The role of mediator in maintaining and differentiating human mesenchymal stem cells
Full Project (May 1, 2015 - Present)
The maintenance of healthy cell state is required to prevent a number of human diseases, including developmental defects, autoimmune disease, and cancer. Small changes in the ability of a cell to properly regulate transcription and gene expression can result in large phenotypic changes. As medicine looks to novel therapies to treat human disease, adult stem cells and their therapeutic potential are being heavily investigated. The interest in stem cells is in their inherent cellular properties of self-renewal and their ability to be directed toward a number of terminally differentiated cell fates. To optimize the use of these cells in the clinic, it is first important that we gain a better understanding of what maintains their cell state as a healthy, multipotent cell, and what is necessary for them to properly differentiate down a specific lineage.
Regulation of gene expression relies on a coordinated interaction of environmental stimuli, internal signaling cascades, transcription factors, chromatin modifiers, microRNAs (miRNAs), and the transcriptional machinery. Here we propose exploring the role of a large multisubunit protein complex in maintaining the unique properties of mesenchymal stem cells (MSCs), a population of adult stem cells found in human bone marrow, adipose tissue, and umbilical cord blood, recently identified to have tremendous therapeutic potential. Earlier work in this field demonstrated a critical role for Mediator in maintaining embryonic stem cell state by facilitating long-range cell-type specific interactions that promoted gene expression profiles necessary to maintain the pluripotency of embryonic stem cells (Kagey et al. 2010). The goal of the project proposed here is to determine the role that specific Mediator subunits have in adult mesenchymal stem cell state. Specifically we are interested in identifying the genes regulated by Mediator, how expression of those genes is altered following the loss of specific Mediator subunits, how these changes in gene expression affect cell fate commitments, and finally how we can use this information to better understand the use of MSCs in clinical settings. The growing interest in adult stem cells and their use in the clinic demands more in-depth study of the mechanisms that control their distinct cell properties.