A conserved role for the ALS-linked splicing factor SFPQ in repression of pathogenic cryptic last exons.
A conserved role for the ALS-linked splicing factor SFPQ in repression of pathogenic cryptic last exons.
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DOI：
10.1038/s41467-021-22098-z
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发表时间：
2021-03-26
影响因子：
16.6
通讯作者：
Houart C
中科院分区：
文献类型：
--
作者：
Gordon PM;Hamid F;Makeyev EV;Houart C
RNA结合蛋白SFPQ在神经元发育中起重要作用，并且与几种神经退行性疾病相关，包括肌萎缩侧索硬化症（ALS）、额颞叶痴呆（FTD）和阿尔茨海默病。在这里，我们报告说，sfpq的损失导致过早终止的多个成绩单，由于广泛激活以前未注释的神秘的最后一个外显子（克莱斯）。这些SFPQ抑制的克莱斯优先出现在具有神经元功能的基因的长内含子中，并且可以抑制基因表达输出和/或产生干扰正常基因功能的短肽。我们发现，这样的一个肽编码的CLE-containing Epha 4 B mRNA亚型是负责神经发育缺陷的sfpq突变体。SFPQ的未被发现的CLE抑制活性在小鼠和人类中是保守的，并且发现SFPQ抑制的克莱斯在ALS iPSC衍生的神经元中表达。这些结果大大扩展了我们对SFPQ功能的理解，并揭示了与人类神经病理学广泛相关的基因调控机制。SFPQ是一种剪接因子，其突变与肌萎缩侧索硬化（ALS）患者相关。在这里，作者表明SFPQ抑制了斑马鱼、小鼠和人类细胞中致病性隐蔽最后外显子的使用。
The RNA-binding protein SFPQ plays an important role in neuronal development and has been associated with several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer’s disease. Here, we report that loss of sfpq leads to premature termination of multiple transcripts due to widespread activation of previously unannotated cryptic last exons (CLEs). These SFPQ-inhibited CLEs appear preferentially in long introns of genes with neuronal functions and can dampen gene expression outputs and/or give rise to short peptides interfering with the normal gene functions. We show that one such peptide encoded by the CLE-containing epha4b mRNA isoform is responsible for neurodevelopmental defects in the sfpq mutant. The uncovered CLE-repressive activity of SFPQ is conserved in mouse and human, and SFPQ-inhibited CLEs are found expressed across ALS iPSC-derived neurons. These results greatly expand our understanding of SFPQ function and uncover a gene regulation mechanism with wide relevance to human neuropathologies. SFPQ is a splicing factor and its mutations are associated to amyotrophic lateral sclerosis (ALS) patients. Here, the authors show that SFPQ represses the use of pathogenic cryptic last exons in zebrafish, mouse and human cells.
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影响因子：
64.8
作者：
通讯作者：
--
FOX-3和PSF相互作用以激活神经细胞特异性替代剪接。
影响因子：
14.9
作者：
Kim KK;Kim YC;Adelstein RS;Kawamoto S
通讯作者：
Kawamoto S
影响因子：
3.1
作者：
Guvenek, Aysegul;Tian, Bin
通讯作者：
Tian, Bin
影响因子：
9.5
作者：
Hubisz, Melissa J.;Pollard, Katherine S.;Siepel, Adam
通讯作者：
Siepel, Adam
影响因子：
16.2
作者：
Holt CE;Schuman EM
通讯作者：
Schuman EM