My long-term goal is to spend a career guiding a productive research laboratory teaching students and fellows while making significant contributions to epithelial biology. In particular, I am interested in how cells differentiate into different developmental lineages and retain that cellular memory. I am interested in the epidermis as a model system since the skin has a constant turnover rate with cycles of proliferation and differentiation. These cycles must be tightly regulated or disorders would rapidly arise. I am also interested in how dysregulation of these fundamental processes can lead to human diseases such as cancer. This training proposal will help me attain these goals because of all the techniques and skills I will learn to address the questions of the proposal. Specifically, the training during this award period will provide me with new expertise in epithelial biology, in vivo mammalian model systems, genomics, and cancer biology. My immediate goal is to accomplish the aims of the proposal as described below. Epidermal homeostasis is a tightly regulated process that begins with actively dividing cells that eventually differentiate into enucleated corneocytes that form the water-impermeable layer of the skin. Perturbations in the balance between growth and differentiation can lead to a variety of human skin disorders. Increased proliferation and diminished differentiation can lead to hyperproliferative disorders such as psoriasis, basal or squamous cell carcinomas. Thus, a comprehensive understanding of the regulators of epidermal growth and differentiation would be key to unlocking the molecular mechanisms underlying skin disorders which could potentially lead to the development of target guided therapies for skin disorders. This effort aims to define the role of epigenetic modifiers in epidermal growth, differentiation, and neoplasia. Our previous findings demonstrated that the histone demethylase, JMJD3, controls epidermal differentiation by removal of methyl marks on H3K27me3 marked epidermal differentiation gene promoters. Because of the central role of JMJD3 in epidermal differentiation, functional alterations in JMJD3 may contribute to neoplasia.
Aim I will characterize the role of JMDJ3 in human epidermal tumor progression. In order to identify other epigenetic modifiers with a role in epidermal growth and differentiation, we systematically depleted the function of DNA and histone modifying enzymes and found DNA methyltransferase 1 (DNMT1) and Histone deacetylase 2 (HDAC2) to have effects on epidermal growth and differentiation.
Aim II focuses on characterizing the role of DNMT1 and HDAC2 on epidermal growth, differentiation and neoplasia.
Abnormalities in epidermal growth and differentiation result in a wide range of disorders including psoriasis, squamous cell carcinoma, basal cell carcinoma and chronic wounds that negatively impact a large proportion of the U.S. population. This proposal seeks to understand the underlying molecular mechanisms that govern epidermal growth and differentiation as well as molecular events essential for tumor progression. The efforts of this proposal will define the role of epigenetic regulators in epidermal homeostasis and neoplasia, which may yield insights in the development of therapies for epidermal disorders.
|Chen, Yifang; Mistry, Devendra S; Sen, George L (2014) Highly rapid and efficient conversion of human fibroblasts to keratinocyte-like cells. J Invest Dermatol 134:335-344|
|Sen, George L; Boxer, Lisa D; Webster, Dan E et al. (2012) ZNF750 is a p63 target gene that induces KLF4 to drive terminal epidermal differentiation. Dev Cell 22:669-77|
|Mistry, Devendra S; Chen, Yifang; Sen, George L (2012) Progenitor function in self-renewing human epidermis is maintained by the exosome. Cell Stem Cell 11:127-35|
|Sen, George L; Reuter, Jason A; Webster, Daniel E et al. (2010) DNMT1 maintains progenitor function in self-renewing somatic tissue. Nature 463:563-7|