The long non-coding RNA Gomafu is acutely regulated in response to neuronal activation and involved in schizophrenia-associated alternative splicing
The long non-coding RNA Gomafu is acutely regulated in response to neuronal activation and involved in schizophrenia-associated alternative splicing
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DOI：
10.1038/mp.2013.45
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发表时间：
2014-04-01
影响因子：
11
通讯作者：
Mattick, J. S.
中科院分区：
文献类型：
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作者：
Barry, G.;Briggs, J. A.;Mattick, J. S.
精神分裂症（SZ）是一种以神经功能受损为特征的复杂疾病。虽然有缺陷的选择性剪接与SZ有关，但其分子机制尚不清楚。此外，对神经元激活的早期转录组反应的理解有限。在这里，我们分析了这些转录组反应，并表明长链非编码RNA（IncRNA）受到神经元激活的动态调节，包括IncRNA Gomafu的急性下调，该RNA此前与大脑和视网膜发育有关。此外，我们证明，Gomafu直接结合到剪接因子QKI和SRSF 1（丝氨酸/丝氨酸丰富的剪接因子1）和Gomafu的失调导致选择性剪接模式，类似于在SZ中观察到的原型SZ相关基因DISC 1和ERBB 4。最后，我们表明Gomafu在深圳的上级颞回死后皮质灰质中下调。这些结果在功能上将活性调节的lncRNA和神经元功能中的选择性剪接联系起来，并表明它们的失调可能导致神经系统疾病。
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 (IncRNAs) are dynamically regulated by neuronal activation, including acute downregulation of the IncRNA 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.