Rbm10 regulates inflammation development via alternative splicing of Dnmt3b

Abstract

Rbm10 is a RNA binding protein that regulates alternative splicing, but its role in inflammation is not well defined. Here we show that Rbm10 controls appropriate splicing of Dnmt3b, a DNA methyltransferase, to regulate the activity of NFκB-responsive promoters and consequently inflammation development. Rbm10 deficiency suppressed NFκB-mediated responses in vivo and in vitro. Mechanistic analysis showed that Rbm10 deficiency decreased promoter recruitment of NFκB, with increased DNA methylation of the promoter regions in NFκB-responsive genes. Consistently, Rbm10 deficiency increased the expression level of Dnmt3b2, which has enzyme activity, while it decreased the splicing isoform Dnmt3b3, which does not. These two isoforms associated with NFκB efficiently, and over-expression of enzymatically active Dnmt3b2 suppressed the expression of NFκB targets, indicating that Rbm10-mediated Dnmt3b2 regulation is important for the induction of NFκB-mediated transcription. Therefore, Rbm10-dependent Dnmt3b regulation is a possible therapeutic target for various inflammatory diseases.