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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 486-494 |
| Number of pages | 9 |
| Journal | Molecular Psychiatry |
| Volume | 19 |
| Issue number | 4 |
| DOIs | |
| State | Published - 2014 |
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Keywords
- Alternative splicing
- Gomafu
- Neuronal activation
- Quaking homolog
- Schizophrenia
ASJC Scopus subject areas
- Molecular Biology
- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
Cite this
The long non-coding RNA Gomafu is acutely regulated in response to neuronal activation and involved in schizophrenia-associated alternative splicing. / Barry, G.; Briggs, J. A.; Vanichkina, D. P.; Poth, E. M.; Beveridge, N. J.; Ratnu, V. S.; Nayler, S. P.; Nones, K.; Hu, J.; Bredy, T. W.; Nakagawa, S.; Rigo, F.; Taft, R. J.; Cairns, M. J.; Blackshaw, Seth; Wolvetang, E. J.; Mattick, J. S.
In: Molecular Psychiatry, Vol. 19, No. 4, 2014, p. 486-494.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The long non-coding RNA Gomafu is acutely regulated in response to neuronal activation and involved in schizophrenia-associated alternative splicing
AU - Barry, G.
AU - Briggs, J. A.
AU - Vanichkina, D. P.
AU - Poth, E. M.
AU - Beveridge, N. J.
AU - Ratnu, V. S.
AU - Nayler, S. P.
AU - Nones, K.
AU - Hu, J.
AU - Bredy, T. W.
AU - Nakagawa, S.
AU - Rigo, F.
AU - Taft, R. J.
AU - Cairns, M. J.
AU - Blackshaw, Seth
AU - Wolvetang, E. J.
AU - Mattick, J. S.
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
KW - Alternative splicing
KW - Gomafu
KW - Neuronal activation
KW - Quaking homolog
KW - Schizophrenia
UR - http://www.scopus.com/inward/record.url?scp=84897108067&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84897108067&partnerID=8YFLogxK
U2 - 10.1038/mp.2013.45
DO - 10.1038/mp.2013.45
M3 - Article
C2 - 23628989
AN - SCOPUS:84897108067
VL - 19
SP - 486
EP - 494
JO - Molecular Psychiatry
JF - Molecular Psychiatry
SN - 1359-4184
IS - 4
ER -