Role of Mechanosensitive Chromatin Organization In The Nucleus of Eukaryotic Cells

Seelbinder, Benjamin

Graduate Thesis Or Dissertation

Role of Mechanosensitive Chromatin Organization In The Nucleus of Eukaryotic Cells Público Deposited

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Citeable URL: https://scholar.colorado.edu/concern/graduate_thesis_or_dissertations/pr76f440s

Abstract

In the human body, there are about 200 different cell types that share a common genome but have specialized roles. During development, cells use mechanical cues from their environment as a guide for tissue-specific cell differentiation, a phenomenon referred to as mechanosensation. The mechanisms underlying mechanosensitive adaptation of cells to their environment are still debated, however. The cell’s nucleus is thought to be a mechanosensitive organelle as it is tightly connected to all parts of the cytoskeleton. The disruption of nuclear connections, in disease or experiments, have shown to abrogate cellular responses to mechanical stimuli. Furthermore, the spatial organization of chromatin in the nucleus has emerged as a new mechanism to control local and global gene transcription. The organization of chromatin changes dynamically from an unstructured organization in the zygote to a cell type-specific chromatin architecture during development. Since the nucleus is a large organelle within a cell, its morphology has also been directly linked to the function of differentiated cells.

Taken these concepts together, it can be hypothesized that mechanical cues from the environment influence cell behavior through the spatial reorganization of chromatin and, further, that this reorganization is mediated by forces transmitted to nucleus. In this thesis, the dynamic change in chromatin arrangements in response to mechanical stimuli and its role in cell function were investigated. Chapter 1 provides an overview of the hierarchical organization of chromatin in the nucleus and its evolution during development. Showcased are also examples of cell type-specific nuclear architectures and their morphological relevance for distinct cell functions. In Chapter 2, a new device for the live imaging of cells under cyclic stretch is presented and utilized to analyze the dynamic response of mouse embryonic fibroblasts to different magnitudes of strain. Findings from this study suggest that rapid nuclear condensation might be a mechanism to protect from DNA damage under high strain loads. Chapter 3 investigates the influence of contraction-mediated nuclear strains on the reorganization of chromatin in embryonic mouse cardiomyocytes during development. The results from this research showed that CMs establish a cell-type specific nuclear architecture that was mediated through the transfer of strain from myofibrils to the nucleus. Overall, the results in thesis support that intranuclear strains influence the organization of chromatin and direct cell behavior on short-term scales and cell differentiation on long-term scales.

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