Super-promoters: Cooperativity between juxtaposed promoters

Abstract The coordination of transcription through enhancers and promoters is a fundamental process that has a central role in development and disease 1–3 . Convergent transcription, i.e., the collision of sense and antisense transcription, is ubiquitous in mammalian genomes 4–8 and believed to diminish RNA expression 9,10 . Recently, antisense transcription downstream of promoters was found to be surprisingly prevalent 11–13 . However, functional characteristics of promoters with convergent transcription are unknown. Here, we show that convergent transcription marks an unexpectedly cooperative promoter constellation we call super-promoters. By assessing transcriptional dynamic systems, we identified strongly cooperative constituent promoters that are connected through a distinct chromatin structure. Within these super-promoter constellations transcription factors can regulate both constituting promoters by binding to only one of them. Super-promoters comprise about a fourth of all active transcript starts and initiate 5’-overlapping antisense RNAs, an RNA class previously believed to be rare 4 . Visualization of nascent RNA molecules provides evidence for convergent co-transcription at these loci. Our results demonstrate that super-promoters substantially expand the cis -regulatory repertoire and reveal limitations of the standing model of transcription interference. Together, our study revises the promoter architecture of many genes and calls for adjusting the promoter concept.