Characterization of Cerebellum-Specific Ribosomal DNA Epigenetic Modifications in Alzheimer's Disease: Should the Cerebellum Serve as a Control Tissue After All?
Characterization of Cerebellum-Specific Ribosomal DNA Epigenetic Modifications in Alzheimer's Disease: Should the Cerebellum Serve as a Control Tissue After All?
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DOI：
10.1007/s12035-020-01902-9
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发表时间：
2020-03-30
影响因子：
5.1
通讯作者：
Chen, Elizabeth S.
中科院分区：
文献类型：
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作者：
Faria, Tathyane C.;Maldonado, Hector L.;Chen, Elizabeth S.
阿尔茨海默病（AD）是一种神经退行性疾病，被称为最常见的痴呆形式。在AD发病中，已报道异常rRNA表达与发病机制有关。虽然区域特异性表达模式以前曾在AD中报道，但直到最近小脑才受到关注。具体而言，目前尚不清楚DNA甲基化是否是参与AD中rRNA表达调控的机制。因此，我们试图探索两个不同的大脑区域-听觉皮层和小脑-从AD和年龄/性别匹配的对照rDNA甲基化模式。我们的研究结果表明，差异超甲基化在上游CpG区域的rDNA启动子比较小脑控制听觉皮层控制。这表明一个可能的调控区域从rDNA的表达调控。此外，当比较AD和对照小脑样品时，我们观察到rDNA启动子区域的超甲基化以及rDNA含量的增加。此外，我们还观察到增加的rRNA水平在AD相比，控制小脑。虽然仍然被认为是一个无病理的大脑区域，但越来越多的发现继续表明并非如此。事实上，最近已经描述了AD的小脑受到疾病的影响，呈现出独特的分子改变模式。鉴于我们观察到，增加rDNA启动子甲基化并没有沉默rDNA基因表达，我们认为，rDNA启动子超甲基化在rDNA基因组稳定性中起着保护作用，因此，增加了AD小脑中的rRNA水平。
Alzheimer's disease (AD) is a neurodegenerative disease, known as the most common form of dementia. In AD onset, abnormal rRNA expression has been reported to be linked in pathogenesis. Although region-specific expression patterns have previously been reported in AD, it is not until recently that the cerebellum has come under the spotlight. Specifically, it is unclear whether DNA methylation is the mechanism involved in rRNA expression regulation in AD. Hence, we sought to explore the rDNA methylation pattern of two different brain regions - auditory cortex and cerebellum - from AD and age-/sex-matched controls. Our results showed differential hypermethylation at an upstream CpG region to the rDNA promoter when comparing cerebellum controls to auditory cortex controls. This suggests a possible regulatory region from rDNA expression regulation. Moreover, when comparing between AD and control cerebellum samples, we observed hypermethylation of the rDNA promoter region as well as an increase in rDNA content. In addition, we also observed increased rRNA levels in AD compared to control cerebellum. Although still considered a pathology-free brain region, there are growing findings that continue to suggest otherwise. Indeed, cerebellum from AD has been recently described as affected by the disease, presenting a unique pattern of molecular alterations. Given that we observed that increased rDNA promoter methylation did not silence rDNA gene expression, we suggest that rDNA promoter hypermethylation is playing a protective role in rDNA genomic stability and, therefore, increasing rRNA levels in AD cerebellum.