Agewise mapping of genomic oxidative DNA modification demonstrates oxidative-driven reprogramming of pro-longevity genes

Abstract

The accumulation of unrepaired oxidatively damaged DNA can influence both the rate of ageing and life expectancy of an organism. Mapping oxidative DNA damage sites at whole-genome scale will help us to recognize the damage-prone sequence and genomic feature information, which is fundamental for ageing research. Here, we developed an algorithm to map the whole-genome oxidative DNA damage at single-base resolution using Single-Molecule Real-Time (SMRT) sequencing technology. We sequenced the genomic oxidative DNA damage landscape of C. elegans at different age periods to decipher the potential impact of genomic DNA oxidation on physiological ageing. We observed an age-specific pattern of oxidative modification in terms of motifs, chromosomal distribution, and genomic features. Integrating with RNA-Seq data, we demonstrated that oxidative modification in promoter regions was negatively associated with the expression of pro-longevity genes, denoting that oxidative modification in pro-longevity genes may exert epigenetic potential and thus affect lifespan determination. Together, our study opens up a new field for exploration of "oxigenetics," that focuses on the mechanisms of redox-mediated ageing. SummaryO_LIWe developed an algorithm to map the oxidative DNA damage at single-base resolution. C_LIO_LIOxidative DNA damage landscape in C. elegans illustrated an age-specific pattern in terms of motifs, chromosomal distribution, and genomic features. C_LIO_LIOxidative modification in older worms occurred higher frequency at the sex chromosome, with the preference for promoter and exon regions. C_LIO_LIOxidative modification in promoter regions of pro-longevity genes was negatively associated with their expression, suggesting the oxidative-driven transcript reprogramming of pro-longevity genes in physiological ageing. C_LI