Veterinaria 2015 | Volume 3 | Issue 2 | pages 14-20 14 Abstract MicroRNAs (miRNAs) are short, non-coding RNAs that regulate post-transcriptional gene expression in animals and plants. Biogenesis of miRNAs is itself a highly complex process. miRNAs bind to the 3’ untranslated region (UTR), 5’ UTR or/and coding regions of their target mRNAs in a sequence specific manner. Targeting of mRNAs leads to the repression of protein synthesis by a mechanism that is yet to be fully determined. miRNA-mediated translational repression has been proposed to occur in distinct ways. Some reports have also shown miRNA-mediated translational activation. Details regarding the different modes of actions related to transcriptional and post-transcriptional regulation of miRNAs are still emerging. In this review, information regarding the history, biogenesis and different modes of actions of miRNAs are discussed. Keywords: M icroRNAs, biogenesis, translational repression, translational activation, 3’UTR, AGO. MicroRNAs: History, Biogenesis and Modes of Action to Regulate Gene Expression Aayesha Riaz a* , Robert G Dalziel b , Virginia M. Venturina c , M uhammad Ali Shah a a Department of Pathobiology, Faculty of Veterinary and Animal Sciences, PMAS-Arid Agriculture University, Rawalpindi, Pakistan. b Centre for Infectious Diseases and The Roslin Institute, University of Edinburgh, UK. c Pathobiology Department, College of Veterinary Science and Medicine, Central Luzon State University Received; 25 august, 2015 Revised; 19 September 2015 Accepted; 25 September, 2015 *Corresponding author: Aayesha Riaz Emai l: aayeshariaz@uaar.edu.pk To Cite This Manuscript: Riaz A, Dalziel RG, Venturina VM, Shah MA. MicroRNAs: History, biogenesis and modes of action to regulates gene expression. Veterinaria 2015; 2: 14-20. Introduction History MicroRNAs (miRNAs) are small (21-24 nucleotide (nt) in length) non-coding RNAs, which are able to regulate gene expression at the post transcriptional level [1]. The first miRNA; lin-4 (22 nt long) was identified in a nematode; Caenorhabditisis elegans (C. elegans) in 1993 by the Ambros and Ruvkun laboratories simultaneously [2, 3]. It was found to negatively regulate the expression of the lin-14 protein product by targeting complementary sites in the 3’ untranslated region (3’UTR) of the lin-14 mRNA via an antisense RNA-RNA interaction [3, 4]. Mutation in the lin-4 ORF did not affect its function, suggesting that lin-4 did not encode for a protein [2]. This discovery remained unrealized for almost seven years when Reinhart et al, identified a second miRNA; let-7 in C. elegans [5]. let-7 was found to interact with the 3’UTRs of lin-41 and lin57 mRNAs and inhibit their translation [6, 7]. These discoveries unveiled a new family of RNAs which later became known as microRNAs (miRNAs) [8]. It has since been shown miRNAs are expressed in large numbers and present in a diverse range of different species (including algae, arthropods, nematodes, protozoa, vertebrates, plants, and viruses) [1, 9, 10]. The latest miRBase release (v20, June 2013), contains 24521 miRNA loci, processed to produce 30424 mature miRNAs from 206 species [11] . The regulatory roles of miRNAs have been identified in various biological processes including determination of cell fate, proliferation, cell death, immune response and tumorigenesis [12-14]. MiRNA biogenesis miRNA processing in the nucleus The biogenesis of miRNAs is a multi-step process. It involves sequential processing and editing of transcribed miRNA genes ( Figure 1). Then majority of miRNAs are derived from large RNA polymerase (pol) II transcripts, while a small proportion of miRNAs is derived from pol III transcripts [15, 16]. These primary transcripts (pri-miRNAs) are 5’end capped and 3’ end poly adenylated and range from hundreds to thousands of nucleotides in length [17, 18]. Pri-miRNAs are transcribed from introns, exons, intergenic regions or in an antisense direction of annotated genes [17, 19, 20]. A single pri-miRNA transcript can either generate monocistronic miRNA or polycistronic clusters of miRNAs, under the influence of a single promoter or different promoters for individual miRNAs [15, 17, 21]. Approximately 40% of human miRNAs are co-transcribed as clusters encoding more than one miRNA sequences in a single pri-miRNA transcript [22, 23]. A pri-miRNA contains an imperfect double-stranded (ds) stem-loop structure flanked by single-stranded (ss) RNA. One arm of the stem-loop structure includes the mature miRNA [24]. The stem-loop structure and the flanking region of the pri-miRNAs direct the pri-miRNAs to a multiprotein complex called the microprocessor complex [25-28]. The microprocessor complex contains an RNase III enzyme called Drosha and its cofactor protein DiGeorge syndrome critical region gene 8 (DGCR8). DGCR8 interacts with the stem- loop structure and recruits Drosha, which then cleaves the pri-miRNAs precisely at the stem-loop structure