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Nature:阿尔茨海默氏症的免疫基础

摘要 : 最近的全基因组关联研究表明,在非编码区域存在与阿尔茨海默氏症相关的实质性遗传变异,这说明异常基因调控参与了其中。然而,这些变异体的功能此前仍不清楚。通过在一个小鼠模型中对转录和染色质状态的动态进行分析,Elizabeta Gjoneska及同事发现,免疫响应基因和它们的调控区域是被上调的,而那些在突触弹性及学习和记忆中所涉及的调控区域则是被下调的。

 最近的全基因组关联研究表明,在非编码区域存在与阿尔茨海默氏症相关的实质性遗传变异,这说明异常基因调控参与了其中。然而,这些变异体的功能此前仍不清楚。

现在,通过在一个小鼠模型中对转录和染色质状态的动态进行分析,Elizabeta Gjoneska及同事发现,免疫响应基因和它们的调控区域是被上调的,而那些在突触弹性及学习和记忆中所涉及的调控区域则是被下调的。这些变化在该小鼠模型与人类这种疾病之间是高度保守的。

令人吃惊的是,与阿尔茨海默氏症相关的遗传变异体主要是在与免疫相关的高活性增强子中得到富集,在低活性神经增强子中则被耗尽。这表明,阿尔茨海默氏症的遗传易感性可能主要与免疫功能有关,而神经弹性则可能主要受非遗传效应的影响。

nature14252-f1

原文链接:

Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer’s disease

Alzheimer’s disease (AD) is a severe1 age-related neurodegenerative disorder characterized by accumulation of amyloid-β 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, while decreasing-level enhancer orthologues show fetal-brain-specific enhancer activity. Notably, AD-associated genetic variants are specifically enriched in increasing-level enhancer orthologues, 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.

doi:10.1038/nature14252

Epigenomics: Roadmap for regulation

doi:10.1038/518314a

对应Nature杂志: 2015年02月19日Nature杂志精选

来源: Nature 浏览次数:106

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