miRviewer: a multispecies microRNA homologous viewer

<p>Abstract</p> <p>Background</p> <p>MicroRNAs (miRNAs) are short non-coding RNAs that regulate gene expression via binding to the 3' ends of mRNAs. MiRNAs have been associated with many cellular events ascertaining their central role in gene regulation. In order to better understand miRNAs of interest it is of utmost importance to learn about the genomic conservation of these genes.</p> <p>Findings</p> <p>The miRviewer web-server, presented here, encompasses all known miRNAs of currently fully annotated animal genomes in a visual 'birds-eye' view representation. miRviewer provides a graphical outlook of the current miRNA world together with sequence alignments and secondary structures of each miRNA. As a test case we experimentally examined the expression of several miRNAs in various animals.</p> <p>Conclusions</p> <p>miRviewer completes the homologous miRNA space with hundreds of unreported miRNAs and is available at: <url>http://people.csail.mit.edu/akiezun/miRviewer</url></p

Versatility of MicroRNA Biogenesis

MicroRNAs (miRNAs) are short single-stranded RNA molecules that regulate gene expression. MiRNAs originate from large primary (pri) and precursor (pre) transcripts that undergo various processing steps along their biogenesis pathway till they reach their mature and functional form. It is not clear, however, whether all miRNAs are processed similarly. Here we show that the ratio between pre-miRNA and mature miRNA forms varies between different miRNAs. Moreover, over-expression of several factors involved in miRNA biogenesis, including Exportin-5, Drosha, NF90a, NF45 and KSRP, displayed bidirectional effects on pre/mature miRNA ratios, suggesting their intricate biogenesis sensitivity. In an attempt to identify additional factors that might explain the versatility in miRNA biogenesis we have analyzed the contribution of two hnRNP family members, hnRNPH1 and hnRNPR. Knock-down or over-expression of these genes suggested that hnRNPR inhibits, whereas hnRNPH1 facilitates, miRNA processing. Overall, our results emphasize that miRNA biogenesis is versatile

Multi-omics analysis identifies mitochondrial pathways associated with anxiety-related behavior

Author summary Genetic and environmental factors contribute to the etiology of psychiatric diseases but the underlying mechanisms are poorly understood. Chronic psychosocial stress is a well-known risk factor for anxiety disorders. To identify biological pathways involved in psychosocial stress-induced anxiety and resilience to it, we used a well-characterized mouse model of chronic social defeat stress (CSDS) in two inbred mouse strains, C57BL/6NCrl (B6) and DBA/2NCrl (D2), which differ in their susceptibility to stress. We focused on the bed nucleus of the stria terminalis, a key brain region behind stress-response and anxiety, and carried out genome-wide analysis of mRNA, and miRNA expression, and protein abundance. Bioinformatic integration of these data supported differences in mitochondrial pathways as a major stress response. To translate these findings to human anxiety, we investigated blood cell gene expression in mice and in panic disorder patients exposed to fearful situations and experiencing panic attacks. Concurring with our brain findings, expression of mitochondrial pathways was also affected in mouse and human blood cells, suggesting that the observed stress response mechanisms are evolutionarily conserved. Therefore, chronic stress may critically affect cellular energy metabolism, a finding that may offer new targets for therapeutic interventions of stress-related diseases.Peer reviewe

Neuro-Epigenetic Indications of Acute Stress Response in Humans: The Case of MicroRNA-29c.

Stress research has progressively become more integrative in nature, seeking to unfold crucial relations between the different phenotypic levels of stress manifestations. This study sought to unravel stress-induced variations in expression of human microRNAs sampled in peripheral blood mononuclear cells and further assess their relationship with neuronal and psychological indices. We obtained blood samples from 49 healthy male participants before and three hours after performing a social stress task, while undergoing functional magnetic resonance imaging (fMRI). A seed-based functional connectivity (FC) analysis was conducted for the ventro-medial prefrontal cortex (vmPFC), a key area of stress regulation. Out of hundreds of microRNAs, a specific increase was identified in microRNA-29c (miR-29c) expression, corresponding with both the experience of sustained stress via self-reports, and alterations in vmPFC functional connectivity. Explicitly, miR-29c expression levels corresponded with both increased connectivity of the vmPFC with the anterior insula (aIns), and decreased connectivity of the vmPFC with the left dorso-lateral prefrontal cortex (dlPFC). Our findings further revealed that miR-29c mediates an indirect path linking enhanced vmPFC-aIns connectivity during stress with subsequent experiences of sustained stress. The correlative patterns of miR-29c expression and vmPFC FC, along with the mediating effects on subjective stress sustainment and the presumed localization of miR-29c in astrocytes, together point to an intriguing assumption; miR-29c may serve as a biomarker in the blood for stress-induced functional neural alterations reflecting regulatory processes. Such a multi-level model may hold the key for future personalized intervention in stress psychopathology

Mediating role of miR-29c in stress sustainment.

<p>The illustrated mediation model depicts a significant indirect path from vmPFC-aIns FC during the stress task (compared to control, delta beta values) to the change in subjective stress (in R4, 20-min after stress, compared to R3, immediately after stress), through miR-29c fold-change. Specifically, enhanced vmPFC-aIns FC led to higher reported stress levels through increases in miR-29c expression. Beta values are shown next to arrows indicating each link in the analysis. *p<0.05, ⁺p = 0.064.</p

Stress-induced change in miR-29c and sustained subjective stress.

<p><b>A</b>. MiR-29c stress-induced fold-change (axis y) for all participants (coded in axis x); <b>B</b>. ANOVA analysis between groups revealed that increase in miR-29c expression was related to sustained stress.</p

Experimental design, psychological and physiological responses to stress.

<p>Following the acclimation phase and the first blood sample drawn for miRNA expression, participants underwent a scanning session that included control (backward counting) and stress (serial subtraction) tasks; 3-hours following stress induction blood was drawn again. Elicitation of stress is shown by repeated subjective reports of stress levels (R1-4), heart-rate records and salivary cortisol samples (S1-4); for the whole cohort and for separate groups according to stress sustainment vs. recovery. The black line and circle represent the whole sample. ** p<0.001.</p

Correlations between miR-29c fold-change and vmPFC functional connections.

<p><b>A</b>. miR-29c fold-change was positively correlated to vmPFC FC with the aIns; <b>B</b>. miR-29c fold-change was negatively correlated to vmPFC FC with the dlPFC.</p

Stress-induced alterations in vmPFC FC.

<p>Areas that altered FC with the vmPFC seed ROI when contrasting stress vs. control, p(FDR corrected) = 0.0005. (1) Bilateral aIns (2) right IFG (3) dlPFC (4) PCC (5) left IPL. T-score scale is shown at the bottom, with red representing increased FC and green decreased FC. The table presents peak voxels and corresponding T values.</p