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The long non-coding RNA Gomafu is acutely regulated in response to neuronal activation and involved in schizophrenia-associated alternative splicing

Molecular Psychiatry volume 19, pages 486–494 (2014)Cite this article

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Abstract

Schizophrenia (SZ) is a complex disease characterized by impaired neuronal functioning. Although defective alternative splicing has been linked to SZ, the molecular mechanisms responsible are unknown. Additionally, there is limited understanding of the early transcriptomic responses to neuronal activation. Here, we profile these transcriptomic responses and show that long non-coding RNAs (lncRNAs) are dynamically regulated by neuronal activation, including acute downregulation of the lncRNA Gomafu, previously implicated in brain and retinal development. Moreover, we demonstrate that Gomafu binds directly to the splicing factors QKI and SRSF1 (serine/arginine-rich splicing factor 1) and dysregulation of Gomafu leads to alternative splicing patterns that resemble those observed in SZ for the archetypal SZ-associated genes DISC1 and ERBB4. Finally, we show that Gomafu is downregulated in post-mortem cortical gray matter from the superior temporal gyrus in SZ. These results functionally link activity-regulated lncRNAs and alternative splicing in neuronal function and suggest that their dysregulation may contribute to neurological disorders.

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Acknowledgements

Post-mortem human tissue was received from the Australian Brain Donor Programs New South Wales (NSW) Tissue Resource Centre, which is supported by The University of Sydney, National Health and Medical Research Council of Australia, Schizophrenia Research Institute, National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health, and the NSW Department of Health. JSM was supported by an Australia Fellowship grant from the National Health and Medical Research Council (631668) and a Discovery Project grant from the Australian Research Council (DP120100729). NB was supported by NHMRC Project Grant 631057. MC is supported by the Schizophrenia Research Institute and an MC Ainsworth Research Fellowship in Epigenetics. RJT is supported by an Australia Research Council Discovery Early Career Researcher Award. DPV is supported by an ANZ Trustees Scholarship for Medical Research. TB was supported by grants from the National Health and Medical Research Council (APP1023127) and the Australian Research Council (DP1096148).

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Authors and Affiliations

  1. Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia

    G Barry, D P Vanichkina, R J Taft & J S Mattick

  2. Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia

    J A Briggs, S P Nayler & E J Wolvetang

  3. Department of Neuroscience, Neurology and Ophthalmology, Center for High-Throughput Biology and Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    E M Poth & S Blackshaw

  4. Schizophrenia Research Institute, Sydney, NSW, Australia

    N J Beveridge & M J Cairns

  5. The University of Newcastle, Callaghan, NSW, Australia

    N J Beveridge & M J Cairns

  6. Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia

    V S Ratnu & T W Bredy

  7. Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia

    K Nones

  8. Wilmer Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    J Hu

  9. RNA Biology Laboratory, RIKEN Advanced Research Institute, Wako, Saitama, Japan

    S Nakagawa

  10. Isis Pharmaceuticals, Carlsbad, CA, USA

    F Rigo

  11. Garvan Institute of Medical Research, Sydney, NSW, Australia

    J S Mattick

  12. St Vincent’s Clinical School and School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia

    J S Mattick

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  1. G Barry
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Barry, G., Briggs, J., Vanichkina, D. et al. The long non-coding RNA Gomafu is acutely regulated in response to neuronal activation and involved in schizophrenia-associated alternative splicing. Mol Psychiatry 19, 486–494 (2014). https://doi.org/10.1038/mp.2013.45

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