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

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.Emory-NIH Graduate Training in Pharmacological Studies Grant 5T32GM008602-14; American Heart Association predoctoral fellowship (13PRE16920012); National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under award number RO1DK095750; Breast Cancer Campaign UK; Leukemia and Lymphoma Research UK; Prostate Cancer UK