Regulation of antisense transcription by ZWC complex-mediated SPT5 phosphorylation

Abstract

The human genome encodes large numbers of non-coding RNA, including antisense transcripts. However, the molecular mechanism for how antisense RNA transcription is regulated has not been detailed. Here, we report a novel ZWC complex composed of ZC3H4, WDR82, and CK2, which represses divergent antisense transcription from the bidirectional promoters. The ZWC complex preferentially localizes at the promoter regions through direct and simultaneous interaction of ZC3H4 and WDR82 with S5p RNAPII CTD. ZC3H4 depletion leads to increased divergent antisense transcription, more evident from the promoters that naturally produce divergent antisense transcripts. Notably, we further demonstrate that the ZWC complex phosphorylates nine serine and tyrosine residues in the N-terminal acidic region of SPT5, a subunit of DSIF and that this phosphorylation is responsible for the suppression of divergent antisense transcription. Besides an established role in promoter-proximal pausing, our study provides evidence that DSIF regulates antisense transcription production during early transcription.