Centre for Neurodegeneration Research, King's College London, Institute of Psychiatry, De Crespigny Park, London, UK.
Sci Rep. 2012;2:603. doi: 10.1038/srep00603. Epub 2012 Aug 28.
Fused in sarcoma (FUS) and TAR DNA-binding protein 43 (TDP-43) are RNA-binding proteins pathogenetically linked to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), but it is not known if they regulate the same transcripts. We addressed this question using crosslinking and immunoprecipitation (iCLIP) in mouse brain, which showed that FUS binds along the whole length of the nascent RNA with limited sequence specificity to GGU and related motifs. A saw-tooth binding pattern in long genes demonstrated that FUS remains bound to pre-mRNAs until splicing is completed. Analysis of FUS(-/-) brain demonstrated a role for FUS in alternative splicing, with increased crosslinking of FUS in introns around the repressed exons. We did not observe a significant overlap in the RNA binding sites or the exons regulated by FUS and TDP-43. Nevertheless, we found that both proteins regulate genes that function in neuronal development.
融合肉瘤（FUS）和 TAR DNA 结合蛋白 43（TDP-43）是与肌萎缩侧索硬化症（ALS）和额颞叶变性（FTLD）发病机制相关的 RNA 结合蛋白，但尚不清楚它们是否调节相同的转录本。我们使用小鼠大脑中的交联和免疫沉淀（iCLIP）来解决这个问题，结果表明 FUS 沿着新生 RNA 的全长与 GGU 和相关基序具有有限的序列特异性结合。长基因中的锯齿状结合模式表明，FUS 会一直结合到前体 mRNA 上，直到剪接完成。FUS(-/-) 大脑的分析表明 FUS 在可变剪接中起作用，受抑制外显子周围内含子中的 FUS 交联增加。我们没有观察到 FUS 和 TDP-43 的 RNA 结合位点或受其调节的外显子有显著重叠。然而，我们发现这两种蛋白质都调节在神经元发育中起作用的基因。
