Esposito, Andrea
(2020)
Combined polymer physics and machine learning approach to investigate the chromosome 3D structure.
[Tesi di dottorato]
| Tipologia del documento: |
Tesi di dottorato
|
| Lingua: |
English |
| Titolo: |
Combined polymer physics and machine learning approach to investigate the chromosome 3D structure |
| Autori: |
| Autore | Email |
|---|
| Esposito, Andrea | andresposito@na.infn.it |
|
| Data: |
12 Marzo 2020 |
| Numero di pagine: |
93 |
| Istituzione: |
Università degli Studi di Napoli Federico II |
| Dipartimento: |
Fisica |
| Dottorato: |
Fisica |
| Ciclo di dottorato: |
32 |
| Coordinatore del Corso di dottorato: |
| nome | email |
|---|
| Capozziello, Salvatore | capozzie@na.infn.it |
|
| Data: |
12 Marzo 2020 |
| Numero di pagine: |
93 |
| Parole chiave: |
Polymer physics, machine learning, chromosome spatial organization |
| Settori scientifico-disciplinari del MIUR: |
Area 02 - Scienze fisiche > FIS/02 - Fisica teorica, modelli e metodi matematici |
[error in script]
[error in script]
| Depositato il: |
31 Mar 2020 16:20 |
| Ultima modifica: |
17 Nov 2021 10:30 |
| URI: |
http://www.fedoa.unina.it/id/eprint/12999 |
Abstract
The spatial organization of the chromatin in the nucleus is known to play an important role in transcriptional regulation of genes in many organisms. However, the comprehension of genome architecture and of the molecular mechanisms shaping its structure, represents a challenging problem which remains not fully understood. During the last two decades, the development of new technologies has allowed to investigate the three-dimensional spatial folding of chromosomes in a quantitative way. Thanks to these technologies, we now know that chromosomes are characterized by a complex, non-random, 3D organization occurring at different genomic length scales, through local and long-range interactions. The molecular factors underlying their formation are still to be investigated. In this sense, polymer physics is turning out to be a great tool to understand the molecular mechanisms of the 3D chromatin spatial organization from first principles. The studies discussed in the present work have been devised in this general framework. They consist of a detailed description of results and conclusions from the projects that we have conducted in the Physics Department of University of Naples Federico II, under the supervision of Professor Mario Nicodemi, in the group of Complex Systems. Many results have been published or are currently in progress in collaboration with the Epigenetic Regulation and Chromatin Architecture group directed by Prof. Ana Pombo, at Max Delbruck Centre For Molecular Medicine (Berlin) and the Development and Disease Group directed by Professor Stefan Mundlos, at Max Planck Institute for Molecular Genetics (Berlin).
The thesis is organized in four chapters. In Chapter 1, we introduce some basic concepts necessary to the comprehension of this research activity and summarize recent results related to the chromatin spatial organization, as the main experimental techniques, the interpretation of the chromosome interaction data and the relationship between spatial organization and cell functionality. Then, we briefly review the polymer models currently proposed to describe the chromosomes three-dimensional organization in the cell nucleus. In Chapter 2, we outline the ‘Strings and Binders Switch (SBS)’ model, developed in our research group, and we make use of it to quantitatively explain the information contained in the Hi-C interaction data via Molecular Dynamics simulations. We show that the thermodynamic phases envisaged by our mode can be used to explain the long-range contact profile of chromosomes; then we try to schematically model the hierarchical structure of chromatin, and finally we present a theoretical study of the multiple co-localization contact landscape. In Chapter 3, we introduce more sophisticated variant of the SBS polymer model by which we can reconstruct the 3D structure of real genomic region with high accuracy. Next, we employ this model to study the folding mechanisms and the enhancer-promoter communication at some important chromosome loci where the failure of these mechanisms can lead to severe diseases. Finally, in Chapter 4, we extend our modeling genome-wide, i.e. to the entire set of chromosomes of the mouse genome. The increase in statistics obtained with the genome-wide study, allows us to compare our polymer models with epigenetics factors, known to play an important role in gene regulation. In this way, we can clarify the molecular nature of the binding factors inferred by our model.
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