Transposable elements as alternative gene promoters and their silencing mechanisms
(2019) BINP52 20182Degree Projects in Bioinformatics
- Abstract
- Transposable elements (TEs) are genetic entities that have the ability to move around the genome and regulate nearby genes. Therefore, they constitute a potential threat (and sometimes an evolutionary advantage) for the host's genome. Among other regulatory activities, DNA methylation and KRAB-ZNF are responsible for TE silencing. The dysregulation of these silencing mechanisms have been studied before and it is known to have pathogenic consequences. However, just a small number of these studies have made the relation with a change of expression in transposable elements.
Hence, we performed different studies addressing the possible positive effect of TEs as an evolutionary tool, but also their pathogenic consequences when the... (More) - Transposable elements (TEs) are genetic entities that have the ability to move around the genome and regulate nearby genes. Therefore, they constitute a potential threat (and sometimes an evolutionary advantage) for the host's genome. Among other regulatory activities, DNA methylation and KRAB-ZNF are responsible for TE silencing. The dysregulation of these silencing mechanisms have been studied before and it is known to have pathogenic consequences. However, just a small number of these studies have made the relation with a change of expression in transposable elements.
Hence, we performed different studies addressing the possible positive effect of TEs as an evolutionary tool, but also their pathogenic consequences when the regulatory mechanisms (DNA and histone methylation) are disrupted in the mammalian brain.
We analysed chimpanzees' and humans' forebrain neural progenitor cells (fbNPC) to investigate the plausibility of TEs as alternative promoters that could have driven evolution in the human brain. Our results show an upregulation of young L1s in promoter regions of non coding RNAs.
We analysed diseases such as schizophrenia and central nervous system tumors, which are known to have DNA methylation aberrations, and compared them to an in vitro DNMT1 knock out in human NPC, protein which is in charge of conserving DNA methylation. Since DNA methylation is known to be key for brain development, we also included into the analysis brain samples from legally aborted embryos approved by the Swedish National Board of Health and Wellfare. Strikingly, we found an overall activation of young L1s in the different diseases, and similar results on the knock out as the ones described by Jönsson et al. (under revision) [1].
Krüppel-associated box domain zinc finger (KRAB ZNFs) are another type of TE repressors. These proteins attach to TEs and recruit Trim28 to change histone marks or DNA methylation patterns via heterochromatin proteins 1 (HP1), histone deacetylase complexes (NuRD) or histone methyltransferases (SETDB1 or H3K9me3) [29]. We looked at the effects of knocking out Trim28 at an embryonic stage in mice, and in vitro with CRISPR over mice NPC, from which we found an upregulation of LTRs and similar results as Fasching et al. [2]. (Less) - Popular Abstract
- Between friends and enemies
“Jumping” genes or transposable elements (TEs), are small fractions of DNA that can move around the genome by being “cut” or “copied and pasted” into a different position (Figure 1). They also have the ability to turn other genes on and off, making us sick or evolve, depending on where they decide to jump to. To prevent the possible negative events, our genome has found ways to prevent them from duplicating. DNA and histone methylation are some of them, which basically cover the TEs, so they can’t move.
This behavior could explain big questions in biology such as “sudden” appearance of disease-related genes, or steps in evolution that are hard to understand (for example, between chimpanzee and humans).... (More) - Between friends and enemies
“Jumping” genes or transposable elements (TEs), are small fractions of DNA that can move around the genome by being “cut” or “copied and pasted” into a different position (Figure 1). They also have the ability to turn other genes on and off, making us sick or evolve, depending on where they decide to jump to. To prevent the possible negative events, our genome has found ways to prevent them from duplicating. DNA and histone methylation are some of them, which basically cover the TEs, so they can’t move.
This behavior could explain big questions in biology such as “sudden” appearance of disease-related genes, or steps in evolution that are hard to understand (for example, between chimpanzee and humans). Therefore, we decided to perform several experiments to try and answer these questions. We first looked at chimpanzee and human neural-like cells to look for differences in the positioning of these elements. We found that a specific type of TEs (young LINE-1s) seem to prefer sitting at the beginning of non-coding RNAs, which are also known to be able to regulate other genes.
We also studied what happens when DNA methylation is removed in human neural-like cells. We compared this experiment with different types of brain tumors, and schizophrenia samples. This is important since it is known that methylation plays an important role in these diseases.
Since DNA methylation is responsible for TE repression, and these diseases suffer from changes in it, we hypothesized to see differences in the amount of TEs if we compare the diseases against the healthy samples, or among the types of tumors. We found more LINE-1s in tumors compared to healthy samples and we also saw a variation between the types of tumors: this provides new insights into cancer biology. These same elements (LINE-1s) were found to have differences between healthy and schizophrenic samples. However, it is important to continue the studies to confirm these results and to find out if the appearance of these elements is a cause or a consequence of the diseases in question.
We found a different type of TEs (ERVKs) to be more present when histone methylation was removed in mice, which is known to produce stress and anxiety-like behavior. These results verify previous knowledge from other studies, but also give us valuable information about these diseases.
Master’s Degree Project in Bioinformatics 60 credits 2019
Department of Biology, Lund University
Advisor: Johan Jakobsson
Molecular Neurogenetics Jakobsson Lab, Faculty of Medicine, Lund University. (Less)
Please use this url to cite or link to this publication:
http://lup.lub.lu.se/student-papers/record/8979768
- author
- Garza Gomez, Raquel
- supervisor
- organization
- course
- BINP52 20182
- year
- 2019
- type
- H2 - Master's Degree (Two Years)
- subject
- language
- English
- id
- 8979768
- date added to LUP
- 2019-06-05 12:42:32
- date last changed
- 2019-06-05 12:42:32
@misc{8979768,
abstract = {{Transposable elements (TEs) are genetic entities that have the ability to move around the genome and regulate nearby genes. Therefore, they constitute a potential threat (and sometimes an evolutionary advantage) for the host's genome. Among other regulatory activities, DNA methylation and KRAB-ZNF are responsible for TE silencing. The dysregulation of these silencing mechanisms have been studied before and it is known to have pathogenic consequences. However, just a small number of these studies have made the relation with a change of expression in transposable elements.
Hence, we performed different studies addressing the possible positive effect of TEs as an evolutionary tool, but also their pathogenic consequences when the regulatory mechanisms (DNA and histone methylation) are disrupted in the mammalian brain.
We analysed chimpanzees' and humans' forebrain neural progenitor cells (fbNPC) to investigate the plausibility of TEs as alternative promoters that could have driven evolution in the human brain. Our results show an upregulation of young L1s in promoter regions of non coding RNAs.
We analysed diseases such as schizophrenia and central nervous system tumors, which are known to have DNA methylation aberrations, and compared them to an in vitro DNMT1 knock out in human NPC, protein which is in charge of conserving DNA methylation. Since DNA methylation is known to be key for brain development, we also included into the analysis brain samples from legally aborted embryos approved by the Swedish National Board of Health and Wellfare. Strikingly, we found an overall activation of young L1s in the different diseases, and similar results on the knock out as the ones described by Jönsson et al. (under revision) [1].
Krüppel-associated box domain zinc finger (KRAB ZNFs) are another type of TE repressors. These proteins attach to TEs and recruit Trim28 to change histone marks or DNA methylation patterns via heterochromatin proteins 1 (HP1), histone deacetylase complexes (NuRD) or histone methyltransferases (SETDB1 or H3K9me3) [29]. We looked at the effects of knocking out Trim28 at an embryonic stage in mice, and in vitro with CRISPR over mice NPC, from which we found an upregulation of LTRs and similar results as Fasching et al. [2].}},
author = {{Garza Gomez, Raquel}},
language = {{eng}},
note = {{Student Paper}},
title = {{Transposable elements as alternative gene promoters and their silencing mechanisms}},
year = {{2019}},
}