Age-associated changes in expression of small, noncoding RNAs, including microRNAs, in C. elegans

Abstract

Small, noncoding RNAs (sncRNAs), including microRNAs (miRNAs), impact diverse biological events through the control of gene expression and genome stability. However, the role of these sncRNAs in aging remains largely unknown. To understand the contribution of sncRNAs to the aging process, we performed small RNA profiling by deep-sequencing over the course of Caenorhabditis elegans (C. elegans) aging. Many small RNAs, including a significant number of miRNAs, change their expression during aging in C. elegans. Further studies of miRNA expression changes under conditions that modify lifespan demonstrate the tight control of their expression during aging. Adult-specific loss of argonaute-like gene-1 (alg-1) activity, which is necessary for miRNA maturation and function, resulted in an abnormal lifespan, suggesting that miRNAs are, indeed, required in adulthood for normal aging. miRNA target prediction algorithms combined with transcriptome data and pathway enrichment analysis revealed likely targets of these age-associated miRNAs with known roles in aging, such as mitochondrial metabolism. Furthermore, a computational analysis of our deep-sequencing data identified additional age-associated sncRNAs, including miRNA star strands, novel miRNA candidates, and endo-siRNA sequences. We also show an increase of specific transfer RNA (tRNA) fragments during aging, which are known to be induced in response to stress in several organisms. This study suggests that sncRNAs including miRNAs contribute to lifespan regulation in C. elegans, and indicates new connections between aging, stress responses, and the small RNA world.

Metatranscriptomic Analysis of Microbes in an Oceanfront Deep-Subsurface Hot Spring Reveals Novel Small RNAs and Type-Specific tRNA Degradation

“…Plasmid-encoded enzymes, the colicins, are involved in the cleavage of the anticodons of specific tRNAs in E. coli (36,43), resulting in the production of tRNA fragments. Similarly, it is reported that tRNA cleavage is a response to stresses in the Eukaryota (15,56), and cancer-or ageassociated changes in fragmented tRNAs have been observed (27,32). Recently, rRNA fragmentation has become another topic of interest (16,39), although the functions of fragmented rRNAs remain unclear.…”

Impact of age-associated increase in 2′-O-methylation of miRNAs on aging and neurodegeneration in Drosophila

“…By now, functional analyses have identified some miRNAs, such as lin-4 in C. elegans (Boehm and Slack 2005;Kenyon 2010; Smith-Vikos and Slack 2012) and miR-34 in Drosophila (Liu et al 2012), as miRNAs with critical roles in organismal and brain aging, respectively. Although most studies have focused on changes in the abundance of miRNAs with age (Ibanez-Ventoso et al 2006;de Lencastre et al 2010;Kato et al 2011), evidence suggests that miRNAs also show heterogeneity in length and sequence in different cell types and biological contexts (Burroughs et al 2010;Marti et al 2010;Li et al 2012;Westholm et al 2012;Llorens et al 2013). Such heterogeneity is mediated by imprecise Drosha and Dicer cleavages (Calabrese et al 2007;Azuma-Mukai et al 2008;Wyman et al 2011), 39 end adenylation/ uridylation (Ruby et al 2006;Landgraf et al 2007;Burroughs et al 2010;Wyman et al 2011), and RNAediting events (Kawahara et al 2007;Nishikura 2010;Alon et al 2012;Ekdahl et al 2012).…”

Alternative genetic code for amino acids and transfer RNA revisited

“…This complex inhibits the initiation of translation by recruiting the general translation initiation factors eIF4E/G/A from capped mRNAs or eIF4G/A from uncapped mRNAs (Figure 4 A) (72) . In addition to oxidative stress, amino-acid-starvation-induced, age-associated, or tissue-specific tRNA fragmentation has also been observed in many eukaryotic cells (63,73,74) ; however, its biological roles are still unclear.…”