Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer's disease.
Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer's disease.
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DOI：
10.1038/nature14252
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发表时间：
2015-02-19
期刊：
影响因子：
64.8
通讯作者：
Kellis M
中科院分区：
文献类型：
--
作者：
Gjoneska E;Pfenning AR;Mathys H;Quon G;Kundaje A;Tsai LH;Kellis M
阿尔茨海默病（AD）是一种严重的年龄相关性神经退行性疾病，其特征在于淀粉样蛋白-β（A β）斑块和神经元缠结的积累、突触和神经元损失以及认知能力下降。一些基因与AD有关，但神经变性过程中染色质状态的改变仍然没有特征。在这里，我们的档案转录和染色质状态动态在早期和晚期病理的诱导小鼠模型的AD样神经退行性病变的海马。我们发现了一个协调的下调突触可塑性基因和调控区，上调免疫反应基因和调控区，这是有针对性的因子，属于ETS家族的转录调节因子，包括PU。1。人类区域的正交增加水平的增强子显示免疫细胞特异性增强子的签名以及免疫细胞表达的数量性状基因座（eQTL），而降低水平的增强子直系同源物显示胎儿脑特异性增强子活性。值得注意的是，AD相关的遗传变异体特别富集在增加水平的增强子直系同源物中，这涉及AD易感性中的免疫过程。事实上，增加增强子重叠已知的AD基因座缺乏蛋白质改变的变体，并牵连其他基因座，不达到全基因组的意义。我们的研究结果揭示了新的见解神经退行性变的机制和建立小鼠作为一个有用的模型，AD调节区的功能研究。
Alzheimer’s disease (AD) is a severe age-related neurodegenerative disorder characterized by accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles, synaptic and neuronal loss, and cognitive decline. Several genes have been implicated in AD, but chromatin state alterations during neurodegeneration remain uncharacterized. Here, we profile transcriptional and chromatin state dynamics across early and late pathology in the hippocampus of an inducible mouse model of AD-like neurodegeneration. We find a coordinated downregulation of synaptic plasticity genes and regulatory regions, and upregulation of immune response genes and regulatory regions, which are targeted by factors that belong to the ETS family of transcriptional regulators, including PU.1. Human regions orthologous to increasing-level enhancers show immune cell-specific enhancer signatures as well as immune cell expression quantitative trait loci (eQTL), while decreasing-level enhancer orthologs show fetal-brain-specific enhancer activity. Notably, AD-associated genetic variants are specifically enriched in increasing-level enhancer orthologs implicating immune processes in AD predisposition. Indeed, increasing enhancers overlap known AD loci lacking protein-altering variants and implicate additional loci that do not reach genome-wide significance. Our results reveal new insights into the mechanisms of neurodegeneration and establish the mouse as a useful model for functional studies of AD regulatory regions.