Dnmt3bas regulates transcriptional induction and alternative splicing of Dnmt3b

Our study identified the mechanism by which Dnmt3bas lncRNA and Dnmt3b cis-regulatory elements control inducible expression and alternative splicing of Dnmt3b . Dnmt3bas knockdown increases transcriptional induction and decreases H3K27me3 at Dnmt3b upstream elements, suggesting that PRC2 targeting by Dnmt3bas fine-tunes Dnmt3b induction. Moreover, we identified the catalytically inactive Dnmt3b6 as a major isoform in naïve ESCs. Alternative splicing switches to include exons during transcriptional induction, thus generating the catalytically active isoform, Dnmt3b1 . While Dnmt3bas overexpression attenuates Dnmt3b induction, we observed a relative increase in the Dnmt3b1 isoform. Towards a mechanism, our data demonstrated that hnRNPL, a Dnmt3bas binding partner, promotes exon inclusion. Therefore, we propose that Dnmt3bas recruits hnRNPL to the Dnmt3b promoter, where its interaction with RNA Pol II coordinates alternative splicing with transcriptional induction. With this two-pronged approach, DNMT3B activity can be tightly controlled during the short developmental window, ensuring the fidelity and specificity of DNA methylation. ### Competing Interest Statement The authors have declared no competing interest.