PROJECT SUMMARY Dysregulation of inflammatory responses are observed in a variety of cutaneous diseases, including autoimmune diseases and infections. A striking feature of these conditions is sexual dimorphism relating to the differential incident rates of these diseases between women and men. Understanding the underlying mechanism for the sex-biased inflammatory responses can point towards previously unappreciated pathways that are critical in regulating immune responses, and therefor can lead to development of sex-specific therapeutic approaches. Current data on the effect of sex-hormones and sex-chromosome regulatory genes insufficiently explain these biologic differences between men and women. We have recently identified differential epigenetic modifications between male and female keratinocytes, setting the stage for our hypothesis that sexually dimorphic epigenetic modifications in keratinocytes affect immune gene transcription and responses. The objective of this project is to identify and target epigenetic modifications that drive sexually dimorphic immune responses, allowing future development of precision therapies for inflammatory skin disorders. Upon the successful completion of this project, we will have characterized epigenetic differences between skin cells in women and men, determined the contribution of these sex-biased epigenetic modifications to immunological responses, and assessed whether they could serve as therapeutic targets for future treatment of immune mediated skin disorders.