Intragenic recruitment of NF-kB drives alternative splicing modifications upon activation by the viral oncogene TAX of HTLV-1
Lamya Ben Ameur, Morgan Thenoz, Guillaume Giraud, Emmanuel Combe, JeanBaptiste Claude, Sebastien Lemaire, Nicolas Fontrodona, Hélène Polveche, Marine Bastien, Antoine Gessain, Eric Wattel, Cyril F. Bourgeois, Didier Auboeuf and Franck Mortreux
Received Date: 25th March 19
The chronic NF-kB activation in inflammation and cancer has long been linked to persistent activation of NF-kB responsive gene promoters. However, NF-kB factors such as RELA also massively bind to gene bodies. Here, we demonstrate that the recruitment of RELA to intragenic regions regulates alternative splicing upon activation of NF-kB by the viral oncogene TAX of HTLV-1. Integrative analysis of RNA splicing and chromatin occupancy, combined with chromatin tethering assays, demonstrate that DNA-bound RELA interacts with and recruits the splicing regulator DDX17 in a NF-kB activation-dependent manner, leading to alternative splicing of target exons thanks to DDX17 RNA helicase activity. This NF-kB/DDX17 axis accounts for a major part of the TAX-induced alternative splicing landscape that mainly affects genes involved in oncogenic pathways. Collectively, our results demonstrate a physical and direct involvement of NF-kB in alternative splicing regulation, which significantly revisits our knowledge of HTLV-1 pathogenesis and other NF-kB-related diseases.
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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.