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

Nat Commun. 2014 Nov 7:5:5395. doi: 10.1038/ncomms6395.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Apoptosis / genetics
  • Apoptosis / physiology*
  • Base Sequence
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Cell Proliferation / physiology*
  • Conserved Sequence*
  • Female
  • Humans
  • Magnetic Resonance Spectroscopy
  • Male
  • Models, Genetic
  • Mutation / genetics
  • Prostatic Neoplasms / pathology
  • RNA, Long Noncoding / chemistry
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / physiology*
  • RNA, Small Nucleolar / chemistry
  • RNA, Small Nucleolar / genetics
  • RNA, Small Nucleolar / physiology*
  • Receptors, Steroid / genetics
  • Receptors, Steroid / physiology*
  • Response Elements / genetics
  • Response Elements / physiology
  • Transcription, Genetic / genetics
  • Transcription, Genetic / physiology*

Substances

  • RNA, Long Noncoding
  • RNA, Small Nucleolar
  • Receptors, Steroid
  • growth arrest specific transcript 5

Associated data

  • PDB/4MCE
  • PDB/4MCF