In this point of view we discuss the role of co-activators and co-repressors of miRNA precursors maturation, the possibility that their functions are post translationally regulated by different signaling pathways, and their potential role in the miRNA-dependent control of cell proliferation and differentiation.
"Furthermore, it has been shown that miRNAs themselves are subjected to post-transcriptional regulation. Various proteins induce processing of specific pri-miRNAs into mature miRNAs by influencing the Drosha-dgcr8 complex, while other proteins block miRNAs maturation by binding to the pre-miRNA –. Thus, microgravity could affect post-transcriptional regulation of miRNAs. In addition, since miRNA biogenesis is globally induced upon DNA damage in an ATM-dependent manner and the loss of ATM abolishes miRNA induction after DNA damage , we suggest that ATM down-regulation in MMG could affect miRNA biogenesis in response to radio-induced DNA damage. "
[Show abstract][Hide abstract] ABSTRACT: Ionizing radiation (IR) can be extremely harmful for human cells since an improper DNA-damage response (DDR) to IR can contribute to carcinogenesis initiation. Perturbations in DDR pathway can originate from alteration in the functionality of the microRNA-mediated gene regulation, being microRNAs (miRNAs) small noncoding RNA that act as post-transcriptional regulators of gene expression. In this study we gained insight into the role of miRNAs in the regulation of DDR to IR under microgravity, a condition of weightlessness experienced by astronauts during space missions, which could have a synergistic action on cells, increasing the risk of radiation exposure.
We analyzed miRNA expression profile of human peripheral blood lymphocytes (PBL) incubated for 4 and 24 h in normal gravity (1 g) and in modeled microgravity (MMG) during the repair time after irradiation with 0.2 and 2Gy of γ-rays. Our results show that MMG alters miRNA expression signature of irradiated PBL by decreasing the number of radio-responsive miRNAs. Moreover, let-7i*, miR-7, miR-7-1*, miR-27a, miR-144, miR-200a, miR-598, miR-650 are deregulated by the combined action of radiation and MMG. Integrated analyses of miRNA and mRNA expression profiles, carried out on PBL of the same donors, identified significant miRNA-mRNA anti-correlations of DDR pathway. Gene Ontology analysis reports that the biological category of "Response to DNA damage" is enriched when PBL are incubated in 1 g but not in MMG. Moreover, some anti-correlated genes of p53-pathway show a different expression level between 1 g and MMG. Functional validation assays using luciferase reporter constructs confirmed miRNA-mRNA interactions derived from target prediction analyses.
On the whole, by integrating the transcriptome and microRNome, we provide evidence that modeled microgravity can affects the DNA-damage response to IR in human PBL.
PLoS ONE 02/2012; 7(2):e31293. DOI:10.1371/journal.pone.0031293 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: MicroRNAs (miRNAs, miRs) are short approximately 22-nucleotide noncoding RNAs that bind to messenger RNA transcripts and in doing so modulate cognate gene expression. In eukaryotes, miRNAs act primarily by causing translational repression although they may also act to destabilize RNA transcripts. During the past few years, a number of studies have demonstrated that miR expression changes as a result of cardiac hypertrophy or heart failure. Additionally, cell-based and transgenic mouse studies have demonstrated that individual miRs can affect a number of aspects of cardiac biology including developmental processes, stem cell differentiation, progression of hypertrophy and failure, ion channel function, as well as angiogenesis, rates of apoptosis, and fibroblast proliferation. In this review, we will summarize several of the miRs known to change in expression in association with heart failure and outline details of what is known about their putative targets. In addition, we will review several aspects of regulation of miR expression that have not been addressed in a cardiovascular context. Finally, as is common to all new and rapidly moving fields, we will highlight some of the gaps and inconsistencies related to miR expression and cardiac phenotypes, particularly those associated with heart failure.
[Show abstract][Hide abstract] ABSTRACT: Skeletal myogenesis is orchestrated by distinct regulatory signaling pathways, including PI3K/AKT, that ultimately control muscle gene expression. Recently discovered myogenic micro-RNAs (miRNAs) are deeply implicated in muscle biology. Processing of miRNAs from their primary transcripts is emerging as a major step in the control of miRNA levels and might be well suited to be regulated by extracellular signals. Here we report that the RNA binding protein KSRP is required for the correct processing of primary myogenic miRNAs upon PI3K/AKT activation in myoblasts C2C12 and in the course of injury-induced muscle regeneration, as revealed by Ksrp knock-out mice analysis. PI3K/AKT activation regulates in opposite ways two distinct KSRP functions inhibiting its ability to promote decay of myogenin mRNA and activating its ability to favor maturation of myogenic miRNAs. This dynamic regulatory switch eventually contributes to the activation of the myogenic program.
Cell death and differentiation 09/2011; 19(3):478-87. DOI:10.1038/cdd.2011.117 · 8.18 Impact Factor
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