A single amino acid substitution confers enhanced methylation activity of mammalian Dnmt3b on chromatin DNA

Recently, the latest achievements made by Prof. Gang Pei’s group were published on Nucleic Acids Res. The researchers found that a single amino acid substitution confers enhanced methylation activity of mammalian Dnmt3b on chromatin DNA.

 

Dnmt3a and Dnmt3b are paralogous enzymes responsible for de novo DNA methylation but with distinguished biological functions. In mice, disruption of Dnmt3b but not Dnmt3a causes global DNA hypomethylation, especially in repetitive sequences, which comprise the large majority of methylated DNA in the genome. By measuring DNA methylation activity of Dnmt3a and Dnmt3b homologues from five species, Prof. Pei’s group found that mammalian Dnmt3b possessed significantly higher methylation activity on chromatin DNA than Dnmt3a and non-mammalian Dnmt3b. Sequence comparison and mutagenesis experiments identified a single amino acid substitution (I662N) in mammalian Dnmt3b as being crucial for its high chromatin DNA methylation activity. Further mechanistic studies demonstrated this substitution markedly enhanced the binding of Dnmt3b to nucleosomes and hence increased the chromatin DNA methylation activity. Moreover, this substitution was crucial for Dnmt3b to efficiently methylate repetitive sequences, which increased dramatically in mammalian genomes. Consistent with their observation that Dnmt3b evolved more rapidly than Dnmt3a during the emergence of mammals, those results demonstrated that the I662N substitution in mammalian Dnmt3b conferred enhanced chromatin DNA methylation activity and contributed to functional adaptation in the epigenetic system.

 

This research was funded by Ministry of Science and Technology, National Natural Science Foundation of China, and Chinese Academy of Sciences.