MicroRNA - Volume 6, Issue 2, 2017

MicroRNAs (miRNAs) are 17-22 nucleotide, non-coding, single stranded RNA molecules that play a key role in post-transcriptional gene regulation. Hypoxia is a reduction in the normal level of tissue oxygen (O2) tension, and is a feature of chronic vascular disease, pulmonary disease and many cancers. Tissue hypoxia can have widespread effects on cellular functions, as O2 availability is critical for many cellular processes. Cells respond to changes in O2 tension through multiple molecular and cellular mechanisms, including changes in gene expression through transcriptional and translational mechanisms. The transcription factor, hypoxia inducible factor-1, plays a dominant role in transcriptional gene regulation in hypoxia. Several hypoxically induced miRNAs have been shown to play important roles in the hypoxic adaptation of cancer cells. Global repression of enzymes critical for miRNA biogenesis seems to be a widespread phenomenon with several different mechanisms operating. This review describes the effects of hypoxia on specific miRNAs and more global effects on miRNA biogenesis, demonstrating that hypoxia is an important regulator of miRNA biogenesis and function.

Objective: RNA is chemically modified with over 100 distinct reactions. Among these reactions, methylation is probably the most extensively studied modification on the RNA molecule. Studies suggest methylation of Adenine residues (m6A) to be widespread in the transcriptome with potentially important roles in biological processes. Method: Here, we review recent literature on m6A modification and potential implications for microRNA (miRNA) mediated gene expression regulation. These implications involve miRNA biogenesis, mRNA-miRNA interactions and m6A target selection. Conclusion: Understanding the extent and functions of m6A is likely to improve our understanding of the complexities of the transcriptome regulation in normal and in disease states.

MicroRNAs are short non-coding RNAs involved in critical biological processes. In the past decade, the deregulation of miRNAs has been well-documented in a wide range of human diseases, including cancer. Overexpression and downregulation of miRNAs affect cellular pathways that contribute to carcinogenesis and tumor progression. This evidence makes miRNAs a suitable candidate for therapeutic applications and leads to developing strategies to manipulate their expression. Consistently, in vitro and in vivo studies show that Let-7, miR-10b, miR-21, miR-34, miR-155 and miR-221 are promising targets to develop miRNAs-based therapy for human malignancies. The purpose of this review is to discuss the different approaches that can be used to restore or reduce miRNAs expression in human cancer and the therapeutic implications.

Physical exercise is a stress that modulates a plethora of cellular mechanisms to promote morphological and metabolic adaptations. Substantial efforts have been made to better understand the modulation of pathways involved in cell plasticity during exercise, but human explorations may be limited because invasive procedures are often required. In recent years, minimally invasive methods for the analysis of microRNAs (miRNAs) modulation in response to exercise have been developed. miRNAs are small molecules that belong to a family of non-coding RNAs. miRNAs have a significant biological impact as they control more than 60% of human genome by targeting specific messenger RNAs. Recent studies conducted in human showed that miRNAs are detectable in a variety of biological fluids such as serum, plasma, saliva, urine and tears. Both endurance and strength exercises modulate the expression of miRNAs coding for actors involved in several cellular processes related to training adaptation. In this review, we discuss recent advances on the development of methods for miRNAs detection and the impact of acute and chronic exercise on their modulation in humans. We especially highlight the most recent studies on the factors that can impact miRNAs modulation during exercise, including the mode of exercise, the nutritional status, the use of ergogenic aids, and hypoxic exposure, and present recent findings on the potential to use miRNAs as biomarkers for anti-doping control. We finally discuss the importance of considering recent data on organelle turnover-related pathways, and current limitations in order to encourage further investigations on this area.

Aim of Study: Since the discovery of microRNAs (miRNAs) in the 1990s, our knowledge about their biology has grown considerably. The increasing number of studies addressing the role of miRNAs in development and in various diseases emphasizes the need for a comprehensive catalogue of accurate sequence, expression and conservation information regarding the large number of miRNAs proposed recently in all organs and tissues. The objective of this study was to provide data on the levels of miRNA expression in 15 tissues of the normal human brain. Materials and Methods: We conducted an analysis of the relative levels of 88 of the most abundantly expressed and best characterized miRNA derived postmortem from well-characterized samples of various regions of the brains from five normal individuals. Results: The cluster analysis revealed some differences in the relative levels of these miRNAs among the brain regions studied. Such diversity can be explained by different functioning of these brain regions. Conclusion: We hope that the data from the current study are a resource that will be useful to our colleagues in this exciting field, as more hypotheses will be generated and tested with regard to small noncoding RNA in the human brain in healthy and disease states.

Background: miRNA are the post transcriptional regulator of the genes. The conserved miR168 family is evaluated for position based nucleotide preference in higher plants. Low density lipoprotein receptor adaptor protein 1 (LDLRAP1) target validated for miR168a obtained from rice origin is reported. Methods: The mature miRNA sequences include miR168-5p and miR168-3p, were obtained from miRBase (v21, June 2014) for 15 families (28 plants). The preferred position based nucleotide sequences were obtained using Data Analysis in Molecular Biology and Evolution software. The miR168-5p was subjected to cross kingdom analysis using psRNATarget. Target expression and functional annotation was analyzed by using Human Protein Atlas database WEB-based Gene SeTAnaLysis Toolkit. Results: miR168-5p shows same nucleotides at positions 1-6, 8-9, 11-12, 15-17 and 19. Also, miR168-3p is present in 3 families (10 plants) shows the same nucleotide at position 1-11, 13-15 and 17-21. The 123 targets in human transcriptome were identified showing 58% cleavage and 41% translation repression. Low density lipoprotein receptor adaptor protein 1 (LDLRAP1) target validated for miR168a obtained from rice origin, could also be targeted from miR168 from any other plant sources. The randomly selected 10 targets include some important genes likeRPL34, ATXN1, AKAPI3 and ALS2 and is involved in transcription, cell trafficking, cell metabolism and neurodegenerative disorder. Conclusion: Our work suggests that miR168 family has conserved sequence in higher plants. The seed region position 2-8 shows 70-95% pairing with human targets. Cleavage site at position 10-14 and these were analysed for the base preference with the targets showed 80-96% Watson Crick pairing.

Background: MicroRNAs are small noncoding RNA molecules that play a critical role in regulating physiological and disease processes. Recent studies have now recognized microRNAs as an important player in cardiac arrhythmogenesis. Molecular insight into arrhythmogenic cardiomyopathy (AC) has primarily focused on mutations in desmosome proteins. To our knowledge, models of AC due to microRNA dysregulation have not been reported. Previously, we reported on miR-130a mediated down-regulation of Connexin43. Objective: Here, we investigate miR-130a-mediated translational repression of Desmocollin2 (DSC2), as it has a predicted target site for miR-130a. DSC2 is an important protein for cell adhesion, which has been shown to be dysregulated in human AC. Method & Results: After induction of miR-130a, transgenic mice demonstrated right ventricular dilation. Surface ECG revealed spontaneous premature ventricular complexes confirming an arrhythmogenic phenotype in αMHC-miR130a mice. Using total protein from whole ventricular lysate, western blot analysis demonstrated an 80% reduction in DSC2 levels in transgenic myocardium. Furthermore, immunofluorescent staining confirmed downregulation of DSC2 in transgenic compared with littermate control myocardium. In transgenic hearts, histologic findings revealed fibrosis and lipid accumulation within both ventricles. To validate DSC2 as a direct target of miR-130a, we performed in vitro target assays in 3T3 fibroblasts, known to express miR-130a. Using a luciferase reporter fused to the 3UTR of DSC2 compared with a control, we found a 42% reduction in luciferase activity with the DSC2 3UTR. This reduction was reversed upon selective inhibition of miR-130a. Conclusion: Overexpression of miR-130a results in a disease phenotype characteristic of AC and therefore, may serve as potential model for microRNA-induced AC.