Study uncovers how transposable elements in Alzheimer's-affected brains could hold the key to new therapeutic approaches, as scientists uncover the genetic links behind these molecular disruptions.
Study: Widespread transposable element dysregulation in human aging brains with Alzheimer's disease. Image Credit: Tushchakorn / Shutterstock.com
A recent Alzheimer’s and Dementia journal study characterizes transposable element (TE) expression dysregulation by using CRISPR interference (CRISPRi) assays to experimentally identify TEs associated with Alzheimer’s disease (AD).
What are TEs?
TEs, wlso known as transposons, viral elements, or jumping genes, constitute about 45% of the human genome. Epigenetic mechanisms, such as histone modifications and DNA methylation, can transcriptionally silence TEs.
The functional significance of TEs significantly declines with aging and in patients with neurodegenerative disorders, such as AD. Previous studies using human postmortem brain tissues and Drosophila melanogaster models have reported that tau protein triggers TE activation, which is linked to active chromatin signatures at multiple endogenous retrovirus (ERV) genomic loci.
TE activation is also crucial during neurodevelopment, which suggests that brain TE regulation is a common feature across the human lifespan. During mouse brain development, higher ERV levels in neurons have been associated with inflammatory responses and activated microglia.
Depression of long-terminal repeat (LTR) families and a panel of long interspersed nuclear elements (LINEs) leads to degenerative phenotypes in human TDP-43 Drosophila neurons and glia, which can be rescued by blocking the expression of TE. Therefore, aging-related brain disorders could also be treated by therapeutically targeting TEs.
Thus, it is crucial to better understand the mechanisms involved in TE dysregulation in the aging human brain.
About the study
TE expression and dysregulation across multiple AD pathologies were analyzed using two complementary approaches. Ribonucleic acid (RNA) sequencing (RNA-seq) data were obtained from three brain biobanks, including the Mount Sinai Brain Bank (MSBB), Mayo Clinic (Mayo), and Religious Orders Study (ROS) or Rush Memory and Aging Project (MAP) (ROS/MAP). TE transcriptomic profiles with matched whole-genome sequencing (WGS) data were considered to identify genes responsible for controlling TE expression.
Study findings
A total of 26,188 genome-wide significant TE-mediated quantitative trait loci (teQTLs) were identified in human brains. To isolate risk loci linked with TE dysregulation, colocalization analysis was conducted by using AD genome-wide association study (GWAS) datasets with DNA methylation QTLs (meQTLs), teQTLs, gene expression QTLs (eQTLs), and H3K27 histone acetylation QTLs (haQTLs).
Human brain cell type-specific enhancer-promoter interactome maps and CRISPRi assays were performed on human induced pluripotent stem cell (iPSC)-derived excitatory neurons. These assays were used to establish the regulatory relationship between an upregulated TE and its potential target gene, C1QTNF4, and short interspersed nuclear element (SINE).
TE dysregulation in AD was associated with amyloid neuropathology, tau pathology, and apolipoprotein ε4 (APOE ε4) genotypes. This dysregulation was both sex- and cell-specific.
The colocalization analysis revealed that upregulation in TEs was associated with changes in gene expression, including C1QTNF4, wound in human iPSC-derived neurons of AD patients. These findings highlight the effectiveness of QTL as an analytical tool to detect TE-related risk genes in AD.
AMP-AD RNA-seq harmonization was used to maintain clinical heterogeneity across samples. This approach enabled the identification of highly reproducible locus-based and region-specific differentially expressed TEs between both Mayo and ROS/MAP brain biobanks.
ERV1 was significantly downregulated in MSBB and ROS/MAP biobanks. However, the overexpression of LINE-1 and ERVs was observed in both Mayo and ROS/MAP brain biobank samples. Chronological ordering analysis of LINE-1 subfamily TEs indicated that L1HS, L1PA, and L1PB are more susceptible in human aging brains with AD.
Consistent with previous reports, the current study observed a decrease in TE expression in human aging AD brains. Reduced TE activity could also influence the host's immune response.
The number of locus-based differentially expressed TEs was proportionate to the sequencing read length (MSBB). Notably, longer sequencing reads, such as Oxford nanopore sequencing reads, could enable the generation of additional TE transcripts.
RNA-seq data from fluorescence-activated cell sorting (FACS)-sorted cell types using frozen brain cell samples indicated an APOE ε4-specific TE activation from a SINE in microglia. The experimental findings also highlight the possible role of TEs in sex-specific gene regulatory networks.
Conclusions
The current study identified widespread TE dysregulation in human aging brains with AD. Activated TE may produce double-stranded RNA (dsRNA), small RNAs (sRNAs), interfering RNAs, and P-element-induced Wimpy testis (PIWI)-interacting RNAs (piRNAs), which may influence nearby genes associated with the inflammatory response.
To determine the precise functional role of TEs in the future, biological mechanisms involved in TE activation, chromatin changes, and target gene dysregulation must be identified.
Journal reference:
- Feng, Y., Yang, X., Hou, Y., et al. (2024) Widespread transposable element dysregulation in human aging brains with Alzheimer's disease. Alzheimer’s and Dementia. doi:10.1002/alz.14164