title: The long non-coding RNA Gomafu is acutely regulated in response to neuronal activation and involved in schizophrenia-associated alternative splicing.
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.
authors: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.
authors: G
authors: G
authors: Barry
authors: Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia.
authors: J A
authors: JA
authors: Briggs
authors: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.
authors: D P
authors: DP
authors: Vanichkina
authors: 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.
authors: E M
authors: EM
authors: Poth
authors: 1] Schizophrenia Research Institute, Sydney, NSW, Australia [2] The University of Newcastle, Callaghan, NSW, Australia.
authors: N J
authors: NJ
authors: Beveridge
authors: Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
authors: V S
authors: VS
authors: Ratnu
authors: Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia.
authors: S P
authors: SP
authors: Nayler
authors: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia.
authors: K
authors: K
authors: Nones
authors: Wilmer Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: J
authors: J
authors: Hu
authors: Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
authors: T W
authors: TW
authors: Bredy
authors: RNA Biology Laboratory, RIKEN Advanced Research Institute, Wako, Saitama, Japan.
authors: S
authors: S
authors: Nakagawa
authors: Isis Pharmaceuticals, Carlsbad, CA, USA.
authors: F
authors: F
authors: Rigo
authors: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.
authors: R J
authors: RJ
authors: Taft
authors: 1] Schizophrenia Research Institute, Sydney, NSW, Australia [2] The University of Newcastle, Callaghan, NSW, Australia.
authors: M J
authors: MJ
authors: Cairns
authors: 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.
authors: S
authors: S
authors: Blackshaw
authors: Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia.
authors: E J
authors: EJ
authors: Wolvetang
authors: 1] Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia [2] Garvan Institute of Medical Research, Sydney, NSW, Australia [3] St Vincent's Clinical School and School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia.
authors: J S
authors: JS
authors: Mattick
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D024202:Electrophoretic Mobility Shift Assay; D004622:Embryo, Mammalian; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D020543:Proteome; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D066247:Receptor, ErbB-4; D012559:Schizophrenia / Q000235:genetics*; D000068103:Serine-Arginine Splicing Factors
chemical_list: C412476:DISC1 protein, human; C517383:Miat long non-coding RNA; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense; D020543:Proteome; C490832:QKI protein, human; D062085:RNA, Long Noncoding; D016601:RNA-Binding Proteins; D000068103:Serine-Arginine Splicing Factors; C587689:ERBB4 protein, human; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4
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