Shape of promoter antisense RNAs regulates ligand-induced transcription activation

The size of the transcriptional program of long non-coding RNAs in the mammalian genome has engendered discussions about their biological roles', particularly the promoter antisense (PAS) transcripts(2,3). Here we report the development of an assay-referred to as chromatin isolation by RNA-Cas13a complex-to quantitatively detect the distribution of RNA in the genome. The assay revealed that PAS RNAs serve as a key gatekeeper of a broad transcriptional pause release program, based on decommissioning the 7SK small nuclear RNA-dependent inhibitory P-TEFb complex. Induction of PAS RNAs by liganded ER alpha led to a significant loss of H3K9me3 and the release of basally recruited HP1 alpha and KAP1 on activated target gene promoters. This release was due to PAS RNA-dependent recruitment of H3K9me3 demethylases, which required interactions with a compact stem-loop structure in the PAS RNAs, an apparent feature of similarly regulated PAS RNAs. Activation of the ER alpha-bound MegaTrans enhancer, which is essential for robust pause release, required the recruitment of phosphorylated KAP1, with its transfer to the cognate promoters permitting 17 beta-oestradiol-induced pause release and activation of the target gene. This study reveals a mechanism, based on RNA structure, that mediates the function of PAS RNAs in gene regulation.

Automated summary

PAS RNAs act as key gatekeepers for a broad transcriptional pause release program, mediating gene regulation through RNA structure and enabling the activation of target genes.