TY - JOUR
T1 - Shape of promoter antisense RNAs regulates ligand-induced transcription activation
AU - Yang, Fan
AU - Tanasa, Bogdan
AU - Micheletti, Rudi
AU - Ohgi, Kenneth A.
AU - Aggarwal, Aneel K.
AU - Rosenfeld, Michael G.
N1 - Funding Information:
Acknowledgements We are grateful to K. Jepsen (Director of IGM, UCSD) for Illumina sequencing, J. Hightower for assistance with figure preparation, M. Ghassemian from the UCSD Biomolecular/Proteomics Mass Spectrometry Facility for mass spectrometry analysis, P. Irving (UNC), and R. Andrews and W. Moss for their suggestions on SHAPE-MaP analysis and on the ScanFold pipeline, respectively. F.Y. was a recipient of the Prostate Cancer Research Program (PCRP) Postdoctoral Training Award of the Department of Defense (W81XWH-16-1-0548). M.G.R. is an investigator with the Howard Hughes Medical Institute. This work was supported by grants from the NIDDK and NHLBI (HL150521, DK018477 and DK039949) to M.G.R. and by NIH grant R35-GM131780 to A.K.A.
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021/7/15
Y1 - 2021/7/15
N2 - The size of the transcriptional program of long non-coding RNAs in the mammalian genome has engendered discussions about their biological roles1, particularly the promoter antisense (PAS) transcripts2,3. 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 ERα led to a significant loss of H3K9me3 and the release of basally recruited HP1α 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 ERα-bound MegaTrans enhancer, which is essential for robust pause release, required the recruitment of phosphorylated KAP1, with its transfer to the cognate promoters permitting 17β-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.
AB - The size of the transcriptional program of long non-coding RNAs in the mammalian genome has engendered discussions about their biological roles1, particularly the promoter antisense (PAS) transcripts2,3. 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 ERα led to a significant loss of H3K9me3 and the release of basally recruited HP1α 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 ERα-bound MegaTrans enhancer, which is essential for robust pause release, required the recruitment of phosphorylated KAP1, with its transfer to the cognate promoters permitting 17β-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.
UR - http://www.scopus.com/inward/record.url?scp=85108903611&partnerID=8YFLogxK
U2 - 10.1038/s41586-021-03589-x
DO - 10.1038/s41586-021-03589-x
M3 - Article
C2 - 34194047
AN - SCOPUS:85108903611
VL - 595
SP - 444
EP - 449
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7867
ER -