Regulation and function of transcription factor dynamics during adipogenesis
Abstract/Contents
- Abstract
- A healthy metabolism requires proper fat tissue function. Thus, the generation of new fat cells through the process of adipogenesis is a critical component in the regulation of metabolic homeostasis and change. Prior work has established an extensive list of key transcriptional regulators of the adipogenic differentiation process including the important early regulator, CEBPB, and the master regulator, PPARG. However, the expression and activation dynamics of these transcriptional regulators along with the functional consequences of the dynamics remain poorly studied. A main challenge has been the lack of tools and techniques to study the dynamics in single cells in the context of adipogenesis. In this thesis, I aimed to overcome these challenges and address the important question of how the dynamics of key transcription factors regulate the process of adipogenesis. I present two works that introduce new fluorescent cell lines and live cell imaging pipelines that enable the quantitative analysis of transcription factor dynamics during adipogenesis. I first demonstrate that slow PPARG dynamics enable pre-adipocyte cells to regulate the degree of fat cell differentiation in response to different patterns of stimulus application. I show that this regulation depends on combination of fast and slow acting positive feedback loops centered on PPARG. This network architecture allows cells to discriminate between pulsatile and continuous stimulus patterns and may explain why loss of pulsatile glucocorticoid patterns in the body is so closely associated with obesity. I then used measurements of PPARG dynamics over the course of the cell cycle to identify a time range during adipogenesis when the decision to proliferate competes with the decision differentiate. Moreover, dynamic measurements enabled me to measure the point in time where cells committed to the differentiated state and I show that this commitment point corresponds to when differentiating cells permanently withdrew from the cell cycle. Taken together my work demonstrates how measuring the dynamics of key regulators of adipogenesis suggested new models for how the number of adipocytes is controlled in fat tissue. Importantly, our findings have more general implications for how other tissues can control the number of terminally differentiated cells since both the response to pulsatile hormonal signals and cell cycle control are general features shared by cells throughout the body.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2019; ©2019 |
| Publication date | 2019; 2019 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Zhao, Michael |
|---|---|
| Degree supervisor | Teruel, Mary |
| Thesis advisor | Teruel, Mary |
| Thesis advisor | Ferrell, James Ellsworth |
| Thesis advisor | O'Brien, Lucy Erin, 1970- |
| Thesis advisor | Sage, Julien |
| Degree committee member | Ferrell, James Ellsworth |
| Degree committee member | O'Brien, Lucy Erin, 1970- |
| Degree committee member | Sage, Julien |
| Associated with | Stanford University, Department of Chemical and Systems Biology. |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Michael Zhao. |
|---|---|
| Note | Submitted to the Department of Chemical and Systems Biology. |
| Thesis | Thesis Ph.D. Stanford University 2019. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2019 by Michael Zhao
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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