N6-methyldeoxyadenine is a transgenerational epigenetic signal for mitochondrial stress adaptation

N6-methyldeoxyadenine (6mA), a major type of DNA methylation in bacteria, represents a part of restriction-modification systems to discriminate host genome from invader DNA(1). With the recent advent of more sensitive detection techniques, 6mA has also been detected in some eukaryotes(2-8). However, the physiological function of this epigenetic mark in eukaryotes remains elusive. Heritable changes in DNA 5mC methylation have been associated with transgenerational inheritance of responses to a high-fat diet(9), thus raising the exciting possibility that 6mA may also be transmitted across generations and serve as a carrier of inheritable information. Using Caenorhabditis elegans as a model, here we report that histone H3K4me3 and DNA 6mA modifications are required for the transmission of mitochondrial stress adaptations to progeny. Intriguingly, the global DNA 6mA level is significantly elevated following mitochondrial perturbation. N6-methyldeoxyadenine marks mitochondrial stress response genes and promotes their transcription to alleviate mitochondrial stress in progeny. These findings suggest that 6mA is a precisely regulated epigenetic mark that modulates stress response and signals transgenerational inheritance in C. elegans.