Profiling of m6A RNA modifications identified an age-associated regulation of AGO2 mRNA stability.

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  • Additional Information
    • Source:
      Publisher: Wiley-Blackwell Country of Publication: England NLM ID: 101130839 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1474-9726 (Electronic) Linking ISSN: 14749718 NLM ISO Abbreviation: Aging Cell Subsets: MEDLINE
    • Publication Information:
      Publication: Oxford, UK : Wiley-Blackwell
      Original Publication: Oxford, UK : Blackwell Pub., c2002-
    • Subject Terms:
      RNA Stability*; Aging/*genetics ; Argonaute Proteins/*genetics ; Methyltransferases/*genetics ; RNA/*genetics; Adult ; Cells, Cultured ; Down-Regulation ; Gene Expression ; Humans ; Male ; Methylation ; Middle Aged ; RNA/blood
    • Abstract:
      Gene expression is dynamically regulated in a variety of mammalian physiologies. During mammalian aging, there are changes that occur in protein expression that are highly controlled by the regulatory steps in transcription, post-transcription, and post-translation. Although there are global profiles of human transcripts during the aging processes available, the mechanism(s) by which transcripts are differentially expressed between young and old cohorts remains unclear. Here, we report on N6-methyladenosine (m6A) RNA modification profiles of human peripheral blood mononuclear cells (PBMCs) from young and old cohorts. An m6A RNA profile identified a decrease in overall RNA methylation during the aging process as well as the predominant modification on proteincoding mRNAs. The m6A-modified transcripts tend to be more highly expressed than nonmodified ones. Among the many methylated mRNAs, those of DROSHA and AGO2 were heavily methylated in young PBMCs which coincided with a decreased steady-state level of AGO2 mRNA in the old PBMC cohort. Similarly, downregulation of AGO2 in proliferating human diploid fibroblasts (HDFs) also correlated with a decrease in AGO2 mRNA modifications and steady-state levels. In addition, the overexpression of RNA methyltransferases stabilized AGO2 mRNA but not DROSHA and DICER1 mRNA in HDFs. Moreover, the abundance of miRNAs also changed in the young and old PBMCs which are possibly due to a correlation with AGO2 expression as observed in AGO2-depleted HDFs. Taken together, we uncovered the role of mRNA methylation on the abundance of AGO2 mRNA resulting in the repression of miRNA expression during the process of human aging.
      (© 2018 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)
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    • Grant Information:
      P30 AG050911 United States AG NIA NIH HHS; P30 CA138313 United States CA NCI NIH HHS
    • Contributed Indexing:
      Keywords: aging; m6A RNA methylation; post transcriptional gene regulation
    • Accession Number:
      0 (AGO2 protein, human)
      0 (Argonaute Proteins)
      63231-63-0 (RNA)
      EC 2.1.1.- (Methyltransferases)
      EC 2.1.1.62 (METTL3 protein, human)
    • Publication Date:
      Date Created: 20180325 Date Completed: 20190912 Latest Revision: 20210109
    • Publication Date:
      20240105
    • Accession Number:
      PMC5946072
    • Accession Number:
      10.1111/acel.12753
    • Accession Number:
      29573145