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

Hdl Handle:
http://hdl.handle.net/10034/604480
Title:
Conserved sequence-specific lincRNA-steroid receptor interactions drive transcriptional repression and direct cell fate
Authors:
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.
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.
Affiliation:
Emory University School of Medicine; Keele University; Scripps Research Institute
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
Publication Date:
7-Nov-2014
URI:
http://hdl.handle.net/10034/604480
DOI:
10.1038/ncomms6395
PubMed ID:
25377354
PubMed Central ID:
PMC4280027
Additional Links:
http://www.nature.com/ncomms/2014/141107/ncomms6395/full/ncomms6395.html
Type:
Article
Language:
en
EISSN:
2041-1723
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.
Appears in Collections:
Institute of Medicine

Full metadata record

DC FieldValue Language
dc.contributor.authorHudson, William H.en
dc.contributor.authorPickard, Mark R.en
dc.contributor.authorde Vera, Ian M.en
dc.contributor.authorKuiper, Emily G.en
dc.contributor.authorMourtada-Maarabouni, Mirnaen
dc.contributor.authorConn, Graeme L.en
dc.contributor.authorKojetin, Douglas J.en
dc.contributor.authorWilliams, Gwyn T.en
dc.contributor.authorOrtlund, Eric A.en
dc.date.accessioned2016-04-05T15:28:10Zen
dc.date.available2016-04-05T15:28:10Zen
dc.date.issued2014-11-07en
dc.identifier.citationHudson, W. H. (2014). Conserved sequence-specific lincRNA-steroid receptor interactions drive transcriptional repression and direct cell fate. Nature Communications, 5. DOI: 10.1038/ncomms6395en
dc.identifier.pmid25377354en
dc.identifier.doi10.1038/ncomms6395en
dc.identifier.urihttp://hdl.handle.net/10034/604480en
dc.description.abstractThe 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.en
dc.description.sponsorshipEmory-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.en
dc.language.isoenen
dc.publisherNature Publishing Groupen
dc.relation.urlhttp://www.nature.com/ncomms/2014/141107/ncomms6395/full/ncomms6395.htmlen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectGAS5en
dc.subjectlncRNAen
dc.subjectSteroid receptorsen
dc.subjectTranscriptional reporessionen
dc.titleConserved sequence-specific lincRNA-steroid receptor interactions drive transcriptional repression and direct cell fateen
dc.typeArticleen
dc.identifier.eissn2041-1723en
dc.contributor.departmentEmory University School of Medicine; Keele University; Scripps Research Instituteen
dc.identifier.journalNature Communicationsen
dc.identifier.pmcidPMC4280027en

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