Yayan Feng, Xiaoyu Yang, Yuan Hou, Yadi Zhou, James B Leverenz, Charis Eng, Andrew A Pieper, Alison Goate, Yin Shen, Feixiong Cheng
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引用次数: 0
摘要
简介转座元件（TE）失调与阿尔茨海默病（AD）大脑神经炎症有关。然而，TE定量性状位点（teQTL）在患有阿尔茨海默病的人类老年大脑中还没有得到很好的表征：方法：我们利用来自三个人类AD大脑生物库的大规模批量和单细胞RNA测序、全基因组测序（WGS）和xQTL来描述TE表达失调的特征，并在人类诱导多能干细胞（iPSC）衍生的神经元中使用CRISPR干扰（CRISPRi）实验验证与AD相关的TE：结果：我们在人类老年大脑中发现了26188个全基因组意义重大的TE表达QTLs（teQTLs）。随后对teQTLs与AD基因座的共定位分析确定了与AD相关的teQTLs和相关基因座TEs。通过CRISPRi测定，我们确定了激活的短穿插核元素（SINE；chr11:47608036-47608220）通过减少人iPSC衍生神经元的神经炎症对C1QTNF4表达的神经特异性抑制作用：我们在人类AD大脑中发现了广泛的TE失调，teQTLs为确定可能的AD风险基因提供了一种补充分析方法：在人类衰老大脑中观察到广泛的转座元件（TE）失调，这些失调与阿尔茨海默病（AD）的神经病理学、载脂蛋白E（APOE）基因型和神经炎症程度有关。利用匹配的 RNA 测序和全基因组测序数据，建立了人类衰老大脑中 TE 定量性状位点（teQTLs）的目录。CRISPR干扰测定显示，MIR家族（chr11: 47608036-47608220）中一个上调的基因间TE抑制了其最近的抗炎基因C1QTNF4在人类诱导多能干细胞衍生神经元中的表达。
Widespread transposable element dysregulation in human aging brains with Alzheimer's disease.
Introduction: Transposable element (TE) dysregulation is associated with neuroinflammation in Alzheimer's disease (AD) brains. Yet, TE quantitative trait loci (teQTL) have not been well characterized in human aged brains with AD.
Methods: We leveraged large-scale bulk and single-cell RNA sequencing, whole-genome sequencing (WGS), and xQTL from three human AD brain biobanks to characterize TE expression dysregulation and experimentally validate AD-associated TEs using CRISPR interference (CRISPRi) assays in human induced pluripotent stem cell (iPSC)-derived neurons.
Results: We identified 26,188 genome-wide significant TE expression QTLs (teQTLs) in human aged brains. Subsequent colocalization analysis of teQTLs with AD genetic loci identified AD-associated teQTLs and linked locus TEs. Using CRISPRi assays, we pinpointed a neuron-specific suppressive role of the activated short interspersed nuclear element (SINE; chr11:47608036-47608220) on expression of C1QTNF4 via reducing neuroinflammation in human iPSC-derived neurons.
Discussion: We identified widespread TE dysregulation in human AD brains and teQTLs offer a complementary analytic approach to identify likely AD risk genes.
Highlights: Widespread transposable element (TE) dysregulations are observed in human aging brains with degrees of neuropathology, apolipoprotein E (APOE) genotypes, and neuroinflammation in Alzheimer's disease (AD). A catalog of TE quantitative trait loci (teQTLs) in human aging brains was created using matched RNA sequencing and whole-genome sequencing data. CRISPR interference assays reveal that an upregulated intergenic TE from the MIR family (chr11: 47608036-47608220) suppresses expression of its nearest anti-inflammatory gene C1QTNF4 in human induced pluripotent stem cell-derived neurons.
期刊介绍：
Alzheimer's & Dementia is a peer-reviewed journal that aims to bridge knowledge gaps in dementia research by covering the entire spectrum, from basic science to clinical trials to social and behavioral investigations. It provides a platform for rapid communication of new findings and ideas, optimal translation of research into practical applications, increasing knowledge across diverse disciplines for early detection, diagnosis, and intervention, and identifying promising new research directions. In July 2008, Alzheimer's & Dementia was accepted for indexing by MEDLINE, recognizing its scientific merit and contribution to Alzheimer's research.
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