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Differential transcript usage unravels gene expression alterations in Alzheimer’s disease human brains
npj Aging ( IF 4.1 ) Pub Date : 2021-01-04 , DOI: 10.1038/s41514-020-00052-5
Diego Marques-Coelho 1, 2 , Lukas da Cruz Carvalho Iohan 1, 2 , Ana Raquel Melo de Farias 1, 3 , Amandine Flaig 3 , , Jean-Charles Lambert 3 , Marcos Romualdo Costa 1, 3
Affiliation  

Alzheimer’s disease (AD) is the leading cause of dementia in aging individuals. Yet, the pathophysiological processes involved in AD onset and progression are still poorly understood. Among numerous strategies, a comprehensive overview of gene expression alterations in the diseased brain could contribute for a better understanding of the AD pathology. In this work, we probed the differential expression of genes in different brain regions of healthy and AD adult subjects using data from three large transcriptomic studies: Mayo Clinic, Mount Sinai Brain Bank (MSBB), and ROSMAP. Using a combination of differential expression of gene and isoform switch analyses, we provide a detailed landscape of gene expression alterations in the temporal and frontal lobes, harboring brain areas affected at early and late stages of the AD pathology, respectively. Next, we took advantage of an indirect approach to assign the complex gene expression changes revealed in bulk RNAseq to individual cell types/subtypes of the adult brain. This strategy allowed us to identify previously overlooked gene expression changes in the brain of AD patients. Among these alterations, we show isoform switches in the AD causal gene amyloid-beta precursor protein (APP) and the risk gene bridging integrator 1 (BIN1), which could have important functional consequences in neuronal cells. Altogether, our work proposes a novel integrative strategy to analyze RNAseq data in AD and other neurodegenerative diseases based on both gene/transcript expression and regional/cell-type specificities.



中文翻译:

差异转录本的使用揭示了阿尔茨海默病人脑中的基因表达变化

阿尔茨海默病(AD)是老年人痴呆的主要原因。然而,AD 发病和进展的病理生理过程仍然知之甚少。在众多策略中,全面概述患病大脑中的基因表达变化可能有助于更好地了解 AD 病理学。在这项工作中,我们利用梅奥诊所、​​西奈山脑库 (MSBB) 和 ROSMAP 等三项大型转录组研究的数据,探讨了健康和 AD 成人受试者不同大脑区域中基因的差异表达。通过结合基因差异表达和亚型转换分析,我们提供了颞叶和额叶基因表达变化的详细情况,分别包含在 AD 病理学早期和晚期受影响的大脑区域。接下来,我们利用间接方法将批量 RNAseq 中揭示的复杂基因表达变化分配给成人大脑的单个细胞类型/亚型。这一策略使我们能够识别 AD 患者大脑中以前被忽视的基因表达变化。在这些改变中,我们发现了 AD 致病基因淀粉样β前体蛋白 (APP) 和风险基因桥接整合子 1 (BIN1) 中的异构体转换,这可能对神经元细胞产生重要的功能影响。总而言之,我们的工作提出了一种新的综合策略,基于基因/转录本表达和区域/细胞类型特异性来分析 AD 和其他神经退行性疾病的 RNAseq 数据。

更新日期:2021-01-04
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