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

Author

Listed:
  • William H. Hudson

    (Emory University School of Medicine
    Discovery and Developmental Therapeutics, Winship Cancer Institute)

  • 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
    Discovery and Developmental Therapeutics, Winship Cancer Institute)

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.

Suggested Citation

  • 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 & Eric A. Ortlund, 2014. "Conserved sequence-specific lincRNA–steroid receptor interactions drive transcriptional repression and direct cell fate," Nature Communications, Nature, vol. 5(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6395
    DOI: 10.1038/ncomms6395
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