Reorganization of the Senescent Genome via Spatial CTCF Clustering

by Spyridon Palikyras
Cumulative thesis
Date of Examination:2023-05-31
Date of issue:2023-07-13
Advisor:Prof. Dr. Argyris Papantonis
Referee:Prof. Dr. Argyris Papantonis
Referee:Dr. Ufuk Günesdogan
Persistent Address: http://dx.doi.org/10.53846/goediss-9932

 

 

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Abstract

English

Cellular senescence is now understood to be a major hallmark of the aging process. Senescence can be induced by many stress factors, including telomere shortening, DNA damage and tumor- suppressor genes activation and is characterized by growth arrest, changes in gene expression and chromatin reorganization. Intensive research in the field has uncovered diverse functional implications for these senescence-inducing cascades. Nowadays, senescence is perceived as a late developmental stage in cell’s life, as a protective mechanism against cancer and as a positive contributor in wound healing. On the other hand, senescence can also be implicated in a range of abnormal contexts, for example tumor progression due to the senescence-associated secretome, and many age-related syndromes. Despite its importance, studying senescence in vitro remains complex and problematic in practice as, usually, cell population nearing senescence are highly heterogenous and it takes a significant amount of time to drive certain cell types into full-fledged senescence. Therefore, in Chapter I, I am discussing the establishment of a novel way for chemically inducing senescence which tackles the aforementioned caveats and allows for robust studies of the replicative senescence cascade. Chromatin organization is also markedly affected upon senescence entry and aging. These changes in chromatin structure range from very focal ones, for example histone modifications, to alterations in heterochromatin organization and, eventually, higher-order chromatin conformation. CTCF holds a prominent role in 3D genome architecture as it functions as an insulator protein between different chromatin domains and is one of the primary factors driving loop formation. Following senescence entry, CTCF has been found to dramatically reorganize into distinct senescence-associated CTCF clusters (SICCs). In Chapter II, I examine how SICCs are formed and maintained in 3D nuclear space, along with their interplay with nuclear speckles, a phase separated repository of RNA-processing related factors. Taken together, this thesis combines the introduction of a new model of chemically-induced senescence with the study of a structural hallmark of senescence entry to offer a new perspective of how genome reorganization crosswalks with cellular aging.
Keywords: CTCF; Senescence; 3D genome; Ageing; Nuclear Speckles; Inflachromene (ICM); Chromatin
 
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