Epigenetic enhancer control in maintaining homeostasis and preventing carcinogenesis in the epidermis

PROJECT ABSTRACT
Epigenetics impacts all areas of cellular physiology, and epigenetic dysregulation is pervasive in human
disease. Given the inherent reversibility of epigenetic changes, this presents a great opportunity for the
discovery of novel therapeutics given the recent rapid development of epigenome-modifying drugs. Intriguingly,
large-scale human sequencing efforts have revealed that sun-damaged, but clinically otherwise normal human
skin, can harbor frequent mutations in epigenetic chromatin modifying enzymes. These include mutations that
have been typically observed in cutaneous squamous cell carcinoma (cSCC), the second most common of all
human malignancies, and a major economic and public health burden. Recent data suggests that these
epigenetic mutations may be important drivers of malignant clone formation in the epidermis, provoking the
hypothesis that proper epigenetic function is required for both maintaining epidermal homeostasis and
preventing the initiation of carcinogenesis. Remarkably, despite the high incidence of both these mutations in
epigenetic modifiers and cSCC, the precise mechanisms by which disruption of chromatin modifying
enzymes drives the initiation of cSCC are virtually unknown. In this proposal, we will utilize multiple model
systems including human patient samples and a variety of transgenic mouse models, combined with several
innovative genome-wide and functional technologies in order to define the mechanistic links between
chromatin regulation, transcription, epidermal cell fate, and the initiation of epidermal carcinogenesis.
Collectively, these studies promise to inform both the development and utilization of epigenetic therapies in the
future.

Grant Number: 5R01AR077615-05
NIH Institute/Center: NIH
Principal Investigator: Brian Capell