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Identifier

000414261

Title

The role of chromatin and epigenetic mechanisms in nuclear architecture

Alternative Title

Ο ρόλος της χρωματίνης και των επιγενετικών μηχανισμών στην αρχιτεκτονική του πυρήνα

Author

Γαλανοπούλου, Ουρανία Β.

Thesis advisor

Ταλιανίδης, Ιωάννης
Χαλεπάκης, Γεώργιος

Abstract

The DNA contains the genetic information of cells and is organized in nucleosomes by being wrapped around histone octamers. Nucleosomes constitute the structural unit of chromatin. N-terminal histone tails protrude from the nucleosome and are subjected to epigenetic modifications including acetylation, methylation, phosphorylation etc. at specific amino acid residues. The combination of these epigenetic modifications across genes lead to different outcome regarding the chromatin state and gene activation status. Monomethylation of lysine 20 at histone H4 is linked to various cellular processes such as DNA replication, DNA damage repair and development, and is positively correlated to transcription activation. It is catalyzed by the lysine methyltransferase Set8, which is tightly regulated by the cell cycle and participates in licensing of replication origins, gene expression regulation, chromatin condensation, DNA damage repair as well as cell cycle progression and development of organisms. Set8 loss-of-function in mice causes lethality in preimplantation stages whereas a liver-specific knock out (Set8^loxp/AlbCre mice) resulted in enlargement of hepatocytes and their nuclei, cell death due to massive DNA damage and prolonged G2 arrest and eventually development of late-onset, spontaneous hepatocellular carcinoma. The purpose of this study was to further examine the necrotic phenotype of Set8^loxp/AlbCre hepatocytes and the enlargement of their nuclei by using immunohistochemistry on cryosections of liver tissue and transmission electron microscopy. It was revealed that Set8 depletion leads to invaginations of the nuclear envelope and the formation of intranuclear vacuoles that include cytoplasmic components but exclude nuclear proteins; this phenomenon can be called ‘endonucleosis’. Transmission electron microscope images and immunostaining of trimethylation of H4K20me3 showed that heterochromatin might be dissociated from the nuclear lamina in Set8^loxp/AlbCre mice. In conclusion, Set8 protein seems to be involved in the structural integrity of the nucleus; this hypothesis is in line with the notion that the genome contains non-genetic functions e.g. as a determinant of nuclear size and robustness. In depth-investigation of endonucleosis as a characteristic of cell death and the role of Set8 in the various cellular processes could provide help in dealing with the pathological conditions mediated by Set8, given that a large number of studies link this protein to physiological and pathological processes e.g. erythroid maturation, adipogenesis, maintenance of adult skin and human carcinogenesis.

Language

English

Subject

Epigenetics

SET8

Επιγενετική

Issue date

2018-03-23

Collection

School/Department--School of Sciences and Engineering--Department of Biology--Post-graduate theses

Type of Work--Post-graduate theses

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