Uterine leiomyomas (UL), also known as uterine fibroids, are benign smooth muscle tumors with excessive depostition of extracellular matrix proteins. UL is a major health problem worldwide, because it affects almost 70-80% of all women and disproportionally African Americans, but still remains poorly understood. The long term goal of our team is to systematically discover novel mechanisms regulating key molecular events that contribute to leiomyoma. The immediate goal of this R01 application is to test the hypothesis that altered epigenomic signatures define normal myometrial tissues and leiomyomas, and therapy treated human tissues. Using genome-wide studies integrated with bioinformatic and other analyses, we will determine the epigenomic signatures in uterine fibrosis for the first time. This unbiased study will identify epigenomic differentiating features of normal and diseased tissues and may allow for development of Epitherapy (targeting the epigenome) for leiomyomas The proposed work is scientifically, translationally, and clinically significant and highly innovative because it represents the first systematic exploration of the epigenome in leiomyomas. Results obtained from this analysis will be used to generate new hypotheses to better understand the molecular underpinning of leiomyomas.