ZC3H4, ARS2, and WDR82 coordinate non-coding transcriptional termination and are opposed by telescripting on protein-coding genes [PNUTS_ChIP-seq]

There are thousands of unstable non-coding (nc) RNAs in humans, but their transcriptional regulation is poorly characterized compared to protein-coding transcripts. We recently identified a restrictor complex containing ZC3H4 and WDR82, which terminates non-coding transcription. Here we show that the ncRNA termination factor, ARS2, and the nuclear exosome targeting complex (NEXT) are part of this complex.ARS2/NEXT and WDR82 contact different parts of ZC3H4, which are required for its transcription regulatory function. They facilitateZC3H4-mediated termination by different mechanisms: ARS2 aids substrate targeting and WDR82 mediates RNA polymerase II interaction.ZC3H4 and WDR82 predominantly affect antisense, unstable, and intragenic ncRNAs. We provide an explanation for this by showing that U1 telescripting shields hundreds of protein-coding transcripts from their termination functions.We have defined an expanded ZC3H4 restrictor complex, its principles of action, and how protein-coding transcripts evade it. Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) for PNUTS occupancy in HCT116 cells.