Widespread transposable element dysregulation in human aging brains with Alzheimer's disease

被引：1

作者：

Feng, Yayan ^{[1
,2
]}

Yang, Xiaoyu ^{[1
,3
]}

Hou, Yuan ^{[1
,2
]}

Zhou, Yadi ^{[1
,2
]}

Leverenz, James B. ^{[4
]}

Eng, Charis ^{[2
,5
,6
,7
]}

Pieper, Andrew A. ^{[8
,9
,10
,11
,12
,13
]}

Goate, Alison ^{[14
,15
,16
]}

Shen, Yin ^{[3
,17
,18
]}

Cheng, Feixiong ^{[1
,2
,5
,7
]}

机构：

[1] Cleveland Clin, Genome Ctr, Lerner Res Inst, Cleveland, OH USA

[2] Cleveland Clin, Genom Med Inst, Lerner Res Inst, Cleveland, OH USA

[3] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA USA

[4] Cleveland Clin, Neurol Inst, Lou Ruvo Ctr Brain Hlth, Cleveland, OH USA

[5] Case Western Reserve Univ, Cleveland Clin, Lerner Coll Med, Dept Mol Med, Cleveland, OH USA

[6] Case Western Reserve Univ, Sch Med, Dept Genet & Genome Sci, Cleveland, OH USA

[7] Case Western Reserve Univ, Case Comprehens Canc Ctr, Sch Med, Cleveland, OH USA

[8] Case Western Reserve Univ, Dept Psychiat, Cleveland, OH USA

[9] Univ Hosp Cleveland, Brain Hlth Med Ctr, Harrington Discovery Inst, Med Ctr, Cleveland, OH USA

[10] Louis Stokes Cleveland VA Med Ctr, Geriatr Psychiat, GRECC, Cleveland, OH USA

[11] Case Western Reserve Univ, Inst Transformat Mol Med, Sch Med, Cleveland, OH USA

[12] Case Western Reserve Univ, Sch Med, Dept Neurosci, Cleveland, OH USA

[13] Case Western Reserve Univ, Sch Med, Dept Pathol, Cleveland, OH USA

[14] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY USA

[15] Icahn Sch Med Mt Sinai, Nash Dept Neurosci, New York, NY USA

[16] Icahn Sch Med Mt Sinai, Ronald M Loeb Ctr Alzheimers Dis, New York, NY USA

[17] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA

[18] Univ Calif San Francisco, Weill Inst Neurosci, San Francisco, CA USA

来源：

ALZHEIMERS & DEMENTIA | 2024年 / 20卷 / 11期

关键词：

Alzheimer's disease; CRISPR interference; neuroinflammation; transposable elements; transposable element expression quantitative trait loci; GENOME-WIDE ASSOCIATION; SQUALENE SYNTHASE; RISK LOCI; TAU; TRANSCRIPTOME; METAANALYSIS; VARIANTS; LINE-1; BETA; TOOL;

D O I：

10.1002/alz.14164

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

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.

引用

页码：7495 / 7517

页数：23

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