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Transposable Elements in Neural Progenitor Cells

Fasching, Liana LU (2015) In Lund University Faculty of Medicine Doctoral Dissertation Series 2015:107.
Abstract (Swedish)
Popular Abstract in English

In an organism the DNA contains the entire biological information that is needed to be able to exist and function. Those segments, also known as DNA sequences are a genetic code, which is further packaged into units called genes. The entity of all genes is called genome. Today we know, that only a small proportion of genes encode for proteins, which are responsible for major biological functions in an organism, thus more than 90% of the DNA is referred to as non-coding DNA. For decades scientists were debating the purpose of the large non-coding proportion, and called it “junk DNA”.

Currently we know that the non-coding part of the genome actually plays an important role regarding... (More)
Popular Abstract in English

In an organism the DNA contains the entire biological information that is needed to be able to exist and function. Those segments, also known as DNA sequences are a genetic code, which is further packaged into units called genes. The entity of all genes is called genome. Today we know, that only a small proportion of genes encode for proteins, which are responsible for major biological functions in an organism, thus more than 90% of the DNA is referred to as non-coding DNA. For decades scientists were debating the purpose of the large non-coding proportion, and called it “junk DNA”.

Currently we know that the non-coding part of the genome actually plays an important role regarding regulation of gene expression. Gene expression converts the information that is saved in DNA sequences into cellular components with a specific function. Since the entire genetic code is stored in each cell of an organism, gene expression is a highly regulated process. Not all genes can be active in all cells of the body at the same time. Therefore it has to be assured that only those genes, which are important for that specific cell type are activated. Different cell types are the basis for generating specific tissues, which are then further organised into organs. What happens to the majority of the genome that is non-coding DNA? Non-coding DNA has a distinct function in regulating gene expression. Processes that regulate gene expression are called epigenetic mechanisms. Those mechanisms can be seen like a light switch having two functions: switching “on” or “off”. Genes that are needed for the cell to function are switched “on” while genes that are not needed are shut “off”.

By winding DNA around histones, which is a certain type of proteins, DNA gets condensed and less accessible to be activated. DNA that is wound tightly around histones is called heterochromatin and keeps the DNA silenced and therefore inactive.



Since a few decades it is known, that about 50% of our genome are transposable elements, which are mobile genetic elements inherited over generations. Evolution is a continuous process characterised by optimal adaptation of an organism over millions of years to a changing environment. Transposable elements, if correctly regulated by epigenetic mechanisms, seem to have a positive effect on the host organism and are debated to drive evolution. If these transposable elements are not correctly regulated, they can cause many different diseases, like for example cancer. By now we know, that transposable elements can be active in the brain.

In my thesis, I investigate the regulation of transposable elements in mouse and human neural progenitor cells, which is a characterised cell type that is able to develop into several brain-specific cells. Therefore I have activated transposable elements in neural progenitor cells by removing their regulatory mechanism. I looked for resulting changes and found that these mobile elements are able to switch “on” genes. I show that transposable elements seem to be important for the brain. The studies included in my thesis demonstrate that the regulation of transposable elements is different compared to what has been previously reported for other organs like heart or skin. These gained results provide novel insights into why the brain has developed into such a complex organ with so many different cell types.



Popular Abstract in Swedish

DNA innehåller hela den biologiska information som behövs för en levande organism att kunna existera och fungera. Denna information består av segment, även kända som DNA-sekvenser, som bildar en genetisk kod, som i sin tur bildar enheter som kallas gener. Helheten av alla gener kallas för arvsmassan. Numera vet vi att endast en liten andel av gener kodar för proteiner som ansvarar för grundläggande biologiska funktioner i en organism. Av denna anledning beskrivs mer än 90% av DNA som icke-kodande DNA. I årtionden har forskarna diskuterat syftet med den proportionerligt stora andelen av icke-kodande DNA och kallat den för "skräp-DNA".



Numera vet vi att den icke-kodande delen av genomet spelar en viktig roll när det gäller reglering av genuttryck. Genuttryck omvandlar den informationen som sparas i DNA-sekvenser i cellulära komponenter med specifika funktioner. Eftersom organismens hela genetiska kod finns lagrad i dess varje cell, är genuttryck en mycket strikt reglerad process. Alla gener kan inte vara aktiva i alla celler i kroppen samtidigt. Av denna anledning säkerställs att endast de gener som är viktiga för en specifik celltyp är aktiverade. Olika celltyper är grunden för att specifika vävnader skapas, vävnader som sedan grupperas i olika organtyper. Men vad är det som händer med den icke-kodande delen av DNA? Jo, icke-kodande DNA har en distinkt funktion i regleringen av genuttryck. De regulatoriska processerna i genuttryck kallas för epigenetiska mekanismer. Dessa mekanismer kan jämföras med en strömbrytare som har två funktioner - "på" eller "av". Gener som behövs för att cellen ska fungera slås "på" medan gener som inte behövs stängs "av". Genom att linda sig runt histoner, som är en viss typ av proteiner, kondenseras DNA och blir mindre tillgängligt för att aktiveras. DNA som är tätt packat runt histoner kallas för heterokromatin och håller det tystat och därför inaktivt.



Det har varit känt i ett par decennier nu, att cirka 50% av vår arvsmassa består av transposabla element som är rörliga genetiska element. Dessa element förs vidare från generation till generation. Evolution är en pågående process därigenom en organism adapteras optimalt till en föränderlig miljö under miljontals år. Transposabla element, i fall de regleras på rätt sätt genom epigenetiska mekanismer, tycks ha positiva effekter på värdorganismen och det debatteras i fall de för själva evolutionen framåt. Om dessa transposabla element inte regleras på ett korrekt sätt, kan de orsaka många olika sjukdomar, som till exempel cancer. Numera vet vi även att transposabla element kan vara aktiva i hjärnan.



I min avhandling undersöker jag regleringen av transposabla element i mus och mänskliga neurala stamceller, som är celler som kan utvecklas till olika typer av hjärnspecifika celler. Jag aktiverade därför transposabla element i neurala stamceller genom att ta bort deras regleringsmekanism. Därefter letade jag efter förändringar och fann att dessa mobila element kan slå på gener. Jag påvisar att transposabla element verkar vara viktiga för hjärnan. De studier som ingår i min avhandling visar att regleringen av transposabla element är annorlunda i hjärnan jämfört med vad som tidigare rapporterats om andra organ, t.ex. hjärta eller hud. Dessa resultat ger nya insikter om varför hjärnan har utvecklats till ett sådant oerhört komplext organ med så många olika celltyper. (Less)
Abstract
More than 90% of DNA does not code for proteins and for a long time these sequences were referred to as “junk DNA” due to their unknown purpose. With the advent of new technologies it is now known, that the non-coding part of the genome is of great importance for regulating gene expression and is therefore indispensable.

Transposable elements comprise about 50% of the genome and co-exist as symbionts regulated by epigenetic mechanisms - a highly defined machinery that controls gene expression and is mandatory for a proper development and maintenance of an organism. Although transposable elements are associated with diseases, their role in fine-tuning the host gene expression becomes more and more evident, which seems to justify... (More)
More than 90% of DNA does not code for proteins and for a long time these sequences were referred to as “junk DNA” due to their unknown purpose. With the advent of new technologies it is now known, that the non-coding part of the genome is of great importance for regulating gene expression and is therefore indispensable.

Transposable elements comprise about 50% of the genome and co-exist as symbionts regulated by epigenetic mechanisms - a highly defined machinery that controls gene expression and is mandatory for a proper development and maintenance of an organism. Although transposable elements are associated with diseases, their role in fine-tuning the host gene expression becomes more and more evident, which seems to justify the positive selection during evolution.

A transposable element called Line-1 was found to be active in neural progenitor cells and in the brain. Several studies report Line-1 transcription and frequent retrotransposition during normal brain development, with further evidence that Line-1 induced retrotransposition can influence neuronal gene expression. Today, there is few published data focusing on epigenetic regulation of transposable elements in neural progenitor cells.



In this thesis, I identify TRIM28 as key regulator of certain groups of transposable elements in mouse and human neural progenitor cells. This feature is unique compared to other somatic tissues, where DNA-methylation is prevalent.



Here I demonstrate, that transposable elements MMERVK10C and IAP1 in mouse neural progenitor cells are repressed by the establishment of H3K9me3-associated heterochromatin. De-repressed MMERVK10C and IAP1 furthermore activate nearby genes and generate long non-coding RNAs. Homozygous TRIM28 knockout is lethal, while mice with mono-allelic TRIM28 expression are characterised with a distinct behavioural phenotype.



Moreover we are also able to show that TRIM28 is regulating a fraction of young Alu-elements in human neural progenitor cells, which is not the case in human embryonic stem cells. Furthermore, we report that transcribed Alu-elements influence gene expression of close-by genes.



Studying pluripotent cells revealed that TRIM28 modulates transposable elements in mouse embryonic stem cells. Activation of transposable elements upon TRIM28 depletion induces changes in gene expression of close-by genes and causes alteration of the repressive chromatin mark H3K9me3 at transposable element loci. Upregulated genes were shown to have bivalent promoters, characterised by H3K4me3 and H3K27me3 and lay close to H3K9me3 regulated transposable elements. These findings in mouse embryonic stem cells are highly relevant for the interpretation of my studies in neural progenitor cells.



Taken together, this thesis demonstrates that the regulation of transposable elements in mouse and human neural progenitor cells is distinct compared to previous reports regarding somatic tissues. These results provide novel insights into why the brain has developed into such a complex organ with so many different cell types. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Dubnau, Joshua, Cold Spring Harbor Laboratory
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Transposable Elements, TRIM28, Epigenetic Regulation, Gene Expression, Neural Progenitor Cells
in
Lund University Faculty of Medicine Doctoral Dissertation Series
volume
2015:107
pages
74 pages
publisher
Molecular Neurogenetics, Faculty of Medicine, Lund University
defense location
Segerfalksalen, BMC A10, Sölvegatan 17, Lund
defense date
2015-10-23 09:00
ISSN
1652-8220
ISBN
978-91-7619-1869-6
language
English
LU publication?
yes
id
0d1555c4-e5fe-4bf3-841d-8136c25555af (old id 8000889)
date added to LUP
2015-09-30 10:46:40
date last changed
2016-09-19 08:44:49
@phdthesis{0d1555c4-e5fe-4bf3-841d-8136c25555af,
  abstract     = {More than 90% of DNA does not code for proteins and for a long time these sequences were referred to as “junk DNA” due to their unknown purpose. With the advent of new technologies it is now known, that the non-coding part of the genome is of great importance for regulating gene expression and is therefore indispensable.<br/><br>
Transposable elements comprise about 50% of the genome and co-exist as symbionts regulated by epigenetic mechanisms - a highly defined machinery that controls gene expression and is mandatory for a proper development and maintenance of an organism. Although transposable elements are associated with diseases, their role in fine-tuning the host gene expression becomes more and more evident, which seems to justify the positive selection during evolution. <br/><br>
A transposable element called Line-1 was found to be active in neural progenitor cells and in the brain. Several studies report Line-1 transcription and frequent retrotransposition during normal brain development, with further evidence that Line-1 induced retrotransposition can influence neuronal gene expression. Today, there is few published data focusing on epigenetic regulation of transposable elements in neural progenitor cells.<br/><br>
<br/><br>
In this thesis, I identify TRIM28 as key regulator of certain groups of transposable elements in mouse and human neural progenitor cells. This feature is unique compared to other somatic tissues, where DNA-methylation is prevalent. <br/><br>
<br/><br>
Here I demonstrate, that transposable elements MMERVK10C and IAP1 in mouse neural progenitor cells are repressed by the establishment of H3K9me3-associated heterochromatin. De-repressed MMERVK10C and IAP1 furthermore activate nearby genes and generate long non-coding RNAs. Homozygous TRIM28 knockout is lethal, while mice with mono-allelic TRIM28 expression are characterised with a distinct behavioural phenotype. <br/><br>
<br/><br>
Moreover we are also able to show that TRIM28 is regulating a fraction of young Alu-elements in human neural progenitor cells, which is not the case in human embryonic stem cells. Furthermore, we report that transcribed Alu-elements influence gene expression of close-by genes. <br/><br>
<br/><br>
Studying pluripotent cells revealed that TRIM28 modulates transposable elements in mouse embryonic stem cells. Activation of transposable elements upon TRIM28 depletion induces changes in gene expression of close-by genes and causes alteration of the repressive chromatin mark H3K9me3 at transposable element loci. Upregulated genes were shown to have bivalent promoters, characterised by H3K4me3 and H3K27me3 and lay close to H3K9me3 regulated transposable elements. These findings in mouse embryonic stem cells are highly relevant for the interpretation of my studies in neural progenitor cells. <br/><br>
<br/><br>
Taken together, this thesis demonstrates that the regulation of transposable elements in mouse and human neural progenitor cells is distinct compared to previous reports regarding somatic tissues. These results provide novel insights into why the brain has developed into such a complex organ with so many different cell types.},
  author       = {Fasching, Liana},
  isbn         = {978-91-7619-1869-6},
  issn         = {1652-8220},
  keyword      = {Transposable Elements,TRIM28,Epigenetic Regulation,Gene Expression,Neural Progenitor Cells},
  language     = {eng},
  pages        = {74},
  publisher    = {Molecular Neurogenetics, Faculty of Medicine, Lund University},
  school       = {Lund University},
  series       = {Lund University Faculty of Medicine Doctoral Dissertation Series},
  title        = {Transposable Elements in Neural Progenitor Cells},
  volume       = {2015:107},
  year         = {2015},
}