Longitudinal intronic RNA-Seq analysis of Parkinson's disease patients reveals disease-specific nascent transcription

被引:7
作者
Koks, Sulev [1 ,2 ]
Pfaff, Abigail L. [1 ,2 ]
Bubb, Vivien J. [3 ]
Quinn, John P. [3 ]
机构
[1] Perron Inst Neurol & Translat Sci, Perth, WA 6009, Australia
[2] Murdoch Univ, Ctr Mol Med & Innovat Therapeut, Perth, WA 6150, Australia
[3] Univ Liverpool, Inst Syst, Dept Pharmacol & Therapeut, Liverpool L69 3BX, Merseyside, England
关键词
Parkinson's disease; transcriptome; whole transcriptome analysis; introns; RNA-Seq; nascent transcript; nascent RNA; PPMI; blood transcriptome; AGGREGATED PROTEINS; METAANALYSIS; GENOME;
D O I
10.1177/15353702221081027
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Transcriptomic studies usually focus on either gene or exon-based annotations, and only limited experiments have reported changes in reads mapping to introns. The analysis of intronic reads allows the detection of nascent transcription that is not influenced by steady-state RNA levels and provides information on actively transcribed genes. Here, we describe substantial intronic transcriptional changes in Parkinson's disease (PD) patients compared to healthy controls (CO) at two different timepoints; at the time of diagnosis (BL) and three years later (V08). We used blood RNA-Seq data from the Parkinson's Progression Markers Initiative (PPMI) cohort and identified significantly changed transcription of intronic reads only in PD patients during this follow-up period. In CO subjects, only nine transcripts demonstrated differentially expressed introns between visits. However, in PD patients, 4873 transcripts had differentially expressed introns at visit V08 compared to BL, many of them in genes previously associated with neurodegenerative diseases, such as LRRK2, C9orf72, LGALS3, KANSL1AS1, and ALS2. In addition, at the time of diagnosis (BL visit), we identified 836 transcripts (e.g. SNCA, DNAJC19, PRRG4) and at visit V08, 2184 transcripts (e.g. PINK1, GBA, ALS2, PLEKHM1) with differential intronic expression specific to PD patients. In contrast, reads mapping to exonic regions demonstrated little variation indicating highly specific changes only in intronic transcription. Our study demonstrated that PD is characterized by substantial changes in the nascent transcription, and description of these changes could help to understand the molecular pathology underpinning this disease.
引用
收藏
页码:945 / 957
页数:13
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