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.
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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.
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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
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PARP-1 is central to transcriptional regulation under both normal and stress conditions, with the governing mechanisms yet to be fully understood. Our biochemical and ChIP-seq-based analyses showed that PARP-1 binds specifically to active histone marks, particularly H4K20me1. We found that H4K20me1 plays a critical role in facilitating PARP-1 binding and the regulation of PARP-1-dependent loci during both development and heat shock stress. Here, we report that the sole H4K20 mono-methylase, pr-set7, and parp-1 Drosophila mutants undergo developmental arrest. RNA-seq analysis showed an absolute correlation between PR-SET7- and PARP-1-dependent loci expression, confirming co-regulation during developmental phases. PARP-1 and PR-SET7 are both essential for activating hsp70 and other heat shock genes during heat stress, with a notable increase of H4K20me1 at their gene body. Mutating pr-set7 disrupts monomethylation of H4K20 along heat shock loci and abolish PARP-1 binding there. These data strongly suggest that H4 monomethylation is a key triggering point in PARP-1 dependent processes in chromatin.
