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An alanine expanded PABPN1 causes increased utilization of intronic polyadenylation sites
npj Aging and Mechanisms of Disease Pub Date : 2017-04-07 , DOI: 10.1038/s41514-017-0007-x
Tooba Abbassi-Daloii , Soheil Yousefi , Eleonora de Klerk , Laurens Grossouw , Muhammad Riaz , Peter A. C. ’t Hoen , Vered Raz

In eukaryote genomes, the polyadenylation site marks termination of mature RNA transcripts by a poly-adenine tail. The polyadenylation site is recognized by a dynamic protein complex, among which the poly-adenine-binding protein nuclear1 plays a key role. Reduced poly-adenine-binding protein nuclear1 levels are found in aged muscles and are even lower in oculopharyngeal muscular dystrophy patients. Oculopharyngeal muscular dystrophy is a rare, late onset autosomal dominant myopathy, and is caused by an alanine expansion mutation in poly-adenine-binding protein nuclear1. Mutant poly-adenine-binding protein nuclear1 forms insoluble nuclear aggregates leading to depletion of functional poly-adenine-binding protein nuclear1 levels. In oculopharyngeal muscular dystrophy models, increased utilization of proximal polyadenylation sites has been observed in tandem 3′-untranslated regions, and most often cause gene upregulation. However, global alterations in expression profiles canonly partly be explained by polyadenylation site switches within the most distal 3′-untranslated region. Most poly-adenine signals are found at the distal 3′-untranslated region, but a significant part is also found in internal gene regions, like introns, exons, and internal 3′-untranslated regions. Here, we investigated poly-adenine-binding protein nuclear1’s role in polyadenylation site utilization in internal gene regions. In the quadriceps muscle of oculopharyngeal muscular dystrophy mice expressing expPABPN1 we found significant polyadenylation site switches between gene regions in 17% of genes with polyadenylation site in multiple regions (N = 574; 5% False Discovery Rate). Polyadenylation site switches between gene regions were associated with differences in transcript expression levels and alterations in open reading frames. Transcripts ending at internal polyadenylation site were confirmed in tibialis anterior muscles from the same mice and in mouse muscle cell cultures overexpressing expPABPN1. The polyadenylation site switches were associated with nuclear accumulation of full-length transcripts. Our results provide further insights into the diverse roles of poly-adenine-binding protein nuclear1 in the post-transcriptional control of muscle gene expression and its relevance for oculopharyngeal muscular dystrophy pathology and muscle aging.



中文翻译:

丙氨酸扩展的PABPN1导致内含子聚腺苷酸化位点利用率提高

在真核生物基因组中,聚腺苷酸化位点标记了成熟的RNA转录物通过聚腺嘌呤尾巴的终止。聚腺苷酸化位点被动态蛋白复合物识别,其中聚腺嘌呤结合蛋白nuclear1发挥关键作用。在老年肌肉中发现降低的聚腺嘌呤结合蛋白nuclear1水平,在眼咽肌营养不良患者中甚至更低。眼咽肌营养不良是一种罕见的,迟发的常染色体显性肌病,由多腺嘌呤结合蛋白nuclear1的丙氨酸扩展突变引起。突变的聚腺嘌呤结合蛋白nucleo1形成不溶性核聚集体,导致功能性聚腺嘌呤结合蛋白nuclear1水平耗竭。在眼咽肌营养不良模型中,在串联的3'非翻译区中观察到近端聚腺苷酸化位点的利用率提高,并且最常见的是引起基因上调。然而,表达谱的整体改变只能部分地由最远端的3'-非翻译区内的聚腺苷酸化位点开关来解释。大多数聚腺嘌呤信号存在于远端3'非翻译区,但也有很大一部分存在于内部基因区域,如内含子,外显子和内部3'非翻译区。在这里,我们调查了内部基因区域中聚腺嘌呤结合蛋白nuclear1在聚腺苷酸化位点利用中的作用。在表达expPABPN1的眼咽肌营养不良小鼠的股四头肌中,我们发现17%的基因的多聚腺苷酸化位点在多个区域具有多聚腺苷酸化位点(N  = 574;5%的错误发现率)。基因区域之间的聚腺苷酸化位点转换与转录表达水平的差异和开放阅读框中的改变有关。在同一只小鼠的胫前肌和过表达expPABPN1的小鼠肌肉细胞培养物中,证实了在内部聚腺苷酸化位点处终止的转录本。聚腺苷酸化位点开关与全长转录本的核积累有关。我们的结果提供了进一步的见解,对腺嘌呤结合蛋白nuclear1在转录后控制肌肉基因表达中的各种作用及其与眼咽肌营养不良症病理和肌肉衰老的相关性。

更新日期:2017-04-07
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