Dysregulation of the epigenetic landscape of normal aging in Alzheimer''s disease [ChIP-Seq]

Aging is the strongest risk factor for Alzheimer''s disease (AD), although the underlying mechanisms remain unclear. The chromatin state, in particular through the mark H4K16ac, has been implicated in aging and thus may play a pivotal role in age-associated neurodegeneration. Here we compared the genome-wide enrichment of H4K16ac in the lateral temporal lobe of AD individuals against both younger and elderly cognitively normal controls. We find that while normal aging leads to H4K16ac enrichment, AD entails dramatic losses of H4K16ac in the proximity of genes linked to aging and AD. Our analysis highlights the presence of three classes of AD-related changes having distinctive functional roles. Furthermore, we discover an association between the genomic locations of significant H4K16ac changes with genetic variants (SNPs) identified in prior AD genome-wide association studies (GWAS) and with expression quantitative trait loci (eQTLs). Our results establish the basis for an epigenetic link between aging and AD. Overall design: ChIP-seq of H4K16ac in healthy and diseased human brains; using 9 young healthy brains (Young), 10 aged healthy brains (Old), and 12 aged diseased brains (AD); H4K16ac and input are included for each sample

衰老是阿尔茨海默病（Alzheimer's disease, AD）最强的风险因素，尽管其潜在发病机制尚未明确。染色质状态，尤其是以组蛋白H4赖氨酸16乙酰化（H4K16ac）为修饰标记的调控通路，已被证实参与衰老进程，因此可能在年龄相关性神经退行性病变中发挥关键调控作用。本研究对比了阿尔茨海默病患者外侧颞叶组织中H4K16ac的全基因组富集水平，并分别以年轻认知正常个体及老年认知正常个体作为对照。我们发现，尽管正常衰老会导致H4K16ac富集程度升高，但阿尔茨海默病患者在与衰老及AD相关基因的邻近区域，出现了H4K16ac的显著缺失。本研究的分析揭示了三类具有独特功能特征的AD相关染色质改变。此外，我们还发现，H4K16ac发生显著改变的基因组区域，与此前阿尔茨海默病全基因组关联研究（Genome-Wide Association Studies, GWAS）中鉴定出的遗传变异——单核苷酸多态性（Single Nucleotide Polymorphism, SNPs）——以及表达数量性状基因座（expression quantitative trait loci, eQTLs）存在显著关联。本研究结果为衰老与阿尔茨海默病之间的表观遗传学关联奠定了研究基础。整体实验设计：对健康及病变人类脑组织中的H4K16ac进行染色质免疫共沉淀测序（ChIP-seq）；共纳入9例年轻健康脑组织样本（年轻组）、10例老年健康脑组织样本（老年对照组）以及12例老年阿尔茨海默病患者脑组织样本（AD组）；所有样本均设置H4K16ac测序样本与Input对照样本。