A first exon termination checkpoint preferentially suppresses extragenic transcription

Interactions between the splicing machinery and RNA Polymerase II (RNA Pol II) increase protein-coding gene transcription. Similarly, exons and splicing signals of enhancer-generated lncRNAs (elncRNAs) augment enhancer activity. However, elncRNAs are inefficiently spliced, suggesting that compared to protein-coding genes they contain qualitatively different exons with a limited ability to drive splicing. We show here that the inefficiently spliced first exons of elncRNAs as well as promoter-antisense lncRNAs (pa-lncRNAs) in human and mouse cells trigger a transcription termination checkpoint that requires WDR82, an RNA Pol II-binding protein, and its RNA-binding partner of previously unknown function, ZC3H4. We propose that the first exons of elncRNAs and pa-lncRNAs are an intrinsic component of a regulatory mechanism that on the one hand maximizes the activity of these cis-regulatory elements by recruiting the splicing machinery, and on the other contains elements that suppress pervasive extragenic transcription.