55 research outputs found
Probing the Limits to MicroRNA-Mediated Control of Gene Expression
No full textAccording to the ‘ceRNA hypothesis’, microRNAs (miRNAs) may act as mediators of an effective positive interaction between long coding or non-coding RNA molecules, carrying significant potential implications for a variety of biological processes. Here, inspired by recent work providing a quantitative description of small regulatory elements as information-convey- ing channels, we characterize the effectiveness of miRNA-mediated regulation in terms of the optimal information flow achievable between modulator (transcription factors) and target nodes (long RNAs). Our findings show that, while a sufficiently large degree of target dere- pression is needed to activate miRNA-mediated transmission, (a) in case of differential mechanisms of complex processing and/or transcriptional capabilities, regulation by a post- transcriptional miRNA-channel can outperform that achieved through direct transcriptional control; moreover, (b) in the presence of large populations of weakly interacting miRNA mol- ecules the extra noise coming from titration disappears, allowing the miRNA-channel to pro- cess information as effectively as the direct channel. These observations establish the limits of miRNA-mediated post-transcriptional cross-talk and suggest that, besides providing a degree of noise buffering, this type of control may be effectively employed in cells both as a failsafe mechanism and as a preferential fine tuner of gene expression, pointing to the spe- cific situations in which each of these functionalities is maximized
A scalable algorithm to explore the Gibbs energy landscape of genome-scale metabolic networks
No full textThe integration of various types of genomic data into predictive models of biological networks is one of the main challenges currently faced by computational biology. Constraint-based models in particular play a key role in the attempt to obtain a quantitative understanding of cellular metabolism at genome scale. In essence, their goal is to frame the metabolic capabilities of an organism based on minimal assumptions that describe the steady states of the underlying reaction network via suitable stoichiometric constraints, specifically mass balance and energy balance (i.e. thermodynamic feasibility). The implementation of these requirements to generate viable configurations of reaction fluxes and/or to test given flux profiles for thermodynamic feasibility can however prove to be computationally intensive. We propose here a fast and scalable stoichiometry-based method to explore the Gibbs energy landscape of a biochemical network at steady state. The method is applied to the problem of reconstructing the Gibbs energy landscape underlying metabolic activity in the human red blood cell, and to that of identifying and removing thermodynamically infeasible reaction cycles in the Escherichia coli metabolic network (iAF1260). In the former case, we produce consistent predictions for chemical potentials (or log-concentrations) of intracellular metabolites; in the latter, we identify a restricted set of loops (23 in total) in the periplasmic and cytoplasmic core as the origin of thermodynamic infeasibility in a large sample (106) of flux configurations generated randomly and compatibly with the prior information available on reaction reversibility. © 2012 De Martino et al
MicroRNAs as a Selective Channel of Communication between Competing RNAs: a Steady-State Theory
No full textAbstractIt has recently been suggested that the competition for a finite pool of microRNAs (miRNA) gives rise to effective interactions among their common targets (competing endogenous RNAs or ceRNAs) that could prove to be crucial for posttranscriptional regulation. We have studied a minimal model of posttranscriptional regulation where the emergence and the nature of such interactions can be characterized in detail at steady state. Sensitivity analysis shows that binding free energies and repression mechanisms are the key ingredients for the cross-talk between ceRNAs to arise. Interactions emerge in specific ranges of repression values, can be symmetrical (one ceRNA influences another and vice versa) or asymmetrical (one ceRNA influences another but not the reverse), and may be highly selective, while possibly limited by noise. In addition, we show that nontrivial correlations among ceRNAs can emerge in experimental readouts due to transcriptional fluctuations even in the absence of miRNA-mediated cross-talk
Implementing preconception expanded carrier screening in a universal health care system: A model-based cost-effectiveness analysis
No full textPurpose: The limited evidence available on the cost-effectiveness (CE) of expanded carrier screening (ECS) prevents its widespread use in most countries, including Italy. Herein, we aimed to estimate the CE of three ECS panels (i.e., American College of Medical Genetics and Genomics (ACMG) Tier 1 screening; "Focused Screening", testing 15 severe highly penetrant conditions, and ACMG Tier 3 screening) compared to no screening, the health care model currently adopted in Italy. Methods: The reference population consisted of Italian couples seeking pregnancy with no increased personal/familial genetic risk. The CE model was developed from the perspective of the Italian universal health-care system and based on the following assumptions: 100% sensitivity of investigated screening strategies; 77% intervention rate of at-risk couples (ARCs); no risk to conceive an affected child by risk-averse couples opting for medical interventions. Results: The incremental CE ratios (ICER) generated by comparing each genetic screening panel with no screening were: -14,875±1,208€/life years gained (LYG) for ACMG1S, -106,863±2,379€/LYG for Focused Screening and -47,277±1,430€/LYG for ACMG3S. ACMG1S and Focused Screening were dominated by ACMG3S. The parameter uncertainty did not significantly affect the outcome of the analyses. Conclusion: From a universal health care system perspective, all the three ECS panels considered in the study would be more cost-effective than no screening
Molecular tools for the genomic assessment of oocyte's reproductive competence
No full textThe most important factor associated with oocytes' developmental competence has been widely identified as the presence of chromosomal abnormalities. However, growing application of genome-wide sequencing (GS) in population diagnostics has enabled the identification of multifactorial genetic predispositions to sub-lethal pathologies, including those affecting IVF outcomes and reproductive fitness. Indeed, GS analysis in families with history of isolated infertility has recently led to the discovery of new genes and variants involved in specific human infertility endophenotypes that impact the availability and the functionality of female gametes by altering unique mechanisms necessary for oocyte maturation and early embryo development. Ongoing advancements in analytical and bioinformatic pipelines for the study of the genetic determinants of oocyte competence may provide the biological evidence required not only for improving the diagnosis of isolated female infertility but also for the development of novel preventive and therapeutic approaches for reproductive failure. Here, we provide an updated discussion and review of the progresses made in preconception genomic medicine in the identification of genetic factors associated with oocyte availability, function, and competence
Effect of the 3D Artificial Nichoid on the Morphology and Mechanobiological Response of Mesenchymal Stem Cells Cultured In Vitro
No full textStem cell fate and behavior are affected by the bidirectional communication of cells and their local microenvironment (the stem cell niche), which includes biochemical cues, as well as physical and mechanical factors. Stem cells are normally cultured in conventional two-dimensional monolayer, with a mechanical environment very different from the physiological one. Here, we compare culture of rat mesenchymal stem cells on flat culture supports and in the "Nichoid", an innovative three-dimensional substrate micro-engineered to recapitulate the architecture of the physiological niche in vitro. Two versions of the culture substrates Nichoid (single-layered or "2D Nichoid" and multi-layered or "3D Nichoid") were fabricated via two-photon laser polymerization in a biocompatible hybrid organic-inorganic photoresist (SZ2080). Mesenchymal stem cells, isolated from rat bone marrow, were seeded on flat substrates and on 2D and 3D Nichoid substrates and maintained in culture up to 2 weeks. During cell culture, we evaluated cell morphology, proliferation, cell motility and the expression of a panel of 89 mesenchymal stem cells' specific genes, as well as intracellular structures organization. Our results show that mesenchymal stem cells adhered and grew in the 3D Nichoid with a comparable proliferation rate as compared to flat substrates. After seeding on flat substrates, cells displayed large and spread nucleus and cytoplasm, while cells cultured in the 3D Nichoid were spatially organized in three dimensions, with smaller and spherical nuclei. Gene expression analysis revealed the upregulation of genes related to stemness and to mesenchymal stem cells' features in Nichoid-cultured cells, as compared to flat substrates. The observed changes in cytoskeletal organization of cells cultured on 3D Nichoids were also responsible for a different localization of the mechanotransducer transcription factor YAP, with an increase of the cytoplasmic retention in cells cultured in the 3D Nichoid. This difference could be explained by alterations in the import of transcription factors inside the nucleus due to the observed decrease of mean nuclear pore diameter, by transmission electron microscopy. Our data show that 3D distribution of cell volume has a profound effect on mesenchymal stem cells structure and on their mechanobiological response, and highlight the potential use of the 3D Nichoid substrate to strengthen the potential effects of MSC in vitro and in vivo
RNA-Based Regulation: Dynamics and Response to Perturbations of Competing RNAs.
No full textThe observation that, through a titration mechanism, microRNAs (miRNAs) can act as mediators of effective interactions among their common targets (competing endogenous RNAs or ceRNAs) has brought forward the idea (i.e., the ceRNA hypothesis) that RNAs can regulate each other in extended cross-talk networks. Such an ability might play a major role in posttranscriptional regulation to shape a cell's protein repertoire. Recent work focusing on the emergent properties of the cross-talk networks has emphasized the high flexibility and selectivity that may be achieved at stationarity. On the other hand, dynamical aspects, possibly crucial on the relevant timescales, are far less clear. We have carried out a dynamical study of the ceRNA hypothesis on a model of posttranscriptional regulation. Sensitivity analysis shows that ceRNA cross-talk is dynamically extended, i.e., it may take place on timescales shorter than those required to achieve stationarity even in cases where no cross-talk occurs in the steady state, and is possibly amplified. In addition, in the case of large, transfection-like perturbations, the system may develop a strongly nonlinear, threshold response. Finally, we show that the ceRNA effect provides a very efficient way for a cell to achieve fast positive shifts in the level of a ceRNA when necessary. These results indicate that competition for miRNAs may indeed provide an elementary mechanism to achieve system-level regulatory effects on the transcriptome over physiologically relevant timescales. Copyright © 2014 Biophysical Society. Published by Elsevier Inc. All rights reserved
How Pairwise Coevolutionary Models Capture the Collective Residue Variability in Proteins?
No full textInternational audienc
Inverse statistical physics of protein sequences: a key issues review
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