IWS1 Stimulates Pol II Transcription Elongation In Vivo

The protein IWS1 (Interacts with SPT6 1) has been implicated in various transcription-associated processes, but whether it has a direct role in RNA polymerase (Pol) II transcription remains unclear. Here, we establish a rapid depletion system for IWS1 in human cells, and use it to elucidate its function in vivo by multi-omics kinetic analysis. We show that IWS1 depletion results in a global decrease of RNA synthesis in vivo that is due to a decrease in Pol II elongation velocity and in vitro biochemical assays reveal that IWS1 directly stimulates Pol II transcription by lowering the nucleosome entry barrier. Further analyses show that H3K36me3 decreases upon IWS1 depletion although the recruitment of the histone methyltransferase SETD2 to chromatin is unaffected. We conclude that IWS1 has a direct role in Pol II transcription and is essential for maintaining normal RNA elongation, which in turn is required for normal chromatin methylation.