N6-methyldeoxyadenosine is a transgenerational epigenetic mark protecting DNA from deletion

DNA N6-adenine methylation (6mA) is emerging as an important DNA modification present in all eukaryotic kingdoms, where its roles mostly involve transcriptional regulation and chromatin modification. Here, we demonstrate a distinct role for 6mA in Paramecium tetraurelia. We find that it is a trans-generational epigenetic mark which distinguishes host DNA from invasive elements, protecting the former. During development, Paramecium deletes around 25% of its germline genome, removing TEs, repetitive sequences and transposon-derived elements, to form a functional somatic genome. We show that 6mA is present in the Paramecium germline nucleus, where it is preferentially located on host DNA and excluded from TEs. Ectopic addition of 6mA to germline DNA causes failure to excise TE-derived sequences, leading to lethality. 6mA presence on a synthetic TE-derived element is sufficient to block its excision during development. These effects are inherited via sexual reproduction, demonstrating their trans-generational capacity.