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

Hudson, William H.
; 
Pickard, Mark R.
; 
de Vera, Ian M.
; 
Kuiper, Emily G.
; 
Mourtada-Maarabouni, Mirna
; 
Conn, Graeme L.
; 
Kojetin, Douglas J.
; 
Williams, Gwyn T.
; 
Ortlund, Eric A.
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Affiliation
Emory University School of Medicine; Keele University; Scripps Research Institute
EPub Date
Publication Date
2014-11-07
Submitted Date
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Chester Medical School
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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. (2014). Conserved sequence-specific lincRNA-steroid receptor interactions drive transcriptional repression and direct cell fate. Nature Communications, 5. DOI: 10.1038/ncomms6395
Publisher
Nature Publishing Group
Journal
Nature Communications
Research Unit
URI
http://hdl.handle.net/10034/604480
DOI
10.1038/ncomms6395
PubMed ID
25377354
PubMed Central ID
PMC4280027
Type
Article
Language
en
Description
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ISSN
EISSN
2041-1723
ISBN
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Sponsors
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.
Additional Links
http://www.nature.com/ncomms/2014/141107/ncomms6395/full/ncomms6395.html