Epigenetics comprises chemical modifications of the DNA and the proteins that the DNA is wrapped around them. These modifications play key roles in establishing and maintaining cellular identity throughout development and adulthood. In recent years, it has become increasingly clear that these actions are more dynamic than initially believed. The alteration of cellular identities during regeneration, ageing, and the formation of tumors is closely linked to systematic changes in epigenetic modifiers. The emergence of cutting-edge single-cell sequencing technologies has enabled thorough explorations of biological processes with high molecular precision. Nevertheless, the regulation of cellular behavior is intricately tied to collective processes occurring in both spatial and temporal dimensions, operating on the mesoscopic and macroscopic scales. However, these larger scales cannot be straightforwardly deduced from microscopic measurements along the DNA sequence. Consequently, the findings obtained from sequencing experiments stay at the descriptive level until they are coupled with methodologies capable of discerning collective degrees of freedom. Here, using statistical physics tools and sequencing technologies, we study the collective processes underlying epigenetic dynamics in cells that change their identity over time. Specifically, we investigate collective epigenetic processes during ageing and the reprogramming of cells after injury.
In the first part of this thesis, we study the mechanistic basis of epigenetic modifications during ageing. Despite the accuracy of machine learning models in predicting the biological age based on epigenetic DNA methylation marks, these tools do not inform about the mechanistic basis of epigenetic ageing. We show that epigenetic ageing is reflected in systematic and collective changes in DNA methylation marks during ageing, which manifests in the stereotypical behavior of two-point correlation functions. We devise a stochastic theory that comprises competition of antagonistic enzymes at the boundaries of genomic regions with atypically high content of cytosine-guanine pairs. We systematically coarse-grain this theory to derive a macroscopic description in terms of a phase-field theory. This model predicts the changes in two-point correlation functions during ageing and explains diverse observations in the field of epigenetic ageing.
In the second part of this thesis, we study the collective epigenetic processes during the regeneration of the liver after injury. In particular, we study the interplay between DNA methylation and the accessibility of chromatin and show the necessity for emergent memory of past injuries in the system. This memory is achieved by considering an effective projection between different scales of epigenetic modifications.
In total, in this thesis, we derived theoretical descriptions of epigenetic processes that have so far only been studied descriptively. We showed that both epigenetic alterations during ageing and during reprogramming rely on an interplay between collective biochemical processes and the geometry of the DNA. With this work, we show how linear DNA sequencing can inform about collective epigenetic processes in space and time.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:91338 |
| Date | 16 May 2024 |
| Creators | Mohammadzadehhashtroud, Aida |
| Contributors | Jülicher, Frank, Rulands, Steffen, Sabass, Benedikt, Technische Universität Dresden, Max Planck Institute für Physik Komplexer Systeme |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:doctoralThesis, info:eu-repo/semantics/doctoralThesis, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
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