Identification of microRNAs dysregulated in cellular senescence driven by endogenous genotoxic stress

Abstract

XFE progeroid syndrome, a disease of accelerated aging caused by deficiency in the DNA repair endonuclease XPF-ERCC1, is modeled by Ercc1 knockout and hypomorphic mice. Tissues and primary cells from these mice senesce prematurely, offering a unique opportunity to identify factors that regulate senescence and aging. We compared microRNA (miRNA) expression in Ercc1-/- primary mouse embryonic fibroblasts (MEFs) and wild-type (WT) MEFs in different growth conditions to identify miRNAs that drive cellular senescence. Microarray analysis showed three differentially expressed miRNAs in passage 7 (P7) Ercc1-/- MEFs grown at 20% O2 compared to Ercc1-/- MEFs grown at 3% O2. Thirty-six differentially expressed miRNAs were identified in Ercc1-/- MEFs at P7 compared to early passage (P3) in 3% O2. Eight of these miRNAs (miR-449a, miR-455*, miR-128, miR-497, miR-543, miR-450b-3p, miR-872 and miR-10b) were similarly downregulated in the liver of progeroid Ercc1-/Δ and old WT mice compared to adult WT mice, a tissue that senesces with aging. Three miRNAs (miR-449a, miR-455* and miR-128) were also downregulated in Ercc1-/Δ and WT old mice kidneys compared to young WT mice. We also discovered that the miRNA expression regulator Dicer is significantly downregulated in tissues of old mice and late passage cells compared to young controls. Collectively these results support the conclusion that the miRNAs identified may play an important role in staving off cellular senescence and their altered expression could be indicative of aging.