Date of Award

Summer 8-2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Molecular Science and Nanotechnology

First Advisor

Dr. Jamie Newman

Abstract

Selective gene expression is crucial in maintaining the self-renewing and differential potential of stem cells. Especially differentiation process requires a constellation of proteins that regulate expression of genes necessary for differentiation towards a specific lineage. Adipogenesis is a process of formation of mature fat cells from precursor cells that is tightly regulated by a number of transcription factors and their cofactors. Dysregulation in the process often leads to metabolic disorders, which is common due to prevalence of obesity. Mediator is a large, evolutionarily conserved, multi-subunit protein complex that functions as a transcriptional coactivator that modulates gene expression by relaying signals from cell type-specific transcription factors to RNA polymerase II. In humans, this complex consists of 30 subunits arranged in four modules. One critical module of the Mediator complex is the kinase module consisting of four subunits: MED12, MED13, CDK8, and CCNC. The kinase module exists in variable association with the 26-subunit Mediator core and affects transcription through phosphorylation of transcription factors and by controlling Mediator structure and function. Many studies have shown the kinase module to be a key player in the maintenance of stem cells that is distinct from a general role in transcription. Genetic studies have revealed that dysregulation of this kinase subunit contributes to the development of many human diseases. This research aims to demonstrate the importance of the Mediator kinase module by examining their expression and interaction with key adipogenic regulators during adipogenesis. It is hypothesized that the kinase module subunits have a role in adipogenesis of hASCs. As we look to use stem cells to understand human development and treat human disease through both cell-based therapies and tissue engineering, this research will address critical gaps in knowledge related to the molecular mechanisms that control cell fate.

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