FUS regulates genes coding for RNA-binding proteins in neurons by binding to their highly conserved introns
FUS regulates genes coding for RNA-binding proteins in neurons by binding to their highly conserved introns
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DOI：
10.1261/rna.037804.112
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发表时间：
2013-04-01
期刊：
影响因子：
4.5
通讯作者：
Mourelatos, Zissimos
中科院分区：
文献类型：
--
作者：
Nakaya, Tadashi;Alexiou, Panagiotis;Mourelatos, Zissimos
肉瘤融合蛋白 (FUS)（一种 RNA 结合蛋白 (RBP)）的显性突变和错误定位或聚集会导致肌萎缩侧索硬化症 (ALS) 和额颞叶变性 (FTLD) 这两种无法治愈的神经系统疾病的神经元变性。然而，FUS 在神经元中的功能尚不清楚。为了揭示 FUS 对神经元转录组的影响，我们对人脑和胚胎干细胞分化的小鼠神经元中的 FUS 免疫沉淀和交联 RNA (HITS-CLIP) 进行高通量测序，并结合 RNA-seq 和 FUS 敲低。我们报告了受 FUS 调控的保守神经元 RNA 靶点和网络。我们发现 FUS 通过与高度保守的内含子结合来调节 RBP 编码基因的剪接。我们的研究结果对于理解 FUS 对神经退行性疾病的影响具有重要意义，并表明 FUS 的扰动可以通过 RBP 转录本的扰动来影响神经元转录组。
Dominant mutations and mislocalization or aggregation of Fused in Sarcoma (FUS), an RNA-binding protein (RBP), cause neuronal degeneration in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD), two incurable neurological diseases. However, the function of FUS in neurons is not well understood. To uncover the impact of FUS in the neuronal transcriptome, we used high-throughput sequencing of immunoprecipitated and cross-linked RNA (HITS-CLIP) of FUS in human brains and mouse neurons differentiated from embryonic stem cells, coupled with RNA-seq and FUS knockdowns. We report conserved neuronal RNA targets and networks that are regulated by FUS. We find that FUS regulates splicing of genes coding for RBPs by binding to their highly conserved introns. Our findings have important implications for understanding the impact of FUS in neurodegenerative diseases and suggest that perturbations of FUS can impact the neuronal transcriptome via perturbations of RBP transcripts.