My long-term career goal is to lead a productive academic research group, promoting science by conducting active research on epithelial biology and nourishing the next generation of dedicated scientists. I am particularly interested in the mechanism underlying epidermal tissue homeostasis, which is tightly controlled by the balance between proliferation and differentiation. Disruptions of epidermal homeostasis underlie a number of diseases including psoriasis, chronic wound healing, and cancer. This K99/R00 proposal aims to define the role of chromatin remodeling during early epidermal tumor progression, and to uncover novel regulators essential for maintaining the epidermal progenitor state. First, we will focus on the role of the BAF/SWI/SNF chromatin remodeling complex in the earliest phases of epidermal tumor progression. Chromatin remodeling complexes directly impact gene expression by using the energy from ATP to disrupt the contact between DNA and nucleosomes. The BAF chromatin remodeling complex is composed of one catalytic subunit, Brg1 or Brm, and 10 interchangeable regulatory subunits encoded by 18 genes.
Aim I will test the hypothesis that recurrent mutations in selected regulatory subunits of the BAF complex, which we have recently observed in squamous cell carcinoma (SCC), facilitate early cancer progression by impairing differentiation. We will do this by regenerating and characterizing human neoplastic tissue with altered function of BAF subunits. This effort is designed to yield insight into the mechanism underlying how the chromatin remodeling process is hijacked in cancer progression. Second, we will identify novel regulators that are required to maintain progenitors in epidermal tissue. We have recently identified the protein arginine methyltransferase, PRMT1, as dominantly required to sustain progenitor function. We have further identified 37 PRMT1-interacting proteins in undifferentiated primary human keratinocytes, through our recent PRMT1 protein complex purification.
Aim II will identify and characterize new regulators among these PRMT1-interacting proteins in maintaining progenitor function, and will shed light on gene regulatory mechanisms underlying human tissue homeostasis. This proposal will define the role of the BAF chromatin remodeling complex in tumor progression, and will also identify new sustainers of epidermal progenitor function, as a basis for new therapies for diseases of skin and other tissues.
Epidermal tissue homeostasis is maintained by precise spatial and temporal control of proliferation and differentiation. Disruption of epidermal homeostasis results in a wide range of human diseases including psoriasis, squamous cell carcinoma, basal cell carcinoma, and chronic wounds. The proposed effort seeks to understand the mechanisms that govern epidermal growth and differentiation as well as molecular events critical for early cancer progression, which may yield new insight and targets for the development of future therapies for these diseases.
| Bao, Xiaomin; Siprashvili, Zurab; Zarnegar, Brian J et al. (2017) CSNK1a1 Regulates PRMT1 to Maintain the Progenitor State in Self-Renewing Somatic Tissue. Dev Cell 43:227-239.e5 |
