Abstract
Most of the sequences in the human genome do not code for proteins but generate thousands of non-coding RNAs (ncRNAs) with regulatory functions. High-throughput sequencing technologies and bioinformatic tools significantly expanded our knowledge about ncRNAs, highlighting their key role in gene regulatory networks, through their capacity to interact with coding and non-coding RNAs, DNAs and proteins. NcRNAs comprise diverse RNA species, including amongst others PIWI-interacting RNAs (piRNAs), involved in transposon silencing, and small nucleolar RNAs (snoRNAs), which participate in the modification of other RNAs such as ribosomal RNAs and transfer RNAs. Recently, a novel class of small ncRNAs generated from the cleavage of tRNAs or pre-tRNAs, called tRNA-derived small RNAs (tRFs) has been identified. tRFs have been suggested to regulate protein translation, RNA silencing and cell survival. While for other ncRNAs an implication in several pathologies is now well established, the potential involvement of piRNAs, snoRNAs and tRFs in human diseases, including diabetes, is only beginning to emerge. In this review, we summarize fundamental aspects of piRNAs, snoRNAs and tRFs biology. We discuss their biogenesis while emphasizing on novel sequencing technologies that allow ncRNA discovery and annotation. Moreover, we give an overview of genomic approaches to decrypt their mechanisms of action and to study their functional relevance. The review will provide a comprehensive landscape of the regulatory roles of these three types of ncRNAs in metabolic disorders by reporting their differential expression in endocrine pancreatic tissue as well as their contribution to diabetes incidence and diabetes-underlying conditions such as inflammation. Based on these discoveries we discuss the potential use of piRNAs, snoRNAs and tRFs as promising therapeutic targets in metabolic disorders.
Highlights
The publication in 2001 of the entire Human Genome Sequence [1, 2] has provided new insights into the biological relevance of our genes and of their transcripts
The newly identified P-element Induced Wimpy Testis (PIWI)-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs) and transfer-derived RNAs (tRFs) are emerging as important regulators of signaling pathways activated or affected during the development of diabetes, placing them as potential therapeutic targets for the treatment of this metabolic disease
The capacity of non-coding RNAs (ncRNAs) to control the stability of genomic elements or transcripts and to modulate several downstream pathways can drastically impact the molecular and functional landscape of the cells, justifying efforts to develop drugs targeting these molecules
Summary
The publication in 2001 of the entire Human Genome Sequence [1, 2] has provided new insights into the biological relevance of our genes and of their transcripts. We will present the mechanisms of action described so far for each of these categories of small non-coding RNAs. we will focus on current studies that demonstrate a role for piRNAs, snoRNAs and tRFs in the pathogenesis of diabetes and associated metabolic disorders. A large proportion of the host genes from which snoRNAs are transcribed code for mRNAs or lncRNAs that are non-functional and are destined to be degraded by the nonsense-mediated RNA decay pathway [44] This makes snoRNA production an actively regulated process for functional and biological purposes. While Angiogenin is the main enzyme responsible for cleaving the anticodon site, different endonucleases have been reported to generate other classes of tRFs, including Dicer, SLNF13, RNase T2, and RNase Z [30, 55, 57]
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