miRNA with subsequent degradation or translation inhibition
miRNA functions in regulation of gene expression. Critically evaluate this statement in relation to genetic disease. MicroRNA (miRNAs) are short, recently identified single stranded non-coding RNAs that account for 1-5% of the human genome, regulate at least 30% of protein coating genes and key players in cell differentiation, growth, mobility and apoptosis (programmed cell death). They bind to the 3′-UTR (untranslated region) of their target mRNAs and repress protein production by destabilizing the mRNA and translational silencing (1). Most miRNAs do not silence their own loci, but other genes instead. The regulatory functions of the microRNAs are accomplished through the RNA induced silencing complex (RISC). The RISC complex occurs when dicer cleaves the pre-miRNA into two complementary short RNA molecules, but only one is integrated into the RISC complex.
After integration, miRNAs exert their regulatory effects by binding to complementary sites within the 3’UTR regions of their mRNA targets which then determines the silencing mechanism employed either cleavage of the target messenger RNA with subsequent degradation or translation inhibition based on the lower complementarity between mRNA and miRNA (1). The synthesis of miRNA by pol II and pol III implies that miRNA is a fundamental regulatory element generated from diverse loci within the human genome, which are involved in controlling gene expression (2). MicroRNAs more often than not instigate gene silencing by binding to target sites found within the 3′-UTR of the targeted mRNA. This collaboration prevents protein production by suppressing protein synthesis and/or by initiating mRNA degradation. Since most target sites on the mRNA have only partial base complementary with their corresponding microRNA, individual microRNAs may target as much as 100 different mRNAs (2). In addition, microRNAs have also been implicated in a number of diseases, they occur due to dysregulation of individual or subset of miRNAs is linked with the pathogenesis of human diseases, such as range cancer, for example breast cancer, lung cancer, gastric cancer and liver cancer. Moreover, cardiovascular disorders, metabolic disorders and viral infections such as HCV and HIV-1 have been associated with microRNAs. Lastly, neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease (2)(8).
Given the systems of activity of miRNAs as mentioned before, three fundamental sorts of transformation instruments influencing miRNA capacity can be visualized : firstly, changes influencing basically miRNAs, either point transformations in the develop grouping or larger transformations, for example, erasures or duplication of the whole miRNA locus; Secondly, besides, changes in the 3′ UTR of mRNAs that can prompt the expulsion or to the begin of another age of a target recognition site for a particular miRNA; and lastly, transformations in qualities which take part in the general procedures of miRNA processing and function and, thusly, are anticipated to effect on global miRNA function (4). In regards to large mutations or duplication/deletion diseases such as Duchenne muscular dystrophy that is a genetic disorder of progressive muscle degeneration and weakness has mir-548f-5 involved in the mutation, choroideremia which is a condition of progressive vision loss which has mir-361 involved and dent disease which is a chronic kidney disorder has miR-500/miR-600/miR-188 involved are predicted to be caused by the deletion of these miRNAs and their ability to play a role in the phenotype observed (4). UP716621 2 A report was made regarding two Spanish families who had had been identified to have two different nucleotide substitutions in the seed region of the human miR-96 affected by an autosomal dominant form of deafness, miR-96, together with miR-182 and miR-183, is transcribed as a single polycistronic transcript and is reported to be expressed in the inner ear. However, they did not find any potential mutation (4). The way that both the above families showed the hearing misfortune post lingually demonstrated that likely neither of the two miR-96 changes brought about disabled advancement of the inward ear. Rather, they could have affected the administrative part that miR-96 plays in the hair cells of the adult cochlea which keep up the gene articulation profiles required for its ordinary capacity (4). There are currently a few cases of sequence varieties in the 3′- UTR of mRNAs adjusting miRNA recognition destinations which have been proposed to have a pathogenic part in human hereditary diseases (10). The first was accounted for by Abelson et al.
(5), who distinguished two independent events of the identical sequence variation in the coupling site for the miR-24 in the 3′- UTR of the SLITRK1 that is a protein coding gene mRNA related with Gilles De La Tourette’s disorder, a developmental neuropsychiatric disorder described by chronic vocal and motor tics. There are two human diseases characterized by mutations in genes involved in miRNA processing or activity, namely DiGeorge syndrome which is caused by the deletion of the region of chromosome known as 22q11.2 that occurs at random in the father’s sperm or the mother’s egg, results in cardiovascular defects, craniofacial defects, immunodeficiency and neurobehavioral alterations (11). Fragile X syndrome which is caused by the loss of function of FRM1 gene which is the gene used to provide instructions for making FMRP a protein that helps regulate the productions of other proteins and plays a role in the development of synapses. This interaction is suggested to be important in the process of synaptic plasticity which, instead, is largely compromised in Fragile X syndrome patients (6). Thus, resulting in a range of developmental problems including learning disabilities and cognitive impairment.
miRNA articulation profiles of a large number of human tumour tests demonstrate that miRNAs are now and then upregulated, yet by and large downregulated in tumours. Moreover, about all miRNAs are differentially communicated in various tumours. Since the miRNA profiles mirror the formative heredity and separation condition of tumours, these profiles can be utilized to group ineffectively separated tumours. For example, expression of both mir-143 and mir-145 is downregulated in colon tumour tissue and in addition in a few cell lines got from different sorts of growths (3). The first report of miRNA associated with cancer came from a study made by Calin et al. In which miR-15 and miR-16 undergo frequent deletions among 65% of B-cell chronic lymphocytic leukaemia (B-CLL) patients. However, miR-15 and miR-16 can be only downregulated without deletion in B-CLL which indicates that the pathogenesis of B-CLL may be attributed to the intracellular abundance of two miRNAs (8).
UP716621 3 The group of the mir-15 and mir-16 genes at chromosome 13q14 lies in a district that is erased in the greater part of B-cell lymphocyte leukaemia’s and expression of miR-15 and miR-16 is downregulated in the dominant part of these leukaemia’s (3)(8) (10). In addition, miR-21 is upregulated while miR-205 is downregulated in breast cancer, miR-200a is upregulated but miR-199a is downregulated in ovarian cancer. This happens because of changes of miRNAs pattern in cells have been found responsible not just for cancers but a range of genetic diseases (8). For example, miR-1 is associated with heart muscle separation and upkeep of muscle gene expression in the two, vertebrates and flies. miR-1 advances the separation of precardiac mesoderm into cardiomyocytes and balances the impacts of basic heart administrative proteins to control the fine harmony amongst separation and multiplication (2) (10).
In recent reports deregulation of mir-1 was reported to be associated with heart failure due to miRNAs function to regulate cardiovascular growth amid its core functions and miR-1 is upregulated in ischaemic heart tissue during cardiac arrhythmias which is a major health problem (7)(9). A couple of miRNAs also have a role in multiple acute and chronic diseases, for instance, miR-126, miR-143 and miR-145 are required to mediate leukocyte adherence to endothelial cells and moreover enrolment of vascular smooth muscle cells to the endothelial plexus in the midst of vascular change. Additionally, miR-126 is involved in the help of vascular respectability by concentrating on molecules related with vascular rebuilding and miR-155 have been shown to associate with monocyte expansion during inflammation due to the induction by cytokines such as TNF alpha and IFN-beta (2)(7) (10).
Additionally, there is a connection between miR-21 and smooth muscle expansion in light of platelet determined development factor-BB and the consumption of miR-21 brings about a decline in cell multiplication and expanded apoptosis (programmed cell death). Linking miR-21 the miRNA mentioned above it also has a role to contribute in the pathogenesis of psoriasis which is a chronic inflammatory skin disease with the help of miR2013 which is overly expressed in skin compared to other organs in the body (7)(8). Moving on, miRNA-200 and miRNA-205 are profoundly communicated in ordinary skin with a positive control of E-cadherin which is a kind of cell adhesion molecule (CAM) that is imperative in the development of adherens intersections to tie cells with each other and is a tumour silencer gene, along these lines they are fundamental in keeping up epithelial steadiness (2)(8).
MiRNA-25 has been attributed to the regulation of gene expression linked to skin colour. Thus, regulating melanin which gives human skin, hair and eye colour that is synthesized in the bottom epidermis is found all around the body while miRNA-434-5p is implicated in skin whitening and lightening by targeting hyaluronidase and tyrosinase genes (2)(7). furthermore, miRNAs have also been associated as key contributors in wound healing. miRNA-210 influences keratinocyte proliferation and wound closure, while miRNA-29a directly regulates collagen expression at the posttranscriptional level (7)(8). UP716621 4 Lastly, the usage of miRNAs as biomarkers have helped in improving public health.
MiRNA biomarkers are used to develop better clinical tests that in future would improve diagnosis and prognosis of diseases because of their gene regulations and easier to be discovered by genomic tools (12). Also, miRNAs can act as oncogenes or tumour suppressors depending on the genes targeted (12) To conclude, since microRNAs have been discovered there was no evidence of them contributing or associating with genetic diseases. However, with recent studies made and cases reported there is now evidence that miRNA play an important role in a diverse range of diseases and developmental diseases. As a class of non-coding RNAs that can upregulate, downregulate and key players in differentiation, growth, mobility and apoptosis (programmed cell death) they could have a positive impact in therapeutics for treating diseases. more than half of the human miRNA genes are located at sites known to be involved in cancers, such as fragile sites, minimal regions of loss of heterozygosity, minimal regions of amplification, or common breakpoint regions. Such locations suggest that some miRNAs are involved in tumorigenesis. However, There were two primary and differentiating contentions against the speculation of miRNAs as genes in charge of human hereditary infections: right off the bat, each miRNA is enriched with such a fundamental part in the control of gene expression and therefore in the direction of essential cell forms that a huge change of their capacity isn’t perfect with cell survival and eventually with life; and besides, considering the immense arrangement of excess in miRNA activities, a critical adjustment of the capacity of a solitary miRNA may just offer ascent to subtle alterations in both the cellular transcriptome and proteome, which causes a disorder of biological procedures and thus leading to a disease phenotype (4). UP716621 5 References: 1.
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