Conserved sequence-specific lincRNA-steroid receptor interactions drive transcriptional repression and direct cell fate

Hudson, William H.; Pickard, Mark R.; de Vera, Ian Mitchelle S.; Kuiper, Emily G.; Mourtada-Maarabouni, Mirna; Conn, Graeme L.; Kojetin, Douglas J.; Williams, Gwyn T.; Ortlund, Eric A.

Abstract

The majority of the eukaryotic genome is transcribed, generating a significant number of long intergenic noncoding RNAs (lincRNAs). Although lincRNAs represent the most poorly understood product of transcription, recent work has shown lincRNAs fulfill important cellular functions. In addition to low sequence conservation, poor understanding of structural mechanisms driving lincRNA biology hinders systematic prediction of their function. Here we report the molecular requirements for the recognition of steroid receptors (SRs) by the lincRNA growth arrest-specific 5 (Gas5), which regulates steroid-mediated transcriptional regulation, growth arrest and apoptosis. We identify the functional Gas5-SR interface and generate point mutations that ablate the SR–Gas5 lincRNA interaction, altering Gas5-driven apoptosis in cancer cell lines. Further, we find that the Gas5 SR-recognition sequence is conserved among haplorhines, with its evolutionary origin as a splice acceptor site. This study demonstrates that lincRNAs can recognize protein targets in a conserved, sequence-specific manner in order to affect critical cell functions.

Citation

Hudson, W. H., Pickard, M. R., de Vera, I. M. S., Kuiper, E. G., Mourtada-Maarabouni, M., Conn, G. L., …Ortlund, E. A. (2014). Conserved sequence-specific lincRNA-steroid receptor interactions drive transcriptional repression and direct cell fate. Nature Communications, 5(1), Article 5395. https://doi.org/10.1038/ncomms6395

• Journal Article Type: Article
• Acceptance Date: Sep 26, 2014
• Online Publication Date: Nov 7, 2014
• Publication Date: Nov 7, 2014
• Deposit Date: Jun 6, 2023
• Journal: Nature Communications
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 5
• Issue: 1
• Article Number: 5395
• ISBN: 20411723
• DOI: https://doi.org/10.1038/ncomms6395
• Keywords: General Physics and Astronomy; General Biochemistry, Genetics and Molecular Biology; General Chemistry; Multidisciplinary
• Public URL: https://keele-repository.worktribe.com/output/440231
• Publisher URL: https://www.nature.com/articles/ncomms6395
• Additional Information: Received: 11 March 2014; Accepted: 26 September 2014; First Online: 7 November 2014; : The authors declare no competing financial interests.