Suppression of premature transcription termination leads to reduced mRNA isoform diversity and neurodegeneration.
Suppression of premature transcription termination leads to reduced mRNA isoform diversity and neurodegeneration.
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抑制过早的转录终止导致mRNA异构体多样性减少和神经变性。
DOI：
10.1016/j.neuron.2022.01.018
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发表时间：
2022-04-20
期刊：
影响因子：
16.2
通讯作者：
Schaffer AE
中科院分区：
文献类型：
--
作者：
LaForce GR;Farr JS;Liu J;Akesson C;Gumus E;Pinkard O;Miranda HC;Johnson K;Sweet TJ;Ji P;Lin A;Coller J;Philippidou P;Wagner EJ;Schaffer AE
严格调控mRNA异构体的表达对于神经元的发育、维持和功能是必不可少的；然而，控制异构体组成和丰度的蛋白质谱系仍然不完整。在这里，我们表明，RNA激酶CLP1通过抑制近端切割和多聚腺苷化来调节mRNA异构体的表达。我们发现，没有CLP1或带有与疾病相关的CLP1p.R140H变体的人干细胞来源的运动神经元具有不同的RNA聚合酶II相关的切割和多腺化复合蛋白的模式，这些蛋白与多腺化位点的使用相关。这些变化导致了对神经元功能至关重要的长基因在体内重复的不平衡的mRNA异构体表达。值得注意的是，我们在神经退行性疾病患者脑组织的3‘末端测序数据中观察到了相同的减少的mRNA亚型多样性的模式。总之，我们的结果确定了CLP1在mRNA3‘末端形成中先前未知的角色，并揭示了神经退行性变中的mRNA误处理特征，这可能提示了一种常见的疾病机制。LaForce等人。利用运动神经元疾病模型检测CLP1在mRNA3‘末端形成中的作用。CLP1通过抑制近端多聚腺苷酸化来调节mRNA的异构体平衡，维持神经元的健康。作者发现，异构体多样性减少是神经退行性疾病的标志。
Tight regulation of mRNA isoform expression is essential for neuronal development, maintenance, and function; however, the repertoire of proteins that govern isoform composition and abundance remains incomplete. Here, we show that the RNA kinase CLP1 regulates mRNA isoform expression through suppression of proximal cleavage and polyadenylation. We found that human stem-cell-derived motor neurons without CLP1 or with the disease-associated CLP1 p.R140H variant had distinct patterns of RNA-polymerase-II-associated cleavage and polyadenylation complex proteins that correlated with polyadenylation site usage. These changes resulted in imbalanced mRNA isoform expression of long genes important for neuronal function that were recapitulated in vivo. Strikingly, we observed the same pattern of reduced mRNA isoform diversity in 3′ end sequencing data from brain tissues of patients with neurodegenerative disease. Together, our results identify a previously uncharacterized role for CLP1 in mRNA 3′ end formation and reveal an mRNA misprocessing signature in neurodegeneration that may suggest a common mechanism of disease. LaForce et al. utilize motor neuron disease models to examine CLP1 function in mRNA 3′ end formation. CLP1 suppresses proximal polyadenylation to regulate mRNA isoform balance and maintain neuronal health. The authors find that diminished isoform diversity is a signature of neurodegenerative disease.
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影响因子：
25
作者：
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通讯作者：
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影响因子：
64.5
作者：
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通讯作者：
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影响因子：
14.9
作者：
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通讯作者：
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