Abstract
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.
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This post is Copyright: Yayan Feng,
Xiaoyu Yang,
Yuan Hou,
Yadi Zhou,
James B. Leverenz,
Charis Eng,
Andrew A. Pieper,
Alison Goate,
Yin Shen,
Feixiong Cheng | October 2, 2024