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Regulation of constitutive heterochromatin during fission yeast meiosis

Kuzdere, Tahsin. Regulation of constitutive heterochromatin during fission yeast meiosis. 2022, Doctoral Thesis, University of Basel, Associated Institution, Faculty of Science.

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Abstract

The genetic information of eukaryotes is stored in the form of DNA inside the nucleus of the cell. There, the DNA molecules do not exist as naked nucleic acids but are rather wound around histone proteins, forming a higher-level structure called chromatin. Over the years chromatin was categorized into two distinct classes, euchromatin and heterochromatin, using broadly speaking “key features” such as histone modifications or transcriptional activity. Whereas euchromatin is regarded as loose and active, heterochromatin is classically viewed as an inert and silent chromatin state marked by mono-, di-, and tri-methylation of lysine 9 of histone H3 (H3K9me/me2/me3). H3K9 methylation, the hallmark of heterochromatin, plays crucial roles in chromatin-dependent gene silencing and maintenance of genome stability by repressing repetitive DNA elements or recruiting downstream factors essential for faithful chromosome segregation. Many of the fundamental principles and mechanisms of these processes have been elucidated using the fission yeast Schizosaccharomyces pombe (S. pombe) as a model system. Importantly, most of our knowledge about the heterochromatic landscape in organisms, as well as its regulation, results from studies performed in mitotically growing cells. Indeed, spatial and temporal regulation of H3K9 methylation during sexual differentiation has remained understudied even though it is such an important aspect of the cell cycle where precise orchestration of chromatin-related events is needed to prevent aberrant chromosome segregation resulting otherwise in diseases associated with aneuploidy.
The fact that the H3K9 methylation landscape during sexual differentiation of S. pombe was still uncharted area marked the beginning of my PhD project. I set out to map H3K9me2 and H3K9me3 during fission yeast meiosis and I was curious to see whether these modifications change throughout meiotic progression. If so, I wanted to figure out how these changes would be regulated.
I was successful in mapping the two heterochromatic histone marks genome- wide during meiosis and showed that constitutive heterochromatin, especially centromeres, loses H3K9me2 temporarily and becomes H3K9me3 when cells initiate sexual differentiation. This is of particular importance since cells lacking the ability to tri-methylate H3K9 exhibit severe meiotic (but not mitotic) chromosome segregation defects. Trying to understand how such a switch in methylation preference can be achieved, I discovered that the histone lysine methyltransferase (HKMT) responsible for methylating H3K9 in S. pombe, Clr4, is differentially phosphorylated during mitosis and early meiosis and that its phosphorylation state anticorrelates with H3K9me3 activity. Lastly, I identified the cyclin-dependent kinase (CDK) Cdc2 as an enzyme required for Clr4 phosphorylation whose inhibition is a prerequisite for meiotic commitment, coinciding well with the timing of Clr4 dephosphorylation.
In summary, my PhD work revealed the dynamics of constitutive heterochromatin during sexual differentiation and demonstrated that different methylation states of H3K9 are of physiological relevance. What I find fascinating is the fact that Cdc2, a highly conserved master regulator of the cell cycle, is involved in the regulation of the specificity of a HKMT. In general, the high degree of conservation of the proteins involved in my PhD work suggest broad conservation of the mechanism described here. If faithful segregation of chromosomes during meiosis in humans is controlled similarly, this could have key implications for understanding genetic disorders, such as Down syndrome or certain forms of cancer.
Advisors:Bühler, Marc and Grosshans, Helge and Simanis, Viesturs
Faculties and Departments:09 Associated Institutions > Friedrich Miescher Institut FMI > Epigenetics > Biological clocks and timers in development (Grosshans)
09 Associated Institutions > Friedrich Miescher Institut FMI > Epigenetics > Non-coding RNAs and chromatin (Bühler)
UniBasel Contributors:Bühler, Marc
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:14719
Thesis status:Complete
Number of Pages:IX, 135
Language:English
Identification Number:
  • urn: urn:nbn:ch:bel-bau-diss147194
edoc DOI:
Last Modified:14 Jun 2022 04:30
Deposited On:13 Jun 2022 12:18

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