21 research outputs found
Balancing noise and plasticity in eukaryotic gene expression
Coupling the control of expression stochasticity (noise) to the ability of
expression change (plasticity) can alter gene function and influence
adaptation. A number of factors, such as transcription re-initiation, strong
chromatin regulation or genome neighboring organization, underlie this
coupling. However, these factors do not necessarily combine in equivalent ways
and strengths in all genes. Can we identify then alternative architectures that
modulate in distinct ways the linkage of noise and plasticity? Here we first
show that strong chromatin regulation, commonly viewed as a source of coupling,
can lead to plasticity without noise. The nature of this regulation is relevant
too, with plastic but noiseless genes being subjected to general activators
whereas plastic and noisy genes experience more specific repression.
Contrarily, in genes exhibiting poor transcriptional control, it is
translational efficiency what separates noise from plasticity, a pattern
related to transcript length. This additionally implies that genome neighboring
organization -as modifier- appears only effective in highly plastic genes. In
this class, we confirm bidirectional promoters (bipromoters) as a configuration
capable to reduce coupling by abating noise but also reveal an important
trade-off, since bipromoters also decrease plasticity. This presents ultimately
a paradox between intergenic distances and modulation, with short intergenic
distances both associated and disassociated to noise at different plasticity
levels. Balancing the coupling among different types of expression variability
appears as a potential shaping force of genome regulation and organization.
This is reflected in the use of different control strategies at genes with
different sets of functional constraints
Correlation of Gut Microbiota Composition with Resistance to Experimental Autoimmune Encephalomyelitis in Rats
Multiple sclerosis is a chronic inflammatory disease of the central nervous system (CNS). It is widely accepted that autoimmune response against the antigens of the CNS is the essential pathogenic force in the disease. It has recently become increasingly appreciated that activated encephalitogenic cells tend to migrate toward gut associated lymphoid tissues (GALTs) and that interrupted balance between regulatory and inflammatory immunity within the GALT might have decisive role in the initiation and propagation of the CNS autoimmunity. Gut microbiota composition and function has the major impact on the balance in the GALT. Thus, our aim was to perform analyses of gut microbiota in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Albino Oxford (AO) rats that are highly resistant to EAE induction and Dark Agouti (DA) rats that develop EAE after mild immunization were compared for gut microbiota composition in different phases after EAE induction. Microbial analyses of the genus Lactobacillus and related lactic acid bacteria showed higher diversity of Lactobacillus spp. in EAE-resistant AO rats, while some members of Firmicutes and Proteobactene (Undibacterium oligocarboniphilum) were detected only in feces of DA rats at the peak of the disease (between 13 and 16 days after induction). Interestingly, in contrast to our previous study where Turicibacter sp. was found exclusively in non immunized AO, but not in DA rats, in this study it was detected in DA rats that remained healthy 16 days after induction, as well as in four of 12 DA rats at the peak of the disease. Similar observation was obtained for the members of Lachnospiraceae. Further, production of a typical regulatory cytokine interleukin-10 was compared in GALT cells of AO and DA rats, and higher production was observed in DA rats. Our data contribute to the idea that gut microbiota and GALT considerably influence multiple sclerosis pathogenesis
Suboptimal global transcriptional response increases the harmful effects of loss-of-function mutations
"Bioinformática con Ñ v1.0": a collaborative project of young Spanish scientists to write a complete book about Bioinformatics
Here we present a project aiming to provide specialized educational bibliography on Bioinformatics for Spanish speakers. The idea of writing a book in Spanish language covering the most important topics in the field of Bioinformatics was born in the XIth Spanish Symposium on Bioinformatics in Barcelona two years ago. Different scientists have been involved in the project, from senior scientists to PhD students from different countries. The book intends to be the beginning of an open project, where all the chapters are susceptible of being updated and new topics can be incorporated in future versions. Current book version can be accessed online at http://goo.gl/UYG0o7.Peer Reviewe
Antagonistic autoregulation speeds up a homogeneous response in Escherichia coli
By integrating positive and negative feedback loops, biological systems establish intricate gene
expression patterns linked to multistability, pulsing, and oscillations. This depends on the specific
characteristics of each interlinked feedback, and thus one would expect additional expression
programs to be found. Here, we investigate one such program associated with an antagonistic positive
and negative transcriptional autoregulatory motif derived from the multiple antibiotic resistance
(mar) system of Escherichia coli. We studied the dynamics of the system by combining a predictive
mathematical model with high-resolution experimental measures of the response both at the
population and single-cell level. We show that in this motif the weak positive autoregulation does not
slow down but rather enhances response speedup in combination with a strong negative feedback
loop. This balance of feedback strengths anticipates a homogeneous population phenotype, which we
corroborate experimentally. Theoretical analysis also emphasized the specific molecular properties
that determine the dynamics of the mar phenotype. More broadly, response acceleration could provide
a rationale for the presence of weak positive feedbacks in other biological scenarios exhibiting these
interlinked regulatory architectures.This work was partially funded by grants GV/2016/079 (GVA) and BFU2011-24691 (MINECO). We thank T. Miyashiro and M. Goulian for strains, T. Cordero and J. Rodriguez-Beltran for technical assistance, and J.L. Rosner and R.G. Martin for discussions on earlier studies on the mar system. We also thank L.D. Hurst for comments on a previous draft.Peer reviewe
Deconstructing a multiple antibiotic resistance regulation through the quantification of its input function
Many essential bacterial responses present complex transcriptional regulation of gene expression. To what extent can the study of
these responses substantiate the logic of their regulation? Here, we show how the input function of the genes constituting the
response, i.e., the information of how their transcription rates change as function of the signals acting on the regulators, can serve
as a quantitative tool to deconstruct the corresponding regulatory logic. To demonstrate this approach, we consider the multiple
antibiotic resistance (mar) response in Escherichia coli. By characterizing the input function of its representative genes in wild-type
and mutant bacteria, we recognize a dual autoregulation motif as main determinant of the response, which is further adjusted by
the interplay with other regulators. We show that basic attributes, like its reaction to a wide range of stress or its moderate
expression change, are associated with a strong negative autoregulation, while others, like the buffering of metabolic signals or the
lack of memory to previous stress, are related to a weak positive autoregulation. With a mathematical model of the input functions,
we identify some constraints fixing the molecular attributes of the regulators, and also notice the relevance of the bicystronic
architecture harboring the dual autoregulation that is unique in E. coli. The input function emerges then as a tool to disentangle the
rationale behind most of the attributes defining the mar phenotype. Overall, the present study supports the value of characterizing
input functions to deconstruct the complexity of regulatory architectures in prokaryotic and eukaryotic systems.
npj Systems Biology and Applications (2017) 3:30 ; doi:10.1038/s41540-017-0031-2Peer reviewe
Tolerance to NADH/NAD+ imbalance anticipates aging and anti-aging interventions
Summary: Redox couples coordinate cellular function, but the consequences of their imbalances are unclear. This is somewhat associated with the limitations of their experimental quantification. Here we circumvent these difficulties by presenting an approach that characterizes fitness-based tolerance profiles to redox couple imbalances using an in silico representation of metabolism. Focusing on the NADH/NAD+ redox couple in yeast, we demonstrate that reductive disequilibria generate metabolic syndromes comparable to those observed in cancer cells. The tolerance of yeast mutants to redox disequilibrium can also explain 30% of the variability in their experimentally measured chronological lifespan. Moreover, by predicting the significance of some metabolites to help stand imbalances, we correctly identify nutrients underlying mechanisms of pathology, lifespan-protecting molecules, or caloric restriction mimetics. Tolerance to redox imbalances becomes, in this way, a sound framework to recognize properties of the aging phenotype while providing a consistent biological rationale to assess anti-aging interventions
The Macroevolutionary Consequences of Niche Construction in Microbial Metabolism
Microorganisms display a stunning metabolic diversity. Understanding the origin of this diversity requires understanding how macroevolutionary processes such as innovation and diversification play out in the microbial world. Metabolic networks, which govern microbial resource use, can evolve through different mechanisms, e.g., horizontal gene transfer or de novo evolution of enzymes and pathways. This process is governed by a combination of environmental factors, selective pressures, and the constraints imposed by the genetic architecture of metabolic networks. In addition, many independent results hint that the process of niche construction, by which organisms actively modify their own and each other's niches and selective pressures, could play a major role in microbial innovation and diversification. Yet, the general principles by which niche construction shapes microbial macroevolutionary patterns remain largely unexplored. Here, we discuss several new hypotheses and directions, and suggest metabolic modeling methods that could allow us to explore large-scale empirical genotype-phenotype-(G-P)-environment spaces in order to study the macroevolutionary effects of niche construction. We hope that this short piece will further stimulate a systematic and quantitative characterization of macroevolutionary patterns and processes in microbial metabolism