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

William H. Hudson, Mark R. Pickard, Ian Mitchelle S. de Vera, Emily G. Kuiper, Mirna Mourtada-Maarabouni, Graeme L. Conn, Douglas J. Kojetin, Gwyn T. Williams and Eric A. Ortlund ()
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William H. Hudson: Emory University School of Medicine
Mark R. Pickard: Institute of Science and Technology in Medicine, School of Life Sciences, Keele University
Ian Mitchelle S. de Vera: Scripps Research Institute
Emily G. Kuiper: Emory University School of Medicine
Mirna Mourtada-Maarabouni: Institute of Science and Technology in Medicine, School of Life Sciences, Keele University
Graeme L. Conn: Emory University School of Medicine
Douglas J. Kojetin: Scripps Research Institute
Gwyn T. Williams: Institute of Science and Technology in Medicine, School of Life Sciences, Keele University
Eric A. Ortlund: Emory University School of Medicine

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms6395

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