EPIGENETIC REGULATION OF EPIDERMAL HOMEOSTASIS AND CUTANEOUS MALIGNANCY
Dr. David Chen is interested in the epigenetic regulation of epidermal homeostasis and cutaneous malignancy. In mouse models of aging, hair graying and loss is a common occurrence despite the varied mechanisms tested. As humans age, our genomic DNA tends to lose the methylation of cytosine residues, which serve as gene regulatory marks. Under the direction of Dr. Tim Ley, the lab generated a mouse model to study the effects of a particular mutation in DNA methyltransferase 3A (DNMT3A) which our lab identified as commonly mutated in acute myeloid leukemia. Mice expressing this dominant negative mutant protein unexpectedly lose their hair, and surprisingly, when the mutated gene is turned off, the mice regrow their hair. From our prior studies, we know that the mutated DNMT3A dominantly suppresses the wild type enzyme’s methyltransferase function, ultimately leading to cells that have a severely depressed ability to methylate DNA. These findings implicate DNA methylation in the regulation of a reversible defect in hair cycling.
The goal of our current study is to understand how DNA methylation affects the ability of hair follicles to maintain homeostasis. A better understanding of how hair cycling is controlled may lead to insight into the mechanisms responsible for alopecia and the potential for its prevention or reversal. Further, epigenetic modifications like DNA methylation are known to be central for the development of many malignancies, and studies are underway to better understand this phenomenon.