title: Impact of age-associated increase in 2'-O-methylation of miRNAs on aging and neurodegeneration in Drosophila.
abstract: MicroRNAs (miRNAs) are 20- to ∼24-nucleotide (nt) small RNAs that impact a variety of biological processes, from development to age-associated events. To study the role of miRNAs in aging, studies have profiled the levels of miRNAs with time. However, evidence suggests that miRNAs show heterogeneity in length and sequence in different biological contexts. Here, by examining the expression pattern of miRNAs by Northern blot analysis, we found that Drosophila miRNAs show distinct isoform pattern changes with age. Surprisingly, an increase of some miRNAs reflects increased 2'-O-methylation of select isoforms. Small RNA deep sequencing revealed a global increase of miRNAs loaded into Ago2, but not into Ago1, with age. Our data suggest increased loading of miRNAs into Ago2, but not Ago1, with age, indicating a mechanism for differential loading of miRNAs with age between Ago1 and Ago2. Mutations in Hen1 and Ago2, which lack 2'-O-methylation of miRNAs, result in accelerated neurodegeneration and shorter life span, suggesting a potential impact of the age-associated increase of 2'-O-methylation of small RNAs on age-associated processes. Our study highlights that miRNA 2'-O-methylation at the 3' end is modulated by differential partitioning of miRNAs between Ago1 and Ago2 with age and that this process, along with other functions of Ago2, might impact age-associated events in Drosophila.
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Masashi
authors.initials: M
authors.lastname: Abe
authors.forename: Ammar
authors.initials: A
authors.lastname: Naqvi
authors.forename: Gert-Jan
authors.initials: GJ
authors.lastname: Hendriks
authors.forename: Virzhiniya
authors.initials: V
authors.lastname: Feltzin
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Zhu
authors.forename: Andrey
authors.initials: A
authors.lastname: Grigoriev
authors.forename: Nancy M
authors.initials: NM
authors.lastname: Bonini
mesh_terms: D000375:Aging / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D060565:Argonaute Proteins / Q000235:genetics / Q000378:metabolism; D004330:Drosophila / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D008745:Methylation; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation; D009474:Neurons / Q000473:pathology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism
chemical_list: C489654:AGO1 protein, Drosophila; C433807:AGO2 protein, Drosophila; D060565:Argonaute Proteins; D029721:Drosophila Proteins; D035683:MicroRNAs; D020033:Protein Isoforms; C521948:Hen1 protein, Drosophila; D008780:Methyltransferases
keywords: 2′-O-methylation; aging; miRNA; miRNA sorting; neurodegeneration