Abstract
SummaryGene 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.
Highlights
Toward the goal of increasing human lifespan of humans, there is great interest in identifying the underlying molecular causes behind the age-associated loss of physiological functions and rise in pathologies
We focused on the m6A RNA modification because it is the most abundant internal modification observed in eukaryotic mRNA, which can affect mRNA splicing and nuclear export; in the cytoplasm, m6A mRNAs are recognized by the RNA-binding protein (RBP) that will mobilize them to processing (P) bodies, where mRNA stability and translation are modulated (Fu, Dominissini, Rechavi & He, 2014; Licht & Jantsch, 2016; Tang et al, 2015)
Between the young and old groups, our analysis identified 1,051 methylated (m6A modification) fragments in the young peripheral blood mononuclear cells (PBMCs) and 826 in the old PBMCs with 778 overlapping sites (Figure 1b and Table S1). m6A RNA predominantly occurs in protein-coding RNAs found in both the young and old PBMCs (Figure 1c), which support earlier observations that m6A methylation occurs primarily in protein-coding transcripts (Dominissini et al, 2012; Meyer Kate et al, 2012)
Summary
Toward the goal of increasing human lifespan of humans, there is great interest in identifying the underlying molecular causes behind the age-associated loss of physiological functions and rise in pathologies. A study observed NAD+-modified RNA has been observed in yeast and mammals, and their results implied a function in mRNA translation and decay (Jiao et al, 2017; Walters et al, 2016). These observations of differential RNA modifications have opened a new area of research, “epitranscriptomics,” where the goal is to decode the fate of RNA modifications that impact decay, translation, and localization. We profile m6A modification of the PBMCs RNA, comparing young versus old donors to identify differences in mRNA expression and miRNA abundance, implicating their involvement in the aging and senescence processes. Global changes in the expression of miRNA suggest that AGO2 mRNA methylation, its stability, and protein levels in old cohorts may be a factor to regulate miRNA abundance and stability
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