Genome-wide histone acetylation analysis reveals altered transcriptional regulation in the Parkinson's disease brain.
Genome-wide histone acetylation analysis reveals altered transcriptional regulation in the Parkinson's disease brain.
复制标题
DOI：
10.1186/s13024-021-00450-7
复制
发表时间：
2021-05-05
影响因子：
15.1
通讯作者：
Tzoulis C
中科院分区：
文献类型：
--
作者：
Toker L;Tran GT;Sundaresan J;Tysnes OB;Alves G;Haugarvoll K;Nido GS;Dölle C;Tzoulis C
帕金森病（PD）是一种复杂的、与年龄相关的神经退行性疾病，其病因尚不清楚。PD与线粒体呼吸功能障碍密切相关，线粒体呼吸功能障碍可导致表观遗传失调和组蛋白乙酰化的特异性改变。然而，尽管表观遗传学在年龄相关性脑疾病中的作用正在显现，但异常组蛋白乙酰化是否参与PD的问题仍未得到解决。我们研究了来自两个独立队列的特发性PD患者（n = 28）和神经健康对照组（n = 21）的新鲜冷冻脑组织。我们进行了全面的免疫印迹，以确定组蛋白的网站与改变乙酰化水平的PD，然后染色质免疫沉淀测序（ChIP-seq）。来自相同个体的RNA测序数据用于评估改变的组蛋白乙酰化对基因表达的影响。免疫印迹分析显示PD中几个组蛋白位点的乙酰化增加，其中H3 K27观察到最显著的变化，H3 K27是活性启动子和增强子的标志物。ChIP-seq分析进一步表明，PD脑中的H3 K27超乙酰化是一种全基因组现象，对与疾病有关的基因具有强烈的偏好，包括SNCA，PARK 7，PRKN和MAPT。ChIP-seq与来自相同个体的转录组数据的整合揭示了在PD患者中启动子H3 K27乙酰化和基因表达之间的相关性减弱，这表明H3 K27乙酰化可能与PD脑中的转录解耦。引人注目的是，这种解耦在核编码的线粒体基因中最为明显，证实了核与线粒体之间的串扰受损参与PD发病机制的观点。我们的研究结果在两个队列中独立重复。我们的研究结果强烈表明，异常组蛋白乙酰化和改变转录调控参与PD的病理生理。我们证明了PD相关基因特别容易发生表观遗传失调，并确定了与疾病相关的新表观遗传特征。在线版本包含补充材料，可通过10.1186/s13024-021-00450-7获取。
Parkinson’s disease (PD) is a complex, age-related neurodegenerative disorder of largely unknown etiology. PD is strongly associated with mitochondrial respiratory dysfunction, which can lead to epigenetic dysregulation and specifically altered histone acetylation. Nevertheless, and despite the emerging role of epigenetics in age-related brain disorders, the question of whether aberrant histone acetylation is involved in PD remains unresolved. We studied fresh-frozen brain tissue from two independent cohorts of individuals with idiopathic PD (n = 28) and neurologically healthy controls (n = 21). We performed comprehensive immunoblotting to identify histone sites with altered acetylation levels in PD, followed by chromatin immunoprecipitation sequencing (ChIP-seq). RNA sequencing data from the same individuals was used to assess the impact of altered histone acetylation on gene expression. Immunoblotting analyses revealed increased acetylation at several histone sites in PD, with the most prominent change observed for H3K27, a marker of active promoters and enhancers. ChIP-seq analysis further indicated that H3K27 hyperacetylation in the PD brain is a genome-wide phenomenon with a strong predilection for genes implicated in the disease, including SNCA, PARK7, PRKN and MAPT. Integration of the ChIP-seq with transcriptomic data from the same individuals revealed that the correlation between promoter H3K27 acetylation and gene expression is attenuated in PD patients, suggesting that H3K27 acetylation may be decoupled from transcription in the PD brain. Strikingly, this decoupling was most pronounced among nuclear-encoded mitochondrial genes, corroborating the notion that impaired crosstalk between the nucleus and mitochondria is involved in the pathogenesis of PD. Our findings independently replicated in the two cohorts. Our findings strongly suggest that aberrant histone acetylation and altered transcriptional regulation are involved in the pathophysiology of PD. We demonstrate that PD-associated genes are particularly prone to epigenetic dysregulation and identify novel epigenetic signatures associated with the disease. The online version contains supplementary material available at 10.1186/s13024-021-00450-7.
登录
查看更多内容
影响因子：
64.8
作者：
Ernst, Jason;Kheradpour, Pouya;Mikkelsen, Tarjei S.;Shoresh, Noam;Ward, Lucas D.;Epstein, Charles B.;Zhang, Xiaolan;Wang, Li;Issner, Robbyn;Coyne, Michael;Ku, Manching;Durham, Timothy;Kellis, Manolis;Bernstein, Bradley E.
通讯作者：
Bernstein, Bradley E.
影响因子：
4.1
作者：
Dickson DW
通讯作者：
Dickson DW
影响因子：
2.9
作者：
Balan, Irina S.;Fiskum, Gary;Kristian, Tibor
通讯作者：
Kristian, Tibor
影响因子：
25
作者：
Girdhar K;Hoffman GE;Jiang Y;Brown L;Kundakovic M;Hauberg ME;Francoeur NJ;Wang YC;Shah H;Kavanagh DH;Zharovsky E;Jacobov R;Wiseman JR;Park R;Johnson JS;Kassim BS;Sloofman L;Mattei E;Weng Z;Sieberts SK;Peters MA;Harris BT;Lipska BK;Sklar P;Roussos P;Akbarian S
通讯作者：
Akbarian S
影响因子：
14.5
作者：
Andrade-Moraes, Carlos Humberto;Oliveira-Pinto, Ana V.;Lent, Roberto
通讯作者：
Lent, Roberto