Bacterial N4-methylcytosine as an epigenetic mark in eukaryotic DNA

DNA modifications are used to regulate gene expression and defend against invading genetic elements. In eukaryotes, modifications predominantly involve C5-methylcytosine (5mC) and occasionally N6-methyladenine (6mA), while bacteria frequently use N4-methylcytosine (4mC) in addition to 5mC and 6mA. Here we report that 4mC can serve as an epigenetic mark in eukaryotes. Bdelloid rotifers, tiny freshwater invertebrates with transposon-poor genomes rich in foreign genes, lack canonical eukaryotic C5-methyltransferases for 5mC addition, but encode an amino-methyltransferase, N4CMT, captured from bacteria >60 Mya. N4CMT deposits 4mC at active transposons and certain tandem repeats, and fusion to a chromodomain shapes its histone-read-DNA-write architecture recognizing silent chromatin marks. Furthermore, amplification of SETDB1 H3K9me3 histone methyltransferases yields variants preferentially binding 4mC-DNA, suggesting DNA-read-histone-write partnership to maintain chromatin-based silencing. Our results show how non-native DNA methyl groups can reshape epigenetic systems to silence transposons and demonstrate the potential of horizontal gene transfer to drive regulatory innovation in eukaryotes. Eukaryotic DNA can be methylated as 5-methylcytosine and N6-methyladenine, but whether other forms of DNA methylation occur has been controversial. Here the authors show that a bacterial DNA methyltransferase was acquired >60 Mya in bdelloid rotifers that catalyzes N4-methylcytosine addition and is involved in suppression of transposon proliferation.

Automated summary

This study discovered a DNA methyltransferase, N4CMT, derived from bacteria in bdelloid rotifers that can deposit 4mC on active transposons and certain tandem repeats, thereby silencing these genes. This suggests that horizontal gene transfer has the potential to drive regulatory innovation in eukaryotes.