miRNA coding transcripts are initially transcribed by RNA polymerase II as long primary miRNAs (several hundred nucleotides long) with a 5′ guano-sine cap and a 3′ polyadenylated tail. Based on current knowledge, it can be stated that genomic regions capable of generating mature functional miRNAs can be present on diverse locations within the genome.Ī general overview of the steps involved in miRNA biogenesis is illustrated in Fig. 147 Since this is a rapidly evolving field, there is potential for future developments to significantly overhaul the current understanding of miRNA genesis. 147 The rest are mostly located in the introns of coding genes and are generally cotranscribed with their host genes and processed separately. 86, 90 It is estimated that approximately 50% of miRNAs are expressed from non– protein coding transcripts. 143 Clusters of miRNA genes that coex-press polycistronically with the potential to be transcribed as a single unit were also discovered. Earlier studies had revealed 2 distinct classes of miRNAs: those that originated from overlapping introns of protein coding transcripts and others that are encoded in exons, underscoring the complexities associated with miRNA maturation. MiRNA genes can vary widely in their location in the genome. The biological significance of a vast majority of annotated miRNAs, however, remains unknown and requires functional validation. 53, 55 The current release (miRBase 20) contains 24 521 entries representing hairpin precursor miRNAs that express 30 424 mature miRNA products in 206 species. An miRNA registry, named miRBase, set up in 2002 serves as the primary online repository for all potential miRNA sequences, annotation, nomenclature, and target prediction information. This resulted in the discovery of multiple miRNAs across different species of plants and animals. The recognition and confirmation of the existence of these small RNAs, now termed microRNAs (mi-RNAs), led to intense research aimed at identifying new members of this family. 9 Many were found to be evolutionarily conserved across species and exhibited cell-type specificity. These RNAs were noncoding, around 19 to 24 nucleotides in length, and derived from a longer precursor with a stem-loop or fold-back structure. 133 The period that followed was marked by a deluge of information wherein multiple laboratories cloned numerous small RNAs from humans, flies, and worms. 141, 159 More importantly, homologues of this gene were subsequently discovered in many other organisms, including humans. In 2000, 2 separate groups discovered that a small RNA, let-7, was essential for the development of a later larval stage to adult in C. This novel mode of regulating gene expression was first thought to be a phenomenon exclusive to C. These 2 studies together brought forth a model wherein base pairing occurred between multiple lin-4 small RNAs to the complementary sites in the 3′ UTR of lin-14 mRNA, thereby causing translational repression of lin-14 and subsequent progression from L1 to L2 during C. The binding between these complementary regions decreased LIN-14 protein expression without causing any significant change in its mRNA levels. Later this group, 93 along with Wightman et al, 183 found that the smaller RNA had antisense complementarity to multiple sites in the 3′ UTR of lin-14 mRNA. The longer sequence formed a stem-loop structure and served as a precursor for the shorter RNA. Instead, it gave rise to 2 small RNAs approximately 21 and 61 nucleotides in length. Interestingly, the transcribed lin-4 was not translated into a biologically active protein. Furthermore, the downregulation of LIN-14 was found to be dependent on the transcription of a second gene called lin-4. In these organisms, the downregulation of LIN-14 protein was found to be essential for the progression from the first larval stage (L1) to L2. miRNAs were discovered in 1993 by Lee and colleagues 93 in the nematode Caenorhabditis elegans. Follow-up studies also revealed that in addition to repressing translation, miRNA binding to its target mRNA also triggered the recruitment and association of mRNA decay factors, leading to mRNA destabilization, degradation, and resultant decrease in expression levels. They primarily function by binding to complementary target sequences in messenger RNA (mRNA) and interfering with the translational machinery, thereby preventing or altering the production of the protein product. MicroRNAs (miRNAs) are a class of small (~19–24 nucleotides in length), endogenous, evolutionarily conserved RNAs that function as posttranscriptional regulators of gene expression. MicroRNAs: Introduction and a Brief History
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