic profiling showed that enriched lipid metabolism genes that were significantly down-regulated upon madR deletion included acyl-coenzyme A (aceyl-CoA) dehydrogenases, implicating it in the indirect control of ß-oxidation pathways. Electromobility shift assays and binding affinities suggest a unique acyl-CoA pool-sensing mechanism, whereby MadR is able to bind a range of acyl-CoAs, including those with unsaturated as well as saturated acyl chains. MadR repression of desA1/desA2 is relieved upon binding of saturated acyl-CoAs of chain length C16 to C24, while no impact is observed upon binding of shorter chain and unsaturated acyl-CoAs. We propose this mechanism of regulation as distinct to other mycolic acid and fatty acid synthesis regulators and place MadR as the key regulatory checkpoint that coordinates mycolic acid remodeling during infection in response to host-derived cell surface perturbation.


Assuntos
Proteínas de Bactérias/metabolismo , Mycobacterium/metabolismo , Ácidos Micólicos/metabolismo , Racemases e Epimerases/metabolismo , Acil Coenzima A/metabolismo , Proteínas de Bactérias/fisiologia , Parede Celular/metabolismo , Ácidos Graxos Dessaturases/metabolismo , Ácidos Graxos/metabolismo , Metabolismo dos Lipídeos/fisiologia , Infecções por Mycobacterium , Mycobacterium tuberculosis/metabolismo , Racemases e Epimerases/fisiologia , Fatores de Transcrição/metabolismo
4.
Environ Sci Technol ; 58(16): 7056-7065, 2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38608141

RESUMO

The sources and sinks of nitrous oxide, as control emissions to the atmosphere, are generally poorly constrained for most environmental systems. Initial depth-resolved analysis of nitrous oxide flux from observation wells and the proximal surface within a nitrate contaminated aquifer system revealed high subsurface production but little escape from the surface. To better understand the environmental controls of production and emission at this site, we used a combination of isotopic, geochemical, and molecular analyses to show that chemodenitrification and bacterial denitrification are major sources of nitrous oxide in this subsurface, where low DO, low pH, and high nitrate are correlated with significant nitrous oxide production. Depth-resolved metagenomes showed that consumption of nitrous oxide near the surface was correlated with an enrichment of Clade II nitrous oxide reducers, consistent with a growing appreciation of their importance in controlling release of nitrous oxide to the atmosphere. Our work also provides evidence for the reduction of nitrous oxide at a pH of 4, well below the generally accepted limit of pH 5.


Assuntos
Óxido Nitroso , Óxido Nitroso/metabolismo , Bactérias/metabolismo , Oxirredutases/metabolismo , Desnitrificação
5.
Nucleic Acids Res ; 49(9): 4891-4906, 2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-33450011

RESUMO

Many of the gene regulatory processes of Plasmodium falciparum, the deadliest malaria parasite, remain poorly understood. To develop a comprehensive guide for exploring this organism's gene regulatory network, we generated a systems-level model of P. falciparum gene regulation using a well-validated, machine-learning approach for predicting interactions between transcription regulators and their targets. The resulting network accurately predicts expression levels of transcriptionally coherent gene regulatory programs in independent transcriptomic data sets from parasites collected by different research groups in diverse laboratory and field settings. Thus, our results indicate that our gene regulatory model has predictive power and utility as a hypothesis-generating tool for illuminating clinically relevant gene regulatory mechanisms within P. falciparum. Using the set of regulatory programs we identified, we also investigated correlates of artemisinin resistance based on gene expression coherence. We report that resistance is associated with incoherent expression across many regulatory programs, including those controlling genes associated with erythrocyte-host engagement. These results suggest that parasite populations with reduced artemisinin sensitivity are more transcriptionally heterogenous. This pattern is consistent with a model where the parasite utilizes bet-hedging strategies to diversify the population, rendering a subpopulation more able to navigate drug treatment.


Assuntos
Regulação da Expressão Gênica , Redes Reguladoras de Genes , Modelos Genéticos , Plasmodium falciparum/genética , Antimaláricos/farmacologia , Artemisininas/farmacologia , Resistência a Medicamentos/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Aprendizado de Máquina , Plasmodium falciparum/efeitos dos fármacos , Biologia de Sistemas , Transcrição Gênica
6.
Anaerobe ; 76: 102600, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35709938

RESUMO

Stickland amino acid fermentations occur primarily among species of Clostridia. An ancient form of metabolism, Stickland fermentations use amino acids as electron acceptors in the absence of stronger oxidizing agents and provide metabolic capabilities to support growth when other fermentable substrates, such as carbohydrates, are lacking. The reactions were originally described as paired fermentations of amino acid electron donors, such as the branched-chain amino acids, with recipients that include proline and glycine. We present a redox-focused view of Stickland metabolism following electron flow through metabolically diverse oxidative reactions and the defined-substrate reductase systems, including for proline and glycine, and the role of dual redox pathways for substrates such as leucine and ornithine. Genetic studies and Environment and Gene Regulatory Interaction Network (EGRIN) models for the pathogen Clostridioides difficile have improved our understanding of the regulation and metabolic recruitment of these systems, and their functions in modulating inter-species interactions within host-pathogen-commensal systems and uses in industrial and environmental applications.


Assuntos
Aminoácidos , Clostridium , Aminoácidos/metabolismo , Clostridium/metabolismo , Fermentação , Glicina/metabolismo , Prolina/metabolismo
7.
Mol Ecol ; 30(18): 4466-4480, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34342082

RESUMO

Corals from the northern Red Sea, in particular the Gulf of Aqaba (GoA), have exceptionally high bleaching thresholds approaching >5℃ above their maximum monthly mean (MMM) temperatures. These elevated thresholds are thought to be due to historical selection, as corals passed through the warmer Southern Red Sea during recolonization from the Arabian Sea. To test this hypothesis, we determined thermal tolerance thresholds of GoA versus central Red Sea (CRS) Stylophora pistillata corals using multi-temperature acute thermal stress assays to determine thermal thresholds. Relative thermal thresholds of GoA and CRS corals were indeed similar and exceptionally high (~7℃ above MMM). However, absolute thermal thresholds of CRS corals were on average 3℃ above those of GoA corals. To explore the molecular underpinnings, we determined gene expression and microbiome response of the coral holobiont. Transcriptomic responses differed markedly, with a strong response to the thermal stress in GoA corals and their symbiotic algae versus a remarkably muted response in CRS colonies. Concomitant to this, coral and algal genes showed temperature-induced expression in GoA corals, while exhibiting fixed high expression (front-loading) in CRS corals. Bacterial community composition of GoA corals changed dramatically under heat stress, whereas CRS corals displayed stable assemblages. We interpret the response of GoA corals as that of a resilient population approaching a tipping point in contrast to a pattern of consistently elevated thermal resistance in CRS corals that cannot further attune. Such response differences suggest distinct thermal tolerance mechanisms that may affect the response of coral populations to ocean warming.


Assuntos
Antozoários , Animais , Antozoários/genética , Recifes de Corais , Resposta ao Choque Térmico , Oceano Índico , Simbiose/genética
8.
Mol Syst Biol ; 15(3): e8584, 2019 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-30833303

RESUMO

The success of Mycobacterium tuberculosis (MTB) stems from its ability to remain hidden from the immune system within macrophages. Here, we report a new technology (Path-seq) to sequence miniscule amounts of MTB transcripts within up to million-fold excess host RNA Using Path-seq and regulatory network analyses, we have discovered a novel transcriptional program for in vivo mycobacterial cell wall remodeling when the pathogen infects alveolar macrophages in mice. We have discovered that MadR transcriptionally modulates two mycolic acid desaturases desA1/desA2 to initially promote cell wall remodeling upon in vitro macrophage infection and, subsequently, reduces mycolate biosynthesis upon entering dormancy. We demonstrate that disrupting MadR program is lethal to diverse mycobacteria making this evolutionarily conserved regulator a prime antitubercular target for both early and late stages of infection.


Assuntos
Antígenos de Bactérias/genética , Proteínas de Bactérias/genética , Redes Reguladoras de Genes , Interações Hospedeiro-Patógeno , Macrófagos/imunologia , Mycobacterium tuberculosis/fisiologia , Tuberculose/microbiologia , Adaptação Fisiológica , Animais , Antígenos de Bactérias/metabolismo , Proteínas de Bactérias/metabolismo , Parede Celular/metabolismo , Macrófagos/microbiologia , Camundongos , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/imunologia , Ácidos Micólicos/metabolismo , Biologia de Sistemas , Tuberculose/imunologia
9.
Mol Syst Biol ; 14(3): e7435, 2018 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-29581148

RESUMO

Transcriptional changes occur presymptomatically and throughout Huntington's disease (HD), motivating the study of transcriptional regulatory networks (TRNs) in HD We reconstructed a genome-scale model for the target genes of 718 transcription factors (TFs) in the mouse striatum by integrating a model of genomic binding sites with transcriptome profiling of striatal tissue from HD mouse models. We identified 48 differentially expressed TF-target gene modules associated with age- and CAG repeat length-dependent gene expression changes in Htt CAG knock-in mouse striatum and replicated many of these associations in independent transcriptomic and proteomic datasets. Thirteen of 48 of these predicted TF-target gene modules were also differentially expressed in striatal tissue from human disease. We experimentally validated a specific model prediction that SMAD3 regulates HD-related gene expression changes using chromatin immunoprecipitation and deep sequencing (ChIP-seq) of mouse striatum. We found CAG repeat length-dependent changes in the genomic occupancy of SMAD3 and confirmed our model's prediction that many SMAD3 target genes are downregulated early in HD.


Assuntos
Perfilação da Expressão Gênica/métodos , Redes Reguladoras de Genes , Doença de Huntington/genética , Proteína Smad3/genética , Animais , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Doença de Huntington/metabolismo , Camundongos , Mapas de Interação de Proteínas , Proteômica , Proteína Smad3/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
10.
Nucleic Acids Res ; 45(1): 255-270, 2017 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-27899637

RESUMO

Genomic robustness is the extent to which an organism has evolved to withstand the effects of deleterious mutations. We explored the extent of genomic robustness in budding yeast by genome wide dosage suppressor analysis of 53 conditional lethal mutations in cell division cycle and RNA synthesis related genes, revealing 660 suppressor interactions of which 642 are novel. This collection has several distinctive features, including high co-occurrence of mutant-suppressor pairs within protein modules, highly correlated functions between the pairs and higher diversity of functions among the co-suppressors than previously observed. Dosage suppression of essential genes encoding RNA polymerase subunits and chromosome cohesion complex suggests a surprising degree of functional plasticity of macromolecular complexes, and the existence of numerous degenerate pathways for circumventing the effects of potentially lethal mutations. These results imply that organisms and cancer are likely able to exploit the genomic robustness properties, due the persistence of cryptic gene and pathway functions, to generate variation and adapt to selective pressures.


Assuntos
Regulação Fúngica da Expressão Gênica , Redes Reguladoras de Genes , Genoma Fúngico , Proteínas de Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/genética , Divisão Celular , Biologia Computacional , Dosagem de Genes , Perfilação da Expressão Gênica , Genes Letais , Aptidão Genética , Mutação , RNA Polimerase II/genética , RNA Polimerase II/metabolismo , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo
11.
Proc Natl Acad Sci U S A ; 113(41): E6172-E6181, 2016 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-27681624

RESUMO

The regulation of host-pathogen interactions during Mycobacterium tuberculosis (Mtb) infection remains unresolved. MicroRNAs (miRNAs) are important regulators of the immune system, and so we used a systems biology approach to construct an miRNA regulatory network activated in macrophages during Mtb infection. Our network comprises 77 putative miRNAs that are associated with temporal gene expression signatures in macrophages early after Mtb infection. In this study, we demonstrate a dual role for one of these regulators, miR-155. On the one hand, miR-155 maintains the survival of Mtb-infected macrophages, thereby providing a niche favoring bacterial replication; on the other hand, miR-155 promotes the survival and function of Mtb-specific T cells, enabling an effective adaptive immune response. MiR-155-induced cell survival is mediated through the SH2 domain-containing inositol 5-phosphatase 1 (SHIP1)/protein kinase B (Akt) pathway. Thus, dual regulation of the same cell survival pathway in innate and adaptive immune cells leads to vastly different outcomes with respect to bacterial containment.


Assuntos
Imunidade Adaptativa/genética , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Imunidade Inata/genética , MicroRNAs/genética , Mycobacterium tuberculosis/imunologia , Tuberculose/genética , Tuberculose/imunologia , Animais , Sobrevivência Celular/genética , Sobrevivência Celular/imunologia , Citocinas/biossíntese , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Ativação Linfocitária , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/virologia , Camundongos , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/genética , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/virologia , Transcriptoma , Tuberculose/metabolismo
12.
PLoS Genet ; 12(12): e1006466, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27935966

RESUMO

Human genome-wide association studies (GWAS) have shown that genetic variation at >130 gene loci is associated with type 2 diabetes (T2D). We asked if the expression of the candidate T2D-associated genes within these loci is regulated by a common locus in pancreatic islets. Using an obese F2 mouse intercross segregating for T2D, we show that the expression of ~40% of the T2D-associated genes is linked to a broad region on mouse chromosome (Chr) 2. As all but 9 of these genes are not physically located on Chr 2, linkage to Chr 2 suggests a genomic factor(s) located on Chr 2 regulates their expression in trans. The transcription factor Nfatc2 is physically located on Chr 2 and its expression demonstrates cis linkage; i.e., its expression maps to itself. When conditioned on the expression of Nfatc2, linkage for the T2D-associated genes was greatly diminished, supporting Nfatc2 as a driver of their expression. Plasma insulin also showed linkage to the same broad region on Chr 2. Overexpression of a constitutively active (ca) form of Nfatc2 induced ß-cell proliferation in mouse and human islets, and transcriptionally regulated more than half of the T2D-associated genes. Overexpression of either ca-Nfatc2 or ca-Nfatc1 in mouse islets enhanced insulin secretion, whereas only ca-Nfatc2 was able to promote ß-cell proliferation, suggesting distinct molecular pathways mediating insulin secretion vs. ß-cell proliferation are regulated by NFAT. Our results suggest that many of the T2D-associated genes are downstream transcriptional targets of NFAT, and may act coordinately in a pathway through which NFAT regulates ß-cell proliferation in both mouse and human islets.


Assuntos
Diabetes Mellitus Tipo 2/genética , Insulina/genética , Fatores de Transcrição NFATC/genética , Animais , Proliferação de Células/genética , Mapeamento Cromossômico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Regulação da Expressão Gênica , Ligação Genética , Genoma , Estudo de Associação Genômica Ampla , Humanos , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Camundongos , Camundongos Obesos , Fatores de Transcrição NFATC/biossíntese , Regiões Promotoras Genéticas
13.
Environ Microbiol ; 20(12): 4197-4209, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30106224

RESUMO

Through complex interspecies interactions, microbial processes drive nutrient cycling and biogeochemistry. However, we still struggle to predict specifically which organisms, communities and biotic and abiotic processes are determining ecosystem function and how environmental changes will alter their roles and stability. While the tools to create such a predictive microbial ecology capability exist, cross-disciplinary integration of high-resolution field measurements, detailed laboratory studies and computation is essential. In this perspective, we emphasize the importance of pursuing a multiscale, systems approach to iteratively link ecological processes measured in the field to testable hypotheses that drive high-throughput laboratory experimentation. Mechanistic understanding of microbial processes gained in controlled lab systems will lead to the development of theory that can be tested back in the field. Using N2 O production as an example, we review the current status of field and laboratory research and layout a plausible path to the kind of integration that is needed to enable prediction of how N-cycling microbial communities will respond to environmental changes. We advocate for the development of realistic and predictive gene regulatory network models for environmental responses that extend from single-cell resolution to ecosystems, which is essential to understand how microbial communities involved in N2 O production and consumption will respond to future environmental conditions.


Assuntos
Ecossistema , Microbiologia Ambiental , Biologia de Sistemas , Monitoramento Ambiental/métodos , Ciclo do Nitrogênio , Óxido Nitroso/metabolismo
14.
Mol Syst Biol ; 13(3): 919, 2017 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-28320772

RESUMO

Managing trade-offs through gene regulation is believed to confer resilience to a microbial community in a fluctuating resource environment. To investigate this hypothesis, we imposed a fluctuating environment that required the sulfate-reducer Desulfovibrio vulgaris to undergo repeated ecologically relevant shifts between retaining metabolic independence (active capacity for sulfate respiration) and becoming metabolically specialized to a mutualistic association with the hydrogen-consuming Methanococcus maripaludis Strikingly, the microbial community became progressively less proficient at restoring the environmentally relevant physiological state after each perturbation and most cultures collapsed within 3-7 shifts. Counterintuitively, the collapse phenomenon was prevented by a single regulatory mutation. We have characterized the mechanism for collapse by conducting RNA-seq analysis, proteomics, microcalorimetry, and single-cell transcriptome analysis. We demonstrate that the collapse was caused by conditional gene regulation, which drove precipitous decline in intracellular abundance of essential transcripts and proteins, imposing greater energetic burden of regulation to restore function in a fluctuating environment.


Assuntos
Desulfovibrio vulgaris/crescimento & desenvolvimento , Mathanococcus/crescimento & desenvolvimento , Biologia de Sistemas/métodos , Desulfovibrio vulgaris/genética , Evolução Molecular Direcionada , Perfilação da Expressão Gênica , Mathanococcus/genética , Oxirredução , Fenótipo , Proteômica , Análise de Sequência de RNA , Análise de Célula Única , Sulfatos/metabolismo
15.
PLoS Comput Biol ; 13(5): e1005489, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28520713

RESUMO

Gene regulatory and metabolic network models have been used successfully in many organisms, but inherent differences between them make networks difficult to integrate. Probabilistic Regulation Of Metabolism (PROM) provides a partial solution, but it does not incorporate network inference and underperforms in eukaryotes. We present an Integrated Deduced And Metabolism (IDREAM) method that combines statistically inferred Environment and Gene Regulatory Influence Network (EGRIN) models with the PROM framework to create enhanced metabolic-regulatory network models. We used IDREAM to predict phenotypes and genetic interactions between transcription factors and genes encoding metabolic activities in the eukaryote, Saccharomyces cerevisiae. IDREAM models contain many fewer interactions than PROM and yet produce significantly more accurate growth predictions. IDREAM consistently outperformed PROM using any of three popular yeast metabolic models and across three experimental growth conditions. Importantly, IDREAM's enhanced accuracy makes it possible to identify subtle synthetic growth defects. With experimental validation, these novel genetic interactions involving the pyruvate dehydrogenase complex suggested a new role for fatty acid-responsive factor Oaf1 in regulating acetyl-CoA production in glucose grown cells.


Assuntos
Redes Reguladoras de Genes , Redes e Vias Metabólicas , Saccharomyces cerevisiae , Redes Reguladoras de Genes/genética , Redes Reguladoras de Genes/fisiologia , Redes e Vias Metabólicas/genética , Redes e Vias Metabólicas/fisiologia , Modelos Biológicos , Fenótipo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Biologia de Sistemas
16.
Nature ; 485(7399): 459-64, 2012 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-22622569

RESUMO

Cellular life emerged ∼3.7 billion years ago. With scant exception, terrestrial organisms have evolved under predictable daily cycles owing to the Earth's rotation. The advantage conferred on organisms that anticipate such environmental cycles has driven the evolution of endogenous circadian rhythms that tune internal physiology to external conditions. The molecular phylogeny of mechanisms driving these rhythms has been difficult to dissect because identified clock genes and proteins are not conserved across the domains of life: Bacteria, Archaea and Eukaryota. Here we show that oxidation-reduction cycles of peroxiredoxin proteins constitute a universal marker for circadian rhythms in all domains of life, by characterizing their oscillations in a variety of model organisms. Furthermore, we explore the interconnectivity between these metabolic cycles and transcription-translation feedback loops of the clockwork in each system. Our results suggest an intimate co-evolution of cellular timekeeping with redox homeostatic mechanisms after the Great Oxidation Event ∼2.5 billion years ago.


Assuntos
Ritmo Circadiano/fisiologia , Sequência Conservada , Evolução Molecular , Peroxirredoxinas/metabolismo , Sequência de Aminoácidos , Animais , Archaea/metabolismo , Bactérias/metabolismo , Biomarcadores/metabolismo , Domínio Catalítico , Relógios Circadianos/genética , Relógios Circadianos/fisiologia , Ritmo Circadiano/genética , Células Eucarióticas/metabolismo , Retroalimentação Fisiológica , Homeostase , Humanos , Modelos Biológicos , Dados de Sequência Molecular , Oxirredução , Peroxirredoxinas/química , Filogenia , Células Procarióticas/metabolismo , Biossíntese de Proteínas , Transcrição Gênica
17.
Environ Microbiol ; 19(8): 3059-3069, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28419704

RESUMO

Microbial populations can withstand, overcome and persist in the face of environmental fluctuation. Previously, we demonstrated how conditional gene regulation in a fluctuating environment drives dilution of condition-specific transcripts, causing a population of Desulfovibrio vulgaris Hildenborough (DvH) to collapse after repeatedly transitioning from sulfate respiration to syntrophic conditions with the methanogen Methanococcus maripaludis. Failure of the DvH to successfully transition contributed to the collapse of this model community. We investigated the mechanistic basis for loss of robustness by examining whether conditional gene regulation altered heterogeneity in gene expression across individual DvH cells. We discovered that robustness of a microbial population across environmental transitions was attributable to the retention of cells in two states that exhibited different condition-specific gene expression patterns. In our experiments, a population with disrupted conditional regulation successfully alternated between cell states. Meanwhile, a population with intact conditional regulation successfully switched between cell states initially, but collapsed after repeated transitions, possibly due to the high energy requirements of regulation. These results demonstrate that the survival of this entire model microbial community is dependent on the regulatory system's influence on the distribution of distinct cell states among individual cells within a clonal population.


Assuntos
Desulfovibrio vulgaris/crescimento & desenvolvimento , Mathanococcus/crescimento & desenvolvimento , Consórcios Microbianos/fisiologia , Interações Microbianas/fisiologia , Desulfovibrio vulgaris/genética , Metabolismo Energético/fisiologia , Oxirredução , Sulfatos/metabolismo
19.
Nucleic Acids Res ; 43(13): e87, 2015 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-25873626

RESUMO

The cMonkey integrated biclustering algorithm identifies conditionally co-regulated modules of genes (biclusters). cMonkey integrates various orthogonal pieces of information which support evidence of gene co-regulation, and optimizes biclusters to be supported simultaneously by one or more of these prior constraints. The algorithm served as the cornerstone for constructing the first global, predictive Environmental Gene Regulatory Influence Network (EGRIN) model for a free-living cell, and has now been applied to many more organisms. However, due to its computational inefficiencies, long run-time and complexity of various input data types, cMonkey was not readily usable by the wider community. To address these primary concerns, we have significantly updated the cMonkey algorithm and refactored its implementation, improving its usability and extendibility. These improvements provide a fully functioning and user-friendly platform for building co-regulated gene modules and the tools necessary for their exploration and interpretation. We show, via three separate analyses of data for E. coli, M. tuberculosis and H. sapiens, that the updated algorithm and inclusion of novel scoring functions for new data types (e.g. ChIP-seq and transcription factor over-expression [TFOE]) improve discovery of biologically informative co-regulated modules. The complete cMonkey2 software package, including source code, is available at https://github.com/baliga-lab/cmonkey2.


Assuntos
Regulação da Expressão Gênica , Software , Algoritmos , Carcinoma de Células Escamosas/genética , Imunoprecipitação da Cromatina , Escherichia coli/genética , Regulação Bacteriana da Expressão Gênica , Neoplasias Pulmonares/genética , Mycobacterium tuberculosis/genética , Regulon , Análise de Sequência de DNA , Fatores de Transcrição/metabolismo
20.
Proc Natl Acad Sci U S A ; 111(41): 14822-7, 2014 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-25267659

RESUMO

Many species have evolved to function as specialized mutualists, often to the detriment of their ability to survive independently. However, there are few, if any, well-controlled observations of the evolutionary processes underlying the genesis of new mutualisms. Here, we show that within the first 1,000 generations of initiating independent syntrophic interactions between a sulfate reducer (Desulfovibrio vulgaris) and a hydrogenotrophic methanogen (Methanococcus maripaludis), D. vulgaris frequently lost the capacity to grow by sulfate respiration, thus losing the primary physiological attribute of the genus. The loss of sulfate respiration was a consequence of mutations in one or more of three key genes in the pathway for sulfate respiration, required for sulfate activation (sat) and sulfate reduction to sulfite (apsA or apsB). Because loss-of-function mutations arose rapidly and independently in replicated experiments, and because these mutations were correlated with enhanced growth rate and productivity, gene loss could be attributed to natural selection, even though these mutations should significantly restrict the independence of the evolved D. vulgaris. Together, these data present an empirical demonstration that specialization for a mutualistic interaction can evolve by natural selection shortly after its origin. They also demonstrate that a sulfate-reducing bacterium can readily evolve to become a specialized syntroph, a situation that may have often occurred in nature.


Assuntos
Desulfovibrio vulgaris/genética , Evolução Molecular Direcionada , Mathanococcus/genética , Técnicas de Cocultura , Mutação/genética , Oxirredução , Fenótipo , Sulfatos/metabolismo , Simbiose
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