Probing the limits to microRNA-mediated control of gene expression

According 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-conveying 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 derepression 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 molecules the extra noise coming from titration disappears, allowing the miRNA-channel to process 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 specific situations in which each of these functionalities is maximized.Comment: 16 page

ceRNA crosstalk stabilizes protein expression and affects the correlation pattern of interacting proteins

Gene expression is a noisy process and several mechanisms, both transcriptional and posttranscriptional, can stabilize protein levels in cells. Much work has focused on the role of miRNAs, showing in particular that miRNA-mediated regulation can buffer expression noise for lowly expressed genes. Here, using in silico simulations and mathematical modeling, we demonstrate that miRNAs can exert a much broader influence on protein levels by orchestrating competition-induced crosstalk between mRNAs. Most notably, we find that miRNA-mediated cross-talk (i) can stabilize protein levels across the full range of gene expression rates, and (ii) modifies the correlation pattern of co-regulated interacting proteins, changing the sign of correlations from negative to positive. The latter feature may constitute a potentially robust signature of the existence of RNA crosstalk induced by endogenous competition for miRNAs in standard cellular conditions

A Dynamical Model for the Transmembrane Potential Regulation by pH

Three physico-chemical cell parameters have been shown by the biologists to be of importance for understanding the cell behavior: the transmembrane potential (TMP) which modifies substantially the cell functional activity, the intracellular pHi whose dynamics influences a number of other ionic fluxes and, to a lesser extent, the cell volume. In this work we present a dynamical model for understanding how the pHi influences the TMP. In this model we consider the HCO3 − /Cl− and Na+/H+ exchangers as well as the bicarbonate/carbon dioxide buffering mechanism and also the ions conductance dependence to the intracellular pHi. We show that the conductances of the ions are the most important factors that have an impact on the TMP evolution and that the intracellular pHi controls the membrane ionic conductance. Therefore, our new dynamical model support the hypothesis that pHi regulates the TMP dynamics due its influence on membrane ionic conductances

Identification of region-specific astrocyte subtypes at single cell resolution

Astrocytes, a major cell type found throughout the central nervous system, have general roles in the modulation of synapse formation and synaptic transmission, blood-brain barrier formation, and regulation of blood flow, as well as metabolic support of other brain resident cells. Crucially, emerging evidence shows specific adaptations and astrocyte-encoded functions in regions, such as the spinal cord and cerebellum. To investigate the true extent of astrocyte molecular diversity across forebrain regions, we used single-cell RNA sequencing. Our analysis identifies five transcriptomically distinct astrocyte subtypes in adult mouse cortex and hippocampus. Validation of our data in situ reveals distinct spatial positioning of defined subtypes, reflecting the distribution of morphologically and physiologically distinct astrocyte populations. Our findings are evidence for specialized astrocyte subtypes between and within brain regions. The data are available through an online database (https://holt-sc.glialab.org/), providing a resource on which to base explorations of local astrocyte diversity and function in the brain.status: publishe

Astrocyte layers in the mammalian cerebral cortex revealed by a single-cell in situ transcriptomic map.

Although the cerebral cortex is organized into six excitatory neuronal layers, it is unclear whether glial cells show distinct layering. In the present study, we developed a high-content pipeline, the large-area spatial transcriptomic (LaST) map, which can quantify single-cell gene expression in situ. Screening 46 candidate genes for astrocyte diversity across the mouse cortex, we identified superficial, mid and deep astrocyte identities in gradient layer patterns that were distinct from those of neurons. Astrocyte layer features, established in the early postnatal cortex, mostly persisted in adult mouse and human cortex. Single-cell RNA sequencing and spatial reconstruction analysis further confirmed the presence of astrocyte layers in the adult cortex. Satb2 and Reeler mutations that shifted neuronal post-mitotic development were sufficient to alter glial layering, indicating an instructive role for neuronal cues. Finally, astrocyte layer patterns diverged between mouse cortical regions. These findings indicate that excitatory neurons and astrocytes are organized into distinct lineage-associated laminae.The study was supported by the Paul G. Allen Foundation Distinguished Investigator Program (E.M.U. and D.H.R.), the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (D.H.R., D.G. and G. C.), BRAIN initiative (1U01 MH105991 to D.G.) and National Institute of Health (1R01 MH109912 to D.G.; P01NS08351 to D.H.R.), National Institute of Health Research and the European Union Seventh Framework (to P.H.), NINDS Informatics Center for Neurogenetics and Neurogenomics (P30 NS062691 to G.C.), Wellcome Trust core support (M.H., O.A.B.), European Research Council (281961 to M.G.H.), Fonds Wetenschappelijk Onderzoek (G066715N and 1523014N to M.G.H.), Stichting Alzheimer Onderzoek (S#16025 to M.G.H.) and VIB Institutional Support and Tech Watch funding (to M.G.H.), Howard Hughes Medical Institute and the Wellcome Trust (to D.H.R.)

A Dynamical Model for the Transmembrane Potential Regulation by pH

Three physico-chemical cell parameters have been shown by the biologists to be of importance for understanding the cell behavior: the transmembrane potential (TMP) which modifies substantially the cell functional activity, the intracellular pHi whose dynamics influences a number of other ionic fluxes and, to a lesser extent, the cell volume. In this work we present a dynamical model for understanding how the pHi influences the TMP. In this model we consider the HCO3 − /Cl− and Na+/H+ exchangers as well as the bicarbonate/carbon dioxide buffering mechanism and also the ions conductance dependence to the intracellular pHi. We show that the conductances of the ions are the most important factors that have an impact on the TMP evolution and that the intracellular pHi controls the membrane ionic conductance. Therefore, our new dynamical model support the hypothesis that pHi regulates the TMP dynamics due its influence on membrane ionic conductances

No Longer Underappreciated: The Emerging Concept of Astrocyte Heterogeneity in Neuroscience

Astrocytes are ubiquitous in the central nervous system (CNS). These cells possess thousands of individual processes, which extend out into the neuropil, interacting with neurons, other glia and blood vessels. Paralleling the wide diversity of their interactions, astrocytes have been reported to play key roles in supporting CNS structure, metabolism, blood-brain-barrier formation and control of vascular blood flow, axon guidance, synapse formation and modulation of synaptic transmission. Traditionally, astrocytes have been studied as a homogenous group of cells. However, recent studies have uncovered a surprising degree of heterogeneity in their development and function, in both the healthy and diseased brain. A better understanding of astrocyte heterogeneity is urgently needed to understand normal brain function, as well as the role of astrocytes in response to injury and disease

Channel capacities as a function of the target’s degree of derepression (AOV).

<p>The black curve corresponds to direct transcriptional control in absence of miRNAs, while the blue curve describes the behavior of the miRNA-mediated post-transcriptional channel. For both channels . The predicted maximal MI in the Poissonian limit given in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004715#pcbi.1004715.s004" target="_blank">S1 Text</a> is shown as a dashed line. Values of the kinetic parameters are reported in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004715#pcbi.1004715.t001" target="_blank">Table 1</a>.</p