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See detailModeling heterogeneity in the pluripotent state: A promising strategy for improving the efficiency and fidelity of stem cell differentiation
Espinosa Angarica, Vladimir UL; del Sol Mesa, Antonio UL

in BioEssays (2016), 38(8),

Pluripotency can be considered a functional characteristic of pluripotent stem cells (PSCs) populations and their niches, rather than a property of individual cells. In this view, individual cells within ... [more ▼]

Pluripotency can be considered a functional characteristic of pluripotent stem cells (PSCs) populations and their niches, rather than a property of individual cells. In this view, individual cells within the population independently adopt a variety of different expression states, maintained by different signaling, transcriptional, and epigenetics regulatory networks. In this review, we propose that generation of integrative network models from single cell data will be essential for getting a better understanding of the regulation of self-renewal and differentiation. In particular, we suggest that the identification of network stability determinants in these integrative models will provide important insights into the mechanisms mediating the transduction of signals from the niche, and how these signals can trigger differentiation. In this regard, the differential use of these stability determinants in subpopulation-specific regulatory networks would mediate differentiation into different cell fates. We suggest that this approach could offer a promising avenue for the development of novel strategies for increasing the efficiency and fidelity of differentiation, which could have a strong impact on regenerative medicine [less ▲]

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See detailExploring the Complete Mutational Space of the LDL receptor LA5 Domain Using Molecular Dynamics: Linking SNPs with Disease Phenotypes in Familial Hypercholesterolemia
Espinosa Angarica, Vladimir UL; Orozco, Modesto; Sancho, Javier

in Human Molecular Genetics (2016), 25(6), 1233-1246

Familial Hypercholesterolemia (FH), a genetic disorder with a prevalence of 0.2 %, represents a high risk factor to develop cardiovascular and cerebrovascular diseases. The majority and most severe FH ... [more ▼]

Familial Hypercholesterolemia (FH), a genetic disorder with a prevalence of 0.2 %, represents a high risk factor to develop cardiovascular and cerebrovascular diseases. The majority and most severe FH cases are associated to mutations in the receptor for Low Density Lipoproteins (LDL-r), but the molecular basis explaining the connection between mutation and phenotype is often unknown, which hinders early diagnosis and treatment of the disease. We have used atomistic simulations to explore the complete SNP mutational space (227 mutants) of the LA5 repeat, the key domain for interacting with LDL that is coded in the exon concentrating the highest number of mutations. Four clusters of mutants of different stability have been identified. The majority of the 50 FH known mutations (33) appear distributed in the unstable clusters, i.e. loss of conformational stability explains 2/3 of FH phenotypes. However, 1/3 of FH phenotypes (17 mutations) do not destabilize the LR5 repeat. Combining our simulations with available structural data from different laboratories, we have defined a consensus binding site for the interaction of the LA5 repeat with LDL-r partner proteins and have found that most (16) of the 17 stable FH mutations occur at binding site residues. Thus, LA5-associated FH arises from mutations that cause either loss of stability or a decrease in domain's binding affinity. Based on this finding we propose the likely phenotype of each possible SNP in the LA5 repeat and outline a procedure to make a full computational diagnosis for FH. [less ▲]

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See detailA differential network analysis approach for lineage specifier prediction in stem cell subpopulations
Okawa, Satoshi UL; Espinosa Angarica, Vladimir UL; Lemischka, Ihor et al

in Systems Biology and Applications (2015)

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See detailPrionScan: an online database of predicted prion domains in complete proteomes.
Espinosa Angarica, Vladimir UL; Angulo, Alfonso; Giner, Arturo et al

in BMC genomics (2014), 15

BACKGROUND: Prions are a particular type of amyloids related to a large variety of important processes in cells, but also responsible for serious diseases in mammals and humans. The number of ... [more ▼]

BACKGROUND: Prions are a particular type of amyloids related to a large variety of important processes in cells, but also responsible for serious diseases in mammals and humans. The number of experimentally characterized prions is still low and corresponds to a handful of examples in microorganisms and mammals. Prion aggregation is mediated by specific protein domains with a remarkable compositional bias towards glutamine/asparagine and against charged residues and prolines. These compositional features have been used to predict new prion proteins in the genomes of different organisms. Despite these efforts, there are only a few available data sources containing prion predictions at a genomic scale. DESCRIPTION: Here we present PrionScan, a new database of predicted prion-like domains in complete proteomes. We have previously developed a predictive methodology to identify and score prionogenic stretches in protein sequences. In the present work, we exploit this approach to scan all the protein sequences in public databases and compile a repository containing relevant information of proteins bearing prion-like domains. The database is updated regularly alongside UniprotKB and in its present version contains approximately 28000 predictions in proteins from different functional categories in more than 3200 organisms from all the taxonomic subdivisions. PrionScan can be used in two different ways: database query and analysis of protein sequences submitted by the users. In the first mode, simple queries allow to retrieve a detailed description of the properties of a defined protein. Queries can also be combined to generate more complex and specific searching patterns. In the second mode, users can submit and analyze their own sequences. CONCLUSIONS: It is expected that this database would provide relevant insights on prion functions and regulation from a genome-wide perspective, allowing researches performing cross-species prion biology studies. Our database might also be useful for guiding experimentalists in the identification of new candidates for further experimental characterization. [less ▲]

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See detailLow-density lipoprotein receptor is a calcium/magnesium sensor - role of LR4 and LR5 ion interaction kinetics in low-density lipoprotein release in the endosome.
Martinez-Olivan, Juan; Rozado-Aguirre, Zurine; Arias-Moreno, Xabier et al

in The FEBS journal (2014), 281(11), 2638-58

The low-density lipoprotein receptor (LDLR) captures circulating lipoproteins and delivers them in the endosome for degradation. Its function is essential for cholesterol homeostasis, and mutations in the ... [more ▼]

The low-density lipoprotein receptor (LDLR) captures circulating lipoproteins and delivers them in the endosome for degradation. Its function is essential for cholesterol homeostasis, and mutations in the LDLR are the major cause of familiar hypercholesterolemia. The release of LDL is usually attributed to endosome acidification. As the pH drops, the affinity of the LDLR/LDL complex is reduced, whereas the strength of a self-complex formed between two domains of the receptor (i.e. the LDL binding domain and the beta-propeller domain) increases. However, an alternative model states that, as a consequence of a drop in both pH and Ca2+ concentration, the LDLR binding domain is destabilized in the endosome, which weakens the LDLR/LDL complex, thus liberating the LDL particles. In the present study, we test a key underlying assumption of the second model, namely that the lipoprotein binding repeats of the receptor (specifically repeats 4 and 5, LR4 and LR5) rapidly sense endosomal changes in Ca2+ concentration. Our kinetic and thermodynamic analysis of Ca2+ and Mg2+ binding to LR4 and LR5, as well as to the tandem of the two (LR4-5), shows that both repeats spontaneously release Ca2+ in a time scale much shorter than endosomal delivery of LDL, thus acting as Ca2+ sensors that become unfolded under endosomal conditions. Our analysis additionally explains the lower Ca2+ affinity of repeat LR4, compared to LR5, as arising from a very slow Ca2+ binding reaction in the former, most likely related to the lower conformational stability of apolipoprotein LR4, compared to apolipoprotein LR5, as determined from thermal unfolding experiments and molecular dynamics simulations. [less ▲]

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See detailThe FurA regulon in Anabaena sp. PCC 7120: in silico prediction and experimental validation of novel target genes.
Gonzalez, Andres; Espinosa Angarica, Vladimir UL; Sancho, Javier et al

in Nucleic acids research (2014), 42(8), 4833-46

In the filamentous cyanobacterium Anabaena sp. PCC 7120, the ferric uptake regulator FurA functions as a global transcriptional regulator. Despite several analyses have focused on elucidating the FurA ... [more ▼]

In the filamentous cyanobacterium Anabaena sp. PCC 7120, the ferric uptake regulator FurA functions as a global transcriptional regulator. Despite several analyses have focused on elucidating the FurA-regulatory network, the number of target genes described for this essential transcription factor is limited to a handful of examples. In this article, we combine an in silico genome-wide predictive approach with experimental determinations to better define the FurA regulon. Predicted FurA-binding sites were identified upstream of 215 genes belonging to diverse functional categories including iron homeostasis, photosynthesis and respiration, heterocyst differentiation, oxidative stress defence and light-dependent signal transduction mechanisms, among others. The probabilistic model proved to be effective at discerning FurA boxes from non-cognate sequences, while subsequent electrophoretic mobility shift assay experiments confirmed the in vitro specific binding of FurA to at least 20 selected predicted targets. Gene-expression analyses further supported the dual role of FurA as transcriptional modulator that can act both as repressor and as activator. In either role, the in vitro affinity of the protein to its target sequences is strongly dependent on metal co-regulator and reducing conditions, suggesting that FurA couples in vivo iron homeostasis and the response to oxidative stress to major physiological processes in cyanobacteria. [less ▲]

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See detailDiscovering putative prion sequences in complete proteomes using probabilistic representations of Q/N-rich domains.
Espinosa Angarica, Vladimir UL; Ventura, Salvador; Sancho, Javier

in BMC genomics (2013), 14

BACKGROUND: Prion proteins conform a special class among amyloids due to their ability to transmit aggregative folds. Prions are known to act as infectious agents in neurodegenerative diseases in animals ... [more ▼]

BACKGROUND: Prion proteins conform a special class among amyloids due to their ability to transmit aggregative folds. Prions are known to act as infectious agents in neurodegenerative diseases in animals, or as key elements in transcription and translation processes in yeast. It has been suggested that prions contain specific sequential domains with distinctive amino acid composition and physicochemical properties that allow them to control the switch between soluble and beta-sheet aggregated states. Those prion-forming domains are low complexity segments enriched in glutamine/asparagine and depleted in charged residues and prolines. Different predictive methods have been developed to discover novel prions by either assessing the compositional bias of these stretches or estimating the propensity of protein sequences to form amyloid aggregates. However, the available algorithms hitherto lack a thorough statistical calibration against large sequence databases, which makes them unable to accurately predict prions without retrieving a large number of false positives. RESULTS: Here we present a computational strategy to predict putative prion-forming proteins in complete proteomes using probabilistic representations of prionogenic glutamine/asparagine rich regions. After benchmarking our predictive model against large sets of non-prionic sequences, we were able to filter out known prions with high precision and accuracy, generating prediction sets with few false positives. The algorithm was used to scan all the proteomes annotated in public databases for the presence of putative prion proteins. We analyzed the presence of putative prion proteins in all taxa, from viruses and archaea to plants and higher eukaryotes, and found that most organisms encode evolutionarily unrelated proteins with susceptibility to behave as prions. CONCLUSIONS: To our knowledge, this is the first wide-ranging study aiming to predict prion domains in complete proteomes. Approaches of this kind could be of great importance to identify potential targets for further experimental testing and to try to reach a deeper understanding of prions' functional and regulatory mechanisms. [less ▲]

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See detailStructure of RdxA--an oxygen-insensitive nitroreductase essential for metronidazole activation in Helicobacter pylori.
Martinez-Julvez, Marta; Rojas, Adriana L.; Olekhnovich, Igor et al

in The FEBS journal (2012), 279(23), 4306-17

The RdxA oxygen-insensitive nitroreductase of the human gastric pathogen Helicobacter pylori is responsible for the susceptibility of this organism to the redox active prodrug metronidazole [2-(2-methyl-5 ... [more ▼]

The RdxA oxygen-insensitive nitroreductase of the human gastric pathogen Helicobacter pylori is responsible for the susceptibility of this organism to the redox active prodrug metronidazole [2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethanol]. Loss-of-function mutations in rdxA are primarily responsible for resistance to this therapeutic. RdxA exhibits potent NADPH oxidase activity under aerobic conditions and metronidazole reductase activity under strictly anaerobic conditions. In the present study, we report the crystal structure of RdxA, which is a homodimer exhibiting domain swapping and containing two molecules of FMN bound at the dimer interface. We have found a gap between the side chain of Tyr47 and the isoalloxazine ring of FMN that appears to be appropriate for substrate binding. The structure does not include residues 97-128, which correspond to a locally unstable part of the NTR from Escherichia coli, and might be involved in cofactor binding. Comparison of H. pylori RdxA with other oxidoreductases of known structure suggests that RdxA may belong to a new subgroup of oxidoreductases in which a cysteine side chain close to the FMN cofactor could be involved in the reductive activity. In this respect, the mutation of C159 to A or S (C159A/S) has resulted in a loss of metronidazole reductase activity but not NADPH oxidase activity. The RdxA structure enables the interpretation of the many loss-of-function mutations described previously, including those affecting C159, a residue whose interaction with FMN is required for the nitroreduction of metronidazole. The present studies provide unique insights into the redox behaviour of the flavin in this key enzyme for metronidazole activation, including a potential use in gene therapy. DATABASE: Structural data have been deposited in the Protein Data Bank under accession number 3QDL. [less ▲]

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See detailProtein dynamics governed by interfaces of high polarity and low packing density.
Espinosa Angarica, Vladimir UL; Sancho, Javier

in PloS one (2012), 7(10), 48212

The folding pathway, three-dimensional structure and intrinsic dynamics of proteins are governed by their amino acid sequences. Internal protein surfaces with physicochemical properties appropriate to ... [more ▼]

The folding pathway, three-dimensional structure and intrinsic dynamics of proteins are governed by their amino acid sequences. Internal protein surfaces with physicochemical properties appropriate to modulate conformational fluctuations could play important roles in folding and dynamics. We show here that proteins contain buried interfaces of high polarity and low packing density, coined as LIPs: Light Interfaces of high Polarity, whose physicochemical properties make them unstable. The structures of well-characterized equilibrium and kinetic folding intermediates indicate that the LIPs of the corresponding native proteins fold late and are involved in local unfolding events. Importantly, LIPs can be identified using very fast and uncomplicated computational analysis of protein three-dimensional structures, which provides an easy way to delineate the protein segments involved in dynamics. Since LIPs can be retained while the sequences of the interacting segments diverge significantly, proteins could in principle evolve new functional features reusing pre-existing encoded dynamics. Large-scale identification of LIPS may contribute to understanding evolutionary constraints of proteins and the way protein intrinsic dynamics are encoded. [less ▲]

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See detailDesign and structure of an equilibrium protein folding intermediate: a hint into dynamical regions of proteins.
Ayuso-Tejedor, Sara; Espinosa Angarica, Vladimir UL; Bueno, Marta et al

in Journal of molecular biology (2010), 400(4), 922-34

Partly unfolded protein conformations close to the native state may play important roles in protein function and in protein misfolding. Structural analyses of such conformations which are essential for ... [more ▼]

Partly unfolded protein conformations close to the native state may play important roles in protein function and in protein misfolding. Structural analyses of such conformations which are essential for their fully physicochemical understanding are complicated by their characteristic low populations at equilibrium. We stabilize here with a single mutation the equilibrium intermediate of apoflavodoxin thermal unfolding and determine its solution structure by NMR. It consists of a large native region identical with that observed in the X-ray structure of the wild-type protein plus an unfolded region. Small-angle X-ray scattering analysis indicates that the calculated ensemble of structures is consistent with the actual degree of expansion of the intermediate. The unfolded region encompasses discontinuous sequence segments that cluster in the 3D structure of the native protein forming the FMN cofactor binding loops and the binding site of a variety of partner proteins. Analysis of the apoflavodoxin inner interfaces reveals that those becoming destabilized in the intermediate are more polar than other inner interfaces of the protein. Natively folded proteins contain hydrophobic cores formed by the packing of hydrophobic surfaces, while natively unfolded proteins are rich in polar residues. The structure of the apoflavodoxin thermal intermediate suggests that the regions of natively folded proteins that are easily responsive to thermal activation may contain cores of intermediate hydrophobicity. [less ▲]

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See detailComparison of DNA binding across protein superfamilies.
Contreras-Moreira, Bruno; Sancho, Javier; Espinosa Angarica, Vladimir UL

in Proteins (2010), 78(1), 52-62

Specific protein-DNA interactions are central to a wide group of processes in the cell and have been studied both experimentally and computationally over the years. Despite the increasing collection of ... [more ▼]

Specific protein-DNA interactions are central to a wide group of processes in the cell and have been studied both experimentally and computationally over the years. Despite the increasing collection of protein-DNA complexes, so far only a few studies have aimed at dissecting the structural characteristics of DNA binding among evolutionarily related proteins. Some questions that remain to be answered are: (a) what is the contribution of the different readout mechanisms in members of a given structural superfamily, (b) what is the degree of interface similarity among superfamily members and how this affects binding specificity, (c) how DNA-binding protein superfamilies distribute across taxa, and (d) is there a general or family-specific code for the recognition of DNA. We have recently developed a straightforward method to dissect the interface of protein-DNA complexes at the atomic level and here we apply it to study 175 proteins belonging to nine representative superfamilies. Our results indicate that evolutionarily unrelated DNA-binding domains broadly conserve specificity statistics, such as the ratio of indirect/direct readout and the frequency of atomic interactions, therefore supporting the existence of a set of recognition rules. It is also found that interface conservation follows trends that are superfamily-specific. Finally, this article identifies tendencies in the phylogenetic distribution of transcription factors, which might be related to the evolution of regulatory networks, and postulates that the modular nature of zinc finger proteins can explain its role in large genomes, as it allows for larger binding interfaces in a single protein molecule. [less ▲]

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See detailFrom sequence to dynamics: the effects of transcription factor and polymerase concentration changes on activated and repressed promoters.
Perez, Abel Gonzalez; Espinosa Angarica, Vladimir UL; Collado-Vides, Julio et al

in BMC molecular biology (2009), 10

BACKGROUND: The fine tuning of two features of the bacterial regulatory machinery have been known to contribute to the diversity of gene expression within the same regulon: the sequence of Transcription ... [more ▼]

BACKGROUND: The fine tuning of two features of the bacterial regulatory machinery have been known to contribute to the diversity of gene expression within the same regulon: the sequence of Transcription Factor (TF) binding sites, and their location with respect to promoters. While variations of binding sequences modulate the strength of the interaction between the TF and its binding sites, the distance between binding sites and promoters alter the interaction between the TF and the RNA polymerase (RNAP). RESULTS: In this paper we estimated the dissociation constants (K(d)) of several E. coli TFs in their interaction with variants of their binding sequences from the scores resulting from aligning them to Positional Weight Matrices. A correlation coefficient of 0.78 was obtained when pooling together sites for different TFs. The theoretically estimated K(d) values were then used, together with the dissociation constants of the RNAP-promoter interaction to analyze activated and repressed promoters. The strength of repressor sites -- i.e., the strength of the interaction between TFs and their binding sites -- is slightly higher than that of activated sites. We explored how different factors such as the variation of binding sequences, the occurrence of more than one binding site, or different RNAP concentrations may influence the promoters' response to the variations of TF concentrations. We found that the occurrence of several regulatory sites bound by the same TF close to a promoter -- if they are bound by the TF in an independent manner -- changes the effect of TF concentrations on promoter occupancy, with respect to individual sites. We also found that the occupancy of a promoter will never be more than half if the RNAP concentration-to-K(p) ratio is 1 and the promoter is subject to repression; or less than half if the promoter is subject to activation. If the ratio falls to 0.1, the upper limit of occupancy probability for repressed drops below 10%; a descent of the limits occurs also for activated promoters. CONCLUSION: The number of regulatory sites may thus act as a versatility-producing device, in addition to serving as a source of robustness of the transcription machinery. Furthermore, our results show that the effects of TF concentration fluctuations on promoter occupancy are constrained by RNAP concentrations. [less ▲]

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See detailImpact of Transcription Units rearrangement on the evolution of the regulatory network of gamma-proteobacteria.
Gonzalez Perez, Abel D.; Gonzalez Gonzalez, Evelyn; Espinosa Angarica, Vladimir UL et al

in BMC genomics (2008), 9

BACKGROUND: In the past years, several studies begun to unravel the structure, dynamical properties, and evolution of transcriptional regulatory networks. However, even those comparative studies that ... [more ▼]

BACKGROUND: In the past years, several studies begun to unravel the structure, dynamical properties, and evolution of transcriptional regulatory networks. However, even those comparative studies that focus on a group of closely related organisms are limited by the rather scarce knowledge on regulatory interactions outside a few model organisms, such as E. coli among the prokaryotes. RESULTS: In this paper we used the information annotated in Tractor_DB (a database of regulatory networks in gamma-proteobacteria) to calculate a normalized Site Orthology Score (SOS) that quantifies the conservation of a regulatory link across thirty genomes of this subclass. Then we used this SOS to assess how regulatory connections have evolved in this group, and how the variation of basic regulatory connection is reflected on the structure of the chromosome. We found that individual regulatory interactions shift between different organisms, a process that may be described as rewiring the network. At this evolutionary scale (the gamma-proteobacteria subclass) this rewiring process may be an important source of variation of regulatory incoming interactions for individual networks. We also noticed that the regulatory links that form feed forward motifs are conserved in a better correlated manner than triads of random regulatory interactions or pairs of co-regulated genes. Furthermore, the rewiring process that takes place at the most basic level of the regulatory network may be linked to rearrangements of genetic material within bacterial chromosomes, which change the structure of Transcription Units and therefore the regulatory connections between Transcription Factors and structural genes. CONCLUSION: The rearrangements that occur in bacterial chromosomes-mostly inversion or horizontal gene transfer events - are important sources of variation of gene regulation at this evolutionary scale. [less ▲]

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See detailPrediction of TF target sites based on atomistic models of protein-DNA complexes.
Espinosa Angarica, Vladimir UL; Perez, Abel Gonzalez; Vasconcelos, Ana T. et al

in BMC bioinformatics (2008), 9

BACKGROUND: The specific recognition of genomic cis-regulatory elements by transcription factors (TFs) plays an essential role in the regulation of coordinated gene expression. Studying the mechanisms ... [more ▼]

BACKGROUND: The specific recognition of genomic cis-regulatory elements by transcription factors (TFs) plays an essential role in the regulation of coordinated gene expression. Studying the mechanisms determining binding specificity in protein-DNA interactions is thus an important goal. Most current approaches for modeling TF specific recognition rely on the knowledge of large sets of cognate target sites and consider only the information contained in their primary sequence. RESULTS: Here we describe a structure-based methodology for predicting sequence motifs starting from the coordinates of a TF-DNA complex. Our algorithm combines information regarding the direct and indirect readout of DNA into an atomistic statistical model, which is used to estimate the interaction potential. We first measure the ability of our method to correctly estimate the binding specificities of eight prokaryotic and eukaryotic TFs that belong to different structural superfamilies. Secondly, the method is applied to two homology models, finding that sampling of interface side-chain rotamers remarkably improves the results. Thirdly, the algorithm is compared with a reference structural method based on contact counts, obtaining comparable predictions for the experimental complexes and more accurate sequence motifs for the homology models. CONCLUSION: Our results demonstrate that atomic-detail structural information can be feasibly used to predict TF binding sites. The computational method presented here is universal and might be applied to other systems involving protein-DNA recognition. [less ▲]

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See detailThe role of DNA-binding specificity in the evolution of bacterial regulatory networks.
Lozada-Chavez, Irma; Espinosa Angarica, Vladimir UL; Collado-Vides, Julio et al

in Journal of molecular biology (2008), 379(3), 627-43

Understanding the mechanisms by which transcriptional regulatory networks (TRNs) change through evolution is a fundamental problem.Here, we analyze this question using data from Escherichia coli and ... [more ▼]

Understanding the mechanisms by which transcriptional regulatory networks (TRNs) change through evolution is a fundamental problem.Here, we analyze this question using data from Escherichia coli and Bacillus subtilis, and find that paralogy relationships are insufficient to explain the global or local role observed for transcription factors (TFs) within regulatory networks. Our results provide a picture in which DNA-binding specificity, a molecular property that can be measured in different ways, is a predictor of the role of transcription factors. In particular, we observe that global regulators consistently display low levels of binding specificity, while displaying comparatively higher expression values in microarray experiments. In addition, we find a strong negative correlation between binding specificity and the number of co-regulators that help coordinate genetic expression on a genomic scale. A close look at several orthologous TFs,including FNR, a regulator found to be global in E. coli and local in B.subtilis, confirms the diagnostic value of specificity in order to understand their regulatory function, and highlights the importance of evaluating the metabolic and ecological relevance of effectors as another variable in the evolutionary equation of regulatory networks. Finally, a general model is presented that integrates some evolutionary forces and molecular properties,aiming to explain how regulons grow and shrink, as bacteria tune their regulation to increase adaptation. [less ▲]

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See detailTractor_DB (version 2.0): a database of regulatory interactions in gamma-proteobacterial genomes.
Perez, Abel Gonzalez; Espinosa Angarica, Vladimir UL; Vasconcelos, Ana Tereza R. et al

in Nucleic acids research (2007), 35(Database issue), 132-6

The version 2.0 of Tractor_DB is now accessible at its three international mirrors: www.bioinfo.cu/Tractor_DB, www.tractor.lncc.br and http://www.ccg.unam.mx/tractorDB. This database contains a collection ... [more ▼]

The version 2.0 of Tractor_DB is now accessible at its three international mirrors: www.bioinfo.cu/Tractor_DB, www.tractor.lncc.br and http://www.ccg.unam.mx/tractorDB. This database contains a collection of computationally predicted Transcription Factors' binding sites in gamma-proteobacterial genomes. These data should aid researchers in the design of microarray experiments and the interpretation of their results. They should also facilitate studies of Comparative Genomics of the regulatory networks of this group of organisms. In this paper we describe the main improvements incorporated to the database in the past year and a half which include incorporating information on the regulatory networks of 13-increasing to 30-new gamma-proteobacteria and developing a new computational strategy to complement the putative sites identified by the original weight matrix-based approach. We have also added dynamically generated navigation tabs to the navigation interfaces. Moreover, we developed a new interface that allows users to directly retrieve information on the conservation of regulatory interactions in the 30 genomes included in the database by navigating a map that represents a core of the known Escherichia coli regulatory network. [less ▲]

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See detailCross-talk between iron and nitrogen regulatory networks in anabaena (Nostoc) sp. PCC 7120: identification of overlapping genes in FurA and NtcA regulons.
Lopez-Gomollon, Sara; Hernandez, Jose A.; Pellicer, Silvia et al

in Journal of molecular biology (2007), 374(1), 267-81

Nitrogen signalling in cyanobacteria involves a complex network in which the availability of iron plays an important role. In the nitrogen-fixing cyanobacterium Anabaena sp. PCC 7120, iron uptake is ... [more ▼]

Nitrogen signalling in cyanobacteria involves a complex network in which the availability of iron plays an important role. In the nitrogen-fixing cyanobacterium Anabaena sp. PCC 7120, iron uptake is controlled by FurA, while NtcA is the master regulator of nitrogen metabolism and shows a mutual dependence with HetR in the first steps of heterocyst development. Expression of FurA is modulated by NtcA and it is enhanced in a hetR(-) background. Iron starvation in cells grown in the presence of combined nitrogen causes a moderate increase in the transcription of glnA that is more evident in a ntcA(-) background. Those results evidence a tight link between the reserves of iron and nitrogen metabolism that leads us to search for target genes potentially co-regulated by FurA and NtcA. Using a bioinformatic approach we have found a significant number of NtcA-regulated genes exhibiting iron boxes in their upstream regions. Our computational predictions have been validated using electrophoretic mobility shift assay (EMSA) analysis. These candidates for dual regulation are involved in different functions such as photosynthesis (i.e. psaL, petH, rbcL, isiA), heterocyst differentiation (i.e. xisA, hanA, prpJ, nifH), transcriptional regulation (several alternative sigma factors) or redox balance (i.e. trxA, ftrC, gor). The identification of common elements overlapping the NtcA and FurA regulons allows us to establish a previously unrecognized transcriptional regulatory connection between iron homeostasis, redox control and nitrogen metabolism. [less ▲]

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See detailComparative studies of transcriptional regulation mechanisms in a group of eight gamma-proteobacterial genomes.
Espinosa Angarica, Vladimir UL; Gonzalez, Abel D.; Vasconcelos, Ana T. et al

in Journal of molecular biology (2005), 354(1), 184-99

Experimental data on the Escherichia coli transcriptional regulation has enabled the construction of statistical models to predict new regulatory elements within its genome. Far less is known about the ... [more ▼]

Experimental data on the Escherichia coli transcriptional regulation has enabled the construction of statistical models to predict new regulatory elements within its genome. Far less is known about the transcriptional regulatory elements in other gamma-proteobacteria with sequenced genomes, so it is of great interest to conduct comparative genomic studies oriented to extracting biologically relevant information about transcriptional regulation in these less studied organisms using the knowledge from E. coli. In this work, we use the information stored in the TRACTOR_DB database to conduct a comparative study on the mechanisms of transcriptional regulation in eight gamma-proteobacteria and 38 regulons. We assess the conservation of transcription factors binding specificity across all the eight genomes and show a correlation between the conservation of a regulatory site and the structure of the transcription unit it regulates. We also find a marked conservation of site-promoter distances across the eight organisms and a correspondence of the statistical significance of co-occurrence of pairs of transcription factor binding sites in the regulatory regions, which is probably related to a conserved architecture of higher-order regulatory complexes in the organisms studied. The results obtained in this study using the information on transcriptional regulation in E. coli enable us to conclude that not only transcription factor-binding sites are conserved across related species but also several of the transcriptional regulatory mechanisms previously identified in E. coli. [less ▲]

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See detailTRACTOR_DB: a database of regulatory networks in gamma-proteobacterial genomes.
Gonzalez, Abel D.; Espinosa Angarica, Vladimir UL; Vasconcelos, Ana T. et al

in Nucleic acids research (2005), 33(Database issue), 98-102

Experimental data on the Escherichia coli transcriptional regulatory system has been used in the past years to predict new regulatory elements (promoters, transcription factors (TFs), TFs' binding sites ... [more ▼]

Experimental data on the Escherichia coli transcriptional regulatory system has been used in the past years to predict new regulatory elements (promoters, transcription factors (TFs), TFs' binding sites and operons) within its genome. As more genomes of gamma-proteobacteria are being sequenced, the prediction of these elements in a growing number of organisms has become more feasible, as a step towards the study of how different bacteria respond to environmental changes at the level of transcriptional regulation. In this work, we present TRACTOR_DB (TRAnscription FaCTORs' predicted binding sites in prokaryotic genomes), a relational database that contains computational predictions of new members of 74 regulons in 17 gamma-proteobacterial genomes. For these predictions we used a comparative genomics approach regarding which several proof-of-principle articles for large regulons have been published. TRACTOR_DB may be currently accessed at http://www.bioinfo.cu/Tractor_DB, http://www.tractor.lncc.br/ or at http://www.cifn.unam.mx/Computational_Genomics/tractorDB. Contact Email id is tractor@cifn.unam.mx. [less ▲]

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