The long-term goal of this project is to elucidate the fundamental gene regulatory mechanisms controlling epidermal tissue homeostasis. Thousands of genes are differentially expressed between undifferentiated and differentiated keratinocytes, yet our current understanding of the gene regulatory mechanisms still remain incomplete. In the context of transcription, which is the first and crucial stage of gene expression, a lot of efforts have been concentrated on the first transcription initiation step. The roles of two other transcription steps, namely the elongation and termination steps, remain largely unexplored. Therefore, this research plan is designed to bridge this knowledge gap by characterizing the regulatory roles of transcription elongation and termination processes in controlling epidermal gene expression. Our preliminary characterization revealed that undifferentiated and differentiated keratinocytes acquire differential expression patterns of transcription elongation and termination regulators. Leveraging our expertise on genomics, proteomics, and human tissue models, we will determine how transcription elongation and termination regulators cooperate with their interacting proteins to differentially regulate the elongation and termination processes to control epidermal progenitor maintenance versus terminal tissue differentiation. Dysregulation of epidermal gene expression underlies the pathogenesis of a spectrum of human skin diseases including psoriasis, chronic wound healing, and cancer. Increased understanding of gene regulation controlled by these under-characterized elongation and termination processes can generate novel therapeutic ideas for treating human skin diseases.
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 fundamental gene regulatory mechanisms that govern epidermal growth and differentiation, which may yield new insight and targets for the development of future therapies for epithelial disorders.