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Investigation of transposable elements in intellectual disability -A CHARACTERIZATION OF DYSREGULATION FROM DE NOVO TRIM28 MUTATIONS

Davis-Hansson, Carrie (2023) MOBN03 20222
Degree Projects in Molecular Biology
Abstract
Transposable elements make up over 50% of the human genome and serve beneficial transcriptional regulatory roles but can also exert deleterious effects when aberrantly expressed. Four de novo missense mutations in the master regulator of transposable elements – corepressor TRIM28 – were identified in four patients with intellectual disability suggesting that dysfunctional transposable element regulation may play an etiological role in their disorders. In this study, we modeled the potential effects of two of the mutations in induced pluripotent stem cells (iPSC) and forebrain neural precursor cells (fbNPC). We analyzed the effects of these mutations through RNA-sequencing and epigenetic profiling with CUT&RUN. We found that the mutations... (More)
Transposable elements make up over 50% of the human genome and serve beneficial transcriptional regulatory roles but can also exert deleterious effects when aberrantly expressed. Four de novo missense mutations in the master regulator of transposable elements – corepressor TRIM28 – were identified in four patients with intellectual disability suggesting that dysfunctional transposable element regulation may play an etiological role in their disorders. In this study, we modeled the potential effects of two of the mutations in induced pluripotent stem cells (iPSC) and forebrain neural precursor cells (fbNPC). We analyzed the effects of these mutations through RNA-sequencing and epigenetic profiling with CUT&RUN. We found that the mutations in TRIM28 cause a substantial dysregulation in transposable elements, protein-coding genes, and lincRNA. We also found evidence that the upregulation of transposable elements drives the transcription of nearby protein-coding genes. Furthermore, we found that the patterns of transcriptional dysregulation differed between iPSCs and fbNPCs. These results are preliminary but would provide the first confirmed link between transcriptional dysregulation of transposable elements and intellectual disability. (Less)
Popular Abstract
Transposons: from foe to friend, to foe again

Nearly all life forms have shared a common enemy. Lurking unseen in our environment, highly specialized ¬¬¬viruses have invaded our cells and hijacked our DNA. Through trickery, these viruses have forced the cells to replicate and reinsert their viral DNA over and over, and over again. Now this viral DNA and other mobile DNA sequences make up over 50% of our genome!

But our cells are not defenseless. These viral and viral-like elements known as transposons have been met with the unyielding power of evolution. Over millions of years, our cells have evolved efficient guardians to stop their endless replication and reinsertion, while slow mutations in the transposons have made them inept –... (More)
Transposons: from foe to friend, to foe again

Nearly all life forms have shared a common enemy. Lurking unseen in our environment, highly specialized ¬¬¬viruses have invaded our cells and hijacked our DNA. Through trickery, these viruses have forced the cells to replicate and reinsert their viral DNA over and over, and over again. Now this viral DNA and other mobile DNA sequences make up over 50% of our genome!

But our cells are not defenseless. These viral and viral-like elements known as transposons have been met with the unyielding power of evolution. Over millions of years, our cells have evolved efficient guardians to stop their endless replication and reinsertion, while slow mutations in the transposons have made them inept – they have been domesticated. Simply put, these transposons work for us now. They have sequences that are used to activate genes that our cells need to function properly. Some can even make proteins that are critical for development! Their transformation is really the ultimate redemption story.

However, some villains never change. There are still transposons that are able to escape and wreak havoc in our cells. Fugitive transposons have been shown to cause cancers and hemophilia. But they don’t have to be reinserted to cause trouble – they can cause chaos by being copied, or active, when they shouldn’t be. Recently, collaborators of ours have found four mutations that have never been identified before in patients that have an intellectual disability of unknown cause. The mutations were found in a gene that encodes the ultimate protector against dysfunctional transposon activity – TRIM28. The mutations are predicted to morph the TRIM28 protein in such a way that it can no longer do its job. Could this mean that the intellectual disability of these patients is caused by the unsupervised activity of transposons?

Our team have generated stem cells with the TRIM28 mutations. We took those stem cells and forced them to become neural stem cells of the cerebral cortex – the most complex brain region. We then used RNA-sequencing technology to compare the mutated and the control cells. RNA-sequencing allows us to read what genes and transposons were active in the cell at the time we collected them. We also used a new technology to read what sort of epigenetic markers change in the mutated cells. These markers are chemical modifications that help silence transposon DNA.

We found that as expected, many transposons in the cells with the TRIM28 mutations increase their activity – they even appear to possibly be driving changes in the activity of protein-coding genes. So, while they are not necessarily copying and inserting as before, these changes could prevent the cells from developing properly. We have even seen substantial changes in expression of genes that are tightly regulated and critical for neurodevelopment in our neural stem cells. This could already indicate that these mutations would have a pathogenic effect in neural cells. For future directions, we will generate other types of neural cells including organoids and mature neurons to see how the mutations affect those cells. There is still work to do but this study would be the first clear link between transposon dysregulation of activity and human neurodevelopmental disease. If we confirm this, clinicians can screen for the mutations when diagnosing patients with intellectual disability. Furthermore, our results will help us elucidate the complex relationship we have with transposons.

Master’s Degree Project in General Molecular Biology, 60 credits, 2023
Department of Biology, Lund University

Advisor: Johan Jakobsson and Laura Castilla-Vallmanya
Laboratory of Molecular Neurogenetics, Wallenberg Neuroscience Center, Biomedical Center (Less)
Please use this url to cite or link to this publication:
author
Davis-Hansson, Carrie
supervisor
organization
course
MOBN03 20222
year
type
H2 - Master's Degree (Two Years)
subject
language
English
id
9135649
date added to LUP
2023-08-30 11:37:57
date last changed
2023-08-30 11:37:57
@misc{9135649,
  abstract     = {{Transposable elements make up over 50% of the human genome and serve beneficial transcriptional regulatory roles but can also exert deleterious effects when aberrantly expressed. Four de novo missense mutations in the master regulator of transposable elements – corepressor TRIM28 – were identified in four patients with intellectual disability suggesting that dysfunctional transposable element regulation may play an etiological role in their disorders. In this study, we modeled the potential effects of two of the mutations in induced pluripotent stem cells (iPSC) and forebrain neural precursor cells (fbNPC). We analyzed the effects of these mutations through RNA-sequencing and epigenetic profiling with CUT&RUN. We found that the mutations in TRIM28 cause a substantial dysregulation in transposable elements, protein-coding genes, and lincRNA. We also found evidence that the upregulation of transposable elements drives the transcription of nearby protein-coding genes. Furthermore, we found that the patterns of transcriptional dysregulation differed between iPSCs and fbNPCs. These results are preliminary but would provide the first confirmed link between transcriptional dysregulation of transposable elements and intellectual disability.}},
  author       = {{Davis-Hansson, Carrie}},
  language     = {{eng}},
  note         = {{Student Paper}},
  title        = {{Investigation of transposable elements in intellectual disability -A CHARACTERIZATION OF DYSREGULATION FROM DE NOVO TRIM28 MUTATIONS}},
  year         = {{2023}},
}