A Single-Nucleus RNA Sequencing Analysis of HERVs and LINE1s in Alzheimer's and Parkinson's Disease
(2022) BINP52 20212Degree Projects in Bioinformatics
- Abstract
- Transposable elements (TEs) are mobile genetic elements that make up roughly 50% of the human genome, with retrotransposons (or transposons which retrotranspose via an RNA intermediate) making up the vast majority of these elements. Recent studies have suggested that TEs could play a role in many neurological conditions, including ALS and dementia. The specific reasons why TEs are associated with these conditions remain somewhat unclear, with potential explanations including mutagenic insertion, immune responses to the presence of transcripts, and cytotoxic peptides resulting from the translation of these transcripts. We sequenced single-nuclei RNA sequencing (snRNA-seq) to profile the impact that TEs have on the development of Alzheimer’s... (More)
- Transposable elements (TEs) are mobile genetic elements that make up roughly 50% of the human genome, with retrotransposons (or transposons which retrotranspose via an RNA intermediate) making up the vast majority of these elements. Recent studies have suggested that TEs could play a role in many neurological conditions, including ALS and dementia. The specific reasons why TEs are associated with these conditions remain somewhat unclear, with potential explanations including mutagenic insertion, immune responses to the presence of transcripts, and cytotoxic peptides resulting from the translation of these transcripts. We sequenced single-nuclei RNA sequencing (snRNA-seq) to profile the impact that TEs have on the development of Alzheimer’s disease (AD) and Parkinson’s disease (PD). Our results show clear evidence for activated microglia and reactive astrocytes in PD, suggesting neuroinflammation. Additionally, using trusTEr, a new bioinformatics pipeline for the quantification of TE expression from single nuclei sequencing datasets, we were able to identify cell type-specific expression patterns of LINE1s and HERVs between diseased and control brains, which raise questions about the functional consequences of an aberrant expression of TEs in the human brain and their role in neuroinflammation. (Less)
- Popular Abstract
- Protein-coding genes – the “important” bits of DNA that contain instructions for our cellular machinery – make up just 2% of our genome. The other 98%, about half of which is a motley crew of ancient viral genes and sequences which have mutated to replicate themselves, have historically been considered irrelevant to study. However, recent research has shown that this so-called “junk DNA” actually gets copied into RNA fairly frequently and has some influence on nearby areas of the genome. Might it impact human health?
Modern bioinformatics research suggests this may be the case. Retrotransposons, which are DNA sequences that have (or had) the ability to retrotranspose (or create copies of themselves throughout our genetic code using RNA... (More) - Protein-coding genes – the “important” bits of DNA that contain instructions for our cellular machinery – make up just 2% of our genome. The other 98%, about half of which is a motley crew of ancient viral genes and sequences which have mutated to replicate themselves, have historically been considered irrelevant to study. However, recent research has shown that this so-called “junk DNA” actually gets copied into RNA fairly frequently and has some influence on nearby areas of the genome. Might it impact human health?
Modern bioinformatics research suggests this may be the case. Retrotransposons, which are DNA sequences that have (or had) the ability to retrotranspose (or create copies of themselves throughout our genetic code using RNA intermediates) make up nearly half our genome but have not been researched so much until recently due to historical constraints in technology. However, what research does exist suggests that RNA intermediates created by retrotransposons can impact brain health in some important ways and are associated with diseases like dementia. For this reason, we chose to research two types of retrotransposons – human endogenous retroviruses (HERVs), which are insertions of viral genetic code which still sometimes create RNA intermediates but never retrotranspose anymore, and long interspersed nuclear element 1s (LINE1s, L1s), which are the only retrotransposons that can still retrotranspose in humans – and their impacts on two common neurodegenerative diseases, Alzheimer’s disease (AD) and Parkinson’s disease (PD). We wanted to see if the expression of these retrotransposons differed between cell types as well, so we used a method called single-nucleus RNA sequencing (snRNA-seq), which let us examine all the RNA produced by each individual cell and identify cell types based on that.
We found that while LINE1s did not show particularly different expression patterns in brains with AD or PD and healthy brains, HERVs showed some interesting patterns. Perhaps most interesting was the fact that a HERV associated with inflammation was much more expressed in PD microglia than in control microglia. This is especially interesting because microglia are a type of brain cell that forms part of the immune system and causes inflammation, and neuroinflammation is an important factor in the development of many neurodegenerative disorders, including PD. We also found that many genes associated with inflammation were highly expressed in these microglia, providing compelling evidence that HERVs in microglia may be involved in the inflammation seen in PD.
Despite these findings, there is much that we still cannot explain. For instance, we are not certain whether the inflammatory response seen is a result of the RNA intermediates from these HERVs or from the viral proteins these intermediates code for – or even whether this difference in expression is a cause or an effect of neuroinflammation. That said, these findings provide exciting opportunities for future research in the field of neuroinflammation and retrotransposon activity. (Less)
Please use this url to cite or link to this publication:
http://lup.lub.lu.se/student-papers/record/9102705
- author
- Acker, Stein
- supervisor
-
- Raquel Garza LU
- organization
- course
- BINP52 20212
- year
- 2022
- type
- H2 - Master's Degree (Two Years)
- subject
- language
- English
- id
- 9102705
- date added to LUP
- 2022-11-04 10:43:07
- date last changed
- 2022-11-04 10:52:17
@misc{9102705,
abstract = {{Transposable elements (TEs) are mobile genetic elements that make up roughly 50% of the human genome, with retrotransposons (or transposons which retrotranspose via an RNA intermediate) making up the vast majority of these elements. Recent studies have suggested that TEs could play a role in many neurological conditions, including ALS and dementia. The specific reasons why TEs are associated with these conditions remain somewhat unclear, with potential explanations including mutagenic insertion, immune responses to the presence of transcripts, and cytotoxic peptides resulting from the translation of these transcripts. We sequenced single-nuclei RNA sequencing (snRNA-seq) to profile the impact that TEs have on the development of Alzheimer’s disease (AD) and Parkinson’s disease (PD). Our results show clear evidence for activated microglia and reactive astrocytes in PD, suggesting neuroinflammation. Additionally, using trusTEr, a new bioinformatics pipeline for the quantification of TE expression from single nuclei sequencing datasets, we were able to identify cell type-specific expression patterns of LINE1s and HERVs between diseased and control brains, which raise questions about the functional consequences of an aberrant expression of TEs in the human brain and their role in neuroinflammation.}},
author = {{Acker, Stein}},
language = {{eng}},
note = {{Student Paper}},
title = {{A Single-Nucleus RNA Sequencing Analysis of HERVs and LINE1s in Alzheimer's and Parkinson's Disease}},
year = {{2022}},
}