• 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.; Emory University School of Medicine; Keele University; Scripps Research Institute (Nature Publishing Group, 2014-11-07)
      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.
    • The developing landscape of diagnostic and prognostic biomarkers for spinal cord injury in cerebrospinal fluid and blood

      Hulme CH; Brown SJ; Fuller HR; Riddell J; Osman A; Chowdhury J; Kumar N; Johnson WE; Wright KT; Keele University, RJAH Orthopaedic Hospital, University of Glasgow, University of Chester (Nature Publishing Group, 2016-12-20)
      STUDY DESIGN: Review study. OBJECTIVES: The identification of prognostic biomarkers of spinal cord injury (SCI) will help to assign SCI patients to the correct treatment and rehabilitation regimes. Further, the detection of biomarkers that predict permanent neurological outcome would aid in appropriate recruitment of patients into clinical trials. The objective of this review is to evaluate the current state-of-play in this developing field. SETTING: Studies from multiple countries were included. METHODS: We have completed a comprehensive review of studies that have investigated prognostic biomarkers in either the blood or cerebrospinal fluid (CSF) of animals and humans following SCI. RESULTS: Targeted and unbiased approaches have identified several prognostic biomarkers in CSF and blood. These proteins associate with cellular damage following SCI and include components from neurons, oligodendrocytes and reactive astrocytes, that is, neurofilament proteins, glial fibrillary acidic protein, Tau and S100 calcium-binding protein β. Unbiased approaches have also identified microRNAs that are specific to SCI, as well as other cell damage-associated proteins. CONCLUSIONS: The discovery and validation of stable, specific, sensitive and reproducible biomarkers of SCI is a rapidly expanding field of research. So far, few studies have utilised unbiased approaches aimed at the discovery of biomarkers within the CSF or blood in this field; however, some targeted approaches have been successfully used. Several studies using various animal models and some with small human patient cohorts have begun to pinpoint biomarkers in the CSF and blood with putative prognostic value. An increased sample size will be required to validate these biomarkers in the heterogeneous clinical setting.