Emerging Classes of Small Non-Coding RNAs With Potential Implications in Diabetes and Associated Metabolic Disorders

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.

PIWI-Interacting RNAs (piRNAs): Promising Applications as Emerging Biomarkers for Digestive System Cancer

“…The potential of piRNAs to affect numerous downstream pathways can bring a significant impact on the molecular and functional landscape of cancer cells, promoting attempts to create future therapies that specifically target piRNAs (Jacovetti et al, 2021). Numerous preclinical research employing piRNA-based therapeutic compounds has already demonstrated outstanding results in terms of the capacity of piRNAs to influence the malignant features of HCC, CRC and GC cells (Cheng et al, 2012;Law et al, 2013;Mai et al, 2018) (Figure 2).…”

Transfer RNA-derived small RNA: an emerging small non-coding RNA with key roles in cancer

“…In contrast, the conversion of RNA load from piRNAs to tsRNAs during sperm maturation also suggests that tsRNAs are involved in epigenetic regulation [ 56 ]. A related study showed that mice deficient in DNA methyltransferase-2 (DNMT2) prevented high-fat diet-induced intergenerational genetic disorders [ 57 ], while the absence of DNMT2 abolished alterations in sperm tsRNAs modification and expression, suggesting a key role for tsRNAs in epigenetic mechanisms [ 58 ]. The above studies indicate that tsRNAs are equivalent to new piRNAs in playing significant roles in the epigenetic regulation of organisms.…”

Small RNAs derived from tRNA fragmentation regulate the functional maturation of neonatal β cells

“…As tRFs can regulate biological processes through protein interactions (Jacovetti et al, 2021), we sought to unveil the molecular bases for the tiRNA-5 function by performing RNA pull-down assays in INS832/13 cells coupled to mass spectrometry. A biotinylated oligonucleotide of tiRNA-5 HisGTG was used as bait due to its enrichment in mitochondrial fractions and Mpc1 immunoprecipitation (Figures 7A and 7B).…”