Dissecting the molecular mechanism and spatiotemporal dynamics controlling senescence entry

by Konstantinos Sofiadis
Doctoral thesis
Date of Examination:2020-02-10
Date of issue:2021-01-21
Advisor:Prof. Dr. Argyris Papantonis
Referee:Prof. Dr. Ralph Kehlenbach
Referee:Prof. Dr. Matthias Dobbelstein
Referee:Dr. Nico Posnien
Referee:Prof. Dr. Michael Zeisberg
Referee:Dr. Ufuk Günesdogan
Referee:PD Dr. Laura C. Zelarayán
Persistent Address: http://dx.doi.org/10.53846/goediss-8409

 

 

Files in this item

Name:Dissertation_Konsntatinos_Sofiadis.pdf
Size:9.86Mb
Format:PDF
Description:PhD thesis

The following license files are associated with this item:

Abstract

English

Senescence represents a programmed cell cycle arrest against aberrant proliferation and tumour development due to accumulated genotoxic or metabolic stress. The tumour-suppressive properties of senescence attracted the attention of the scientific community and led to pioneering studies to fully understand the rules governing the establishment of this homeostatic mechanism. Several groups attempted to characterize the features of senescence and elucidate the molecular pathways that lead to the transition from a proliferating state and to a senescent one. This attempt led to the characterization of a number of intriguing phenotypes associated with the entry into senescence. Interestingly, it was shown that extensive chromatin re-arrangements and altered genomic conformation is part of these phenotypes and contributes to the inhibition of proliferating genes and expression of senescent ones. Nowadays, the contribution of three-dimensional (3D) genome structure in the orchestration of transcriptional pathways in a cell-type and context-dependent manner is well established. The spatiotemporal crosstalk between regulatory elements, such as enhancers and promoters, requires strict organization of 3D genome structure to reassure coordinated wiring of these transcriptional elements. Disruption of genomic structure leads to aberrant gene regulation and has been linked to various pathophysiological phenotypes. Although it was shown that senescence is accompanied by robust alterations in 3D genome architecture, the molecular events that lead to these alterations and their impact on the establishment of senescence were still elusive, especially in a physiological context like that of replicative senescence. In this study we are focusing on the impact of the nuclear evinction of two abundant and conserved proteins, HMGB1 and HMGB2, on the onset of cellular senescence
Keywords: HMGB1; HMGB2; senescence; genome structure; TADs; CTCF foci; transcription
 
Statistik