A histone acetylome-wide association study of Alzheimer's disease identifies disease-associated H3K27ac differences in the entorhinal cortex
A histone acetylome-wide association study of Alzheimer's disease identifies disease-associated H3K27ac differences in the entorhinal cortex
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DOI：
10.1038/s41593-018-0253-7
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发表时间：
2018-11-01
影响因子：
25
通讯作者：
Mill, Jonathan
中科院分区：
文献类型：
--
作者：
Marzi, Sarah J.;Leung, Szi Kay;Mill, Jonathan
我们使用染色质免疫沉淀和高度平行测序，定量了阿尔茨海默病（AD）病例和匹配对照的内嗅皮层样本中赖氨酸H3K27乙酰化（H3K27ac）的全基因组模式。我们观察到与AD神经病理学相关的广泛的乙酰组学变化，在AD病例和对照之间鉴定出4，162个差异峰（错误发现率< 0.05）。差异乙酰化峰在疾病相关生物学途径中富集，包括注释为参与淀粉样蛋白β和tau病理学进展的基因的区域（例如APP、PSEN1、PSEN2和MAPT），以及含有与散发性晚发型AD相关的变体的区域。分区遗传力分析强调了内嗅皮质H3K27ac峰区域中AD风险变体的高度显著富集。AD相关变量H3K27ac与包括CR1、GPR22、KMO、PIM 3、PSEN1和RGCC在内的近端基因的转录变异相关。除了识别与AD神经病理学相关的分子通路外，我们还提出了一个复杂疾病中组蛋白修饰的全基因组研究框架。
We quantified genome-wide patterns of lysine H3K27 acetylation (H3K27ac) in entorhinal cortex samples from Alzheimer's disease (AD) cases and matched controls using chromatin immunoprecipitation and highly parallel sequencing. We observed widespread acetylomic variation associated with AD neuropathology, identifying 4,162 differential peaks (false discovery rate < 0.05) between AD cases and controls. Differentially acetylated peaks were enriched in disease-related biological pathways and included regions annotated to genes involved in the progression of amyloid-beta and tau pathology (for example, APP, PSEN1, PSEN2, and MAPT), as well as regions containing variants associated with sporadic late-onset AD. Partitioned heritability analysis highlighted a highly significant enrichment of AD risk variants in entorhinal cortex H3K27ac peak regions. AD-associated variable H3K27ac was associated with transcriptional variation at proximal genes including CR1, GPR22, KMO, PIM3, PSEN1, and RGCC. In addition to identifying molecular pathways associated with AD neuropathology, we present a framework for genome-wide studies of histone modifications in complex disease.