Epigenetic dysregulation in Alzheimer's disease peripheral immunity.
Epigenetic dysregulation in Alzheimer's disease peripheral immunity.
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阿尔茨海默病外周免疫的表观遗传失调。
DOI：
10.1016/j.neuron.2024.01.013
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发表时间：
2024
期刊：
影响因子：
16.2
通讯作者：
Gate,David
中科院分区：
文献类型：
--
作者：
Ramakrishnan,Abhirami;Piehl,Natalie;Simonton,Brooke;Parikh,Milan;Zhang,Ziyang;Teregulova,Victoria;vanOlst,Lynn;Gate,David
阿尔茨海默病 (AD) 的外周免疫系统尚未通过现代测序方法进行彻底研究。为了研究 AD 外周免疫系统的表观遗传和转录改变，我们使用了单细胞测序策略，包括转座酶可及染色质分析和 RNA 测序。我们发现 AD 患者的外周免疫细胞中有大量开放染色质。在 CD8 T 细胞中，我们发现了与 CXC 基序趋化因子受体 3 基因启动子可共同访问的 acis 调节 DNA 元件。在单核细胞中，我们在核因子 kappa B 亚基 2 基因中的开放染色质区域附近发现了一个新的 AD 特异性 RELA 转录因子结合位点。我们还证明了单核细胞中载脂蛋白 E 基因型依赖性的表观遗传变化。令人惊讶的是，我们还在与散发性 AD 风险相关的基因中发现了差异可及的染色质区域。我们的研究结果为 AD 外周免疫中表观遗传学和遗传风险因素之间的复杂关系提供了新的见解。
The peripheral immune system in Alzheimer's disease (AD) has not been thoroughly studied with modern sequencing methods. To investigate epigenetic and transcriptional alterations to the AD peripheral immune system, we used single-cell sequencing strategies, including assay for transposase-accessible chromatin and RNA sequencing. We reveal a striking amount of open chromatin in peripheral immune cells in AD. In CD8 T cells, we uncover acis-regulatory DNA element co-accessible with the CXC motif chemokine receptor 3 gene promoter. In monocytes, we identify a novel AD-specific RELA transcription factor binding site adjacent to an open chromatin region in the nuclear factor kappa B subunit 2 gene. We also demonstrate apolipoprotein E genotype-dependent epigenetic changes in monocytes. Surprisingly, we also identify differentially accessible chromatin regions in genes associated with sporadic AD risk. Our findings provide novel insights into the complex relationship between epigenetics and genetic risk factors in AD peripheral immunity.