Increased processing of SINE B2 ncRNAs unveils a novel type of transcriptome deregulation in amyloid beta neuropathology
- University of Lethbridge, Canada
Abstract
The functional importance of many non-coding RNAs (ncRNAs) generated by repetitive elements and their connection with pathologic processes remains elusive. B2 RNAs, a class of ncRNAs of the B2 family of SINE repeats, mediate through their processing the transcriptional activation of various genes in response to stress. Here we show that this response is dysfunctional during amyloid beta toxicity and pathology in the mouse hippocampus due to increased levels of B2 RNA processing, leading to constitutively elevated B2 RNA target gene expression and high Trp53 levels. Evidence indicates that Hsf1, a master regulator of stress response, mediates B2 RNA processing in hippocampal cells, and is activated during amyloid toxicity, accelerating the processing of SINE RNAs and gene hyper-activation. Our study reveals that in mouse, SINE RNAs constitute a novel pathway deregulated in amyloid beta pathology, with potential implications for similar cases in the human brain, such as Alzheimer's disease (AD).
Data availability
Short and long-RNA-seq data have been deposited to GEO with access number GSE149243.
-
Mammalian Heat Shock Response and Mechanisms Underlying Its Genome-wide Transcriptional RegulationNCBI Gene Expression Omnibus, GSE71708.
Article and author information
Author details
Majid H Mohajerani
Athanasios Zovoilis
Funding
Alberta Innovates - Health Solutions
- Majid H Mohajerani
Alzheimer Society of Alberta and Northwestern Territories
- Majid H Mohajerani
Canadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canada
- Athanasios Zovoilis
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Joaquín M Espinosa, University of Colorado Anschutz Medical Campus, United States
Ethics
Animal experimentation: All experimental procedures were approved by the institutional animal care committee protocol number1404 and performed in accordance with the standards set out by the Canadian Council for Animal Care.,
Version history
- Received: July 20, 2020
- Accepted: November 15, 2020
- Accepted Manuscript published: November 16, 2020 (version 1)
- Version of Record published: December 4, 2020 (version 2)
Copyright
© 2020, Cheng et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 1,933
- views
-
- 178
- downloads
-
- 9
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Increased processing of SINE B2 ncRNAs unveils a novel type of transcriptome deregulation in amyloid beta neuropathology
eLife 9:e61265.
https://doi.org/10.7554/eLife.61265
Further reading
-
- Genetics and Genomics
LD score regression (LDSC) is a method to estimate narrow-sense heritability from genome-wide association study (GWAS) summary statistics alone, making it a fast and popular approach. In this work, we present interaction-LD score (i-LDSC) regression: an extension of the original LDSC framework that accounts for interactions between genetic variants. By studying a wide range of generative models in simulations, and by re-analyzing 25 well-studied quantitative phenotypes from 349,468 individuals in the UK Biobank and up to 159,095 individuals in BioBank Japan, we show that the inclusion of a cis-interaction score (i.e. interactions between a focal variant and proximal variants) recovers genetic variance that is not captured by LDSC. For each of the 25 traits analyzed in the UK Biobank and BioBank Japan, i-LDSC detects additional variation contributed by genetic interactions. The i-LDSC software and its application to these biobanks represent a step towards resolving further genetic contributions of sources of non-additive genetic effects to complex trait variation.
-
- Evolutionary Biology
- Genetics and Genomics
Copy number variation in large gene families is well characterized for plant resistance genes, but similar studies are rare in animals. The zebrafish (Danio rerio) has hundreds of NLR immune genes, making this species ideal for studying this phenomenon. By sequencing 93 zebrafish from multiple wild and laboratory populations, we identified a total of 1513 NLRs, many more than the previously known 400. Approximately half of those are present in all wild populations, but only 4% were found in 80% or more of the individual fish. Wild fish have up to two times as many NLRs per individual and up to four times as many NLRs per population than laboratory strains. In contrast to the massive variability of gene copies, nucleotide diversity in zebrafish NLR genes is very low: around half of the copies are monomorphic and the remaining ones have very few polymorphisms, likely a signature of purifying selection.
