WDR82-ZC3H4: an evolutionarily conserved complex that selectively limits extragenic transcription

RNA polymerase II (RNA Pol II)-dependent transcription gives rise to stable protein-coding transcripts as well as to a vast array of non-coding, extragenic transcripts. Numerous noncoding RNAs (ncRNAs) are initiated from cis-regulatory regions, including enhancers and promoters. As soon as it emerges from the elongating RNA Pol II, every nascent RNA is recognized by a large number of proteins and protein complexes that impact on its own fate as well as on that of the transcribing RNA Pol II. In particular, interactions between the splicing machinery and RNA Pol II start occurring when the newly synthesized proteincoding exon associates with exon definition and splicing complexes. These interactions reinforce RNA Pol II activity and contribute to recruit coregulatory machineries. Recent evidence suggests that similar interactions also occur at extragenic transcription sites, where the interplay between exons and splicing signals of enhancer-associated lncRNAs (elncRNAs) augments enhancer activity. Here, we provide evidence suggesting that such interactions underlie an early transcription termination checkpoint at extragenic sites mediated by a complex composed of WDR82, a direct binder of RNA Pol II, and ZC3H4, an RNA-binding protein of previously unknown function. We suggest that this checkpoint is activated by the recognition of qualitatively poor splicing and/or exon definition signals such as those that are typically associated with elncRNAs and promoter anti-sense lncRNAs but not with protein-coding mRNAs. We thus propose the existence of an early termination checkpoint, which is evolutionarily conserved from Drosophila to mammals, that is able to limit pervasive non-coding transcription at the level of active cis-regulatory elements.