Bacterial N4-methylcytosine as an epigenetic mark in eukaryotic DNA

Abstract

In eukaryotes, 5-methylcytosine is the predominant DNA base modification, followed by N6-methyladenine. However, N4-methylcytosine (4mC) is confined to bacteria. Here we report that 4mC can serve as an epigenetic mark in eukaryotes. Bdelloid rotifers, freshwater invertebrates with transposon-poor genomes that are rich in foreign genes, lack C5-methyltransferases but encode an amino-methyltransferase, N4CMT, captured from bacteria >60 Mya. N4CMT introduces 4mC into DNA, and its chromodomain shapes the "histone-read-DNA-write" architecture together with a "DNA-read-histone-write" SETDB1/eggless H3K9me3 histone methyltransferase variant preferentially binding 4mC-DNA, to maintain 4mC and silent chromatin at transposons and tandem repeats. Our results bring the third base modification into the eukaryotic repertoire, demonstrate how non-native DNA methyl groups can reshape complex epigenetic systems to suppress transposon proliferation, and establish horizontal gene transfer as the source of regulatory innovation in eukaryotes.

Epigenetics across the evolutionary tree: New paradigms from non‐model animals

“…*Indicates two species of cephalopods – Octopus bimaculoides Euprymna scolopes – who have had some epigenomic analysis by our group [ 6 ] and others. [ 7,8 ] Despite the abundance of animals in the annelid phylum, no datasets from an annelid have deposited to date in BioProject. Scale bar indicates 20% genetic variation.…”

From correlation to causation: The new frontier of transgenerational epigenetic inheritance

“…[ 36 ] It is still not understood how some of these regions can escape reprogramming but DNA methylation seems to be a robust transgenerational epigenetic factor in systems that possess it. Beyond 5mC there are other DNA methylation events, such as N6‐methyladenosine [ 37 ] and N4‐methylcytosine [ 38 ] and other modifications to DNA, including N4‐acetylcytosine [ 39 ] and 5‐hydoxymethyluracil, [ 40 ] which could each play a role in transmitting non‐genetic information across generations. Having a deeper mechanistic understanding of these additional modifications could help reveal whether these rarer DNA modifications could play a role specifically in the inheritance of non‐genetic information.…”

Bdelloid rotifers use hundreds of horizontally acquired genes against fungal pathogens

“…At these rates, the phenomenon is too slow to be equated with the shuffling of alleles in a population by sex, but HGT has been hypothesized to introduce novel biochemical functions that help bdelloids adapt to environmental challenges. Foreign genes are indeed expressed and incorporated into metabolic pathways 66,68 , some of which are not shared by other metazoans 72 . Furthermore, these genes have been found to play a role in desiccation tolerance, nutrient exploitation and repair of DNA damage 66,68,73 .…”