Dnmt3bascoordinates transcriptional induction and alternative exon inclusion to promote catalytically active Dnmt3b expression

SummaryDuring mammalian embryogenesis, DNMT3B activity is critical for the genome-wide establishment of DNA methylation. Using naïve ESC differentiation as a model, we elucidated the mechanism by which lncRNA,Dnmt3bas,controls the inducible expression and alternative splicing ofDnmt3b. Our data showed thatDnmt3basknockdown increased transcriptional induction and decreased H3K27me3 at Dnmt3b cis-regulatory elements post-differentiation. Notably, transcriptional induction ofDnmt3bwas accompanied by exon inclusion, switching the major isoform from catalytically inactiveDnmt3b6to the activeDnmt3b1. WhileDnmt3basoverexpression attenuatedDnmt3binduction, it increased theDnmt3b1:Dnmt3b6ratio. This observation was explained by a specific interaction ofDnmt3baswith hnRNPL, which promotes exon inclusion. These data suggest thatDnmt3bascoordinates alternative splicing and transcriptional induction of Dnmt3b by facilitating the interaction of hnRNPL and RNA Pol II at the Dnmt3b promoter. This two-pronged mechanism would tightly control DNMT3B activity, ensuring the fidelity and specificity ofde novoDNA methylation during development.