A novel N(6)-Deoxyadenine methyltransferase METL-9 modulates C. elegans immunity via dichotomous mechanisms

N(6)-Methyldeoxyadenine (6mA) has been rediscovered as a DNA modification with potential biological function in metazoans. However, the physiological function and regulatory mechanisms regarding the establishment, maintenance and removal of 6mA in eukaryotes are still poorly understood. Here we show that genomic 6mA levels change in response to pathogenic infection in Caenorhabditis elegans (C. elegans). We further identify METL-9 as the methyltransferase that catalyzes DNA 6mA modifications upon pathogen infection. Deficiency of METL-9 impairs the induction of innate immune response genes and renders the animals more susceptible to pathogen infection. Interestingly, METL-9 functions through both 6mA-dependent and -independent mechanisms to transcriptionally regulate innate immunity. Our findings reveal that 6mA is a functional DNA modification in immunomodulation in C. elegans.