Chromatin reorganization, signaling responses and non-coding RNA regulators in homeostasis and senescence

by Natasa Josipovic
Doctoral thesis
Date of Examination:2021-09-15
Date of issue:2022-04-21
Advisor:Prof. Dr. Argyris Papantonis
Referee:Dr. Johannes Soeding
Referee:Prof. Dr. Markus Bohnsack
Referee:Prof. Dr. Patrick Cramer
Referee:Dr. Marieke Oudelaar
Referee:Dr. Ufuk Günesdogan
Persistent Address: http://dx.doi.org/10.53846/goediss-9136

 

 

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Abstract

English

In mammalian cells, a relatively limited fraction of genetic information is utilized in a variety of ways to give rise to distinct cellular phenotypes. Thus, the genotype essentially acts as input for multilayered regulatory networks, which coordinate cellular activities and ultimately shape cell identity and function. Early studies, focusing on individual components of such regulatory networks, have unraveled core principles of cellular functions. Therein, individual, or small groups of genes are regulated by a defined set of locally acting factors. The idea of such individual regulatory units persists, despite new experimental and computational evidence pointing to extensively intertwined “pan-genomic” regulatory networks. In such emerging models, intricate cellular traits originate from numerous interactions, and the mutual dependences between distinct regulatory units are further governed by such factors as 3D chromatin architecture, non-coding RNA, and even regulatory crosstalk between cells. Therefore, understanding the mechanisms of accurate spatiotemporal regulation of gene expression requires not only elucidating the roles of individual factors at local nodes, but also their contribution to a collective pan-genomic network. In light of such a view, I combined genomics and functional studies in primary human cells to study the regulatory modes of three diverse molecular factors in the context of cellular homeostasis. In Chapter 1, I examine the contribution of active RNA polymerase II (RNA Pol II) in the intricate process of setting up chromatin organization following exit from mitosis. In Chapter 2, I examine the role of HMGB1 as an architectural and RNA-binding factor mediating key events in cells exiting homeostatic cell cycle progression to enter replicative senescence. In Chapter 3, I explore the regulatory potential of two circRNAs, circCAMSAP1 and circRAB3IP, in navigate regulation of cell cycle progression and inflammation in human cells. Taken together, these three layers of genomic regulation – via RNA Pol II transcription, a dual-function transcription factor, and a pair of circular non-coding RNAs – exemplify the idea of multi-layered regulation of pan-genomic networks inside human cells.
Keywords: Chromatin; Gene expression; circRNA; Genome structure; Senescence; HMGB1
 
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