1381 Molecular mechanisms of donor dominance in androgenetic alopecia

Androgenetic alopecia (AGA) is a complex genetic trait that is characterized by regional hair follicle miniaturization in response to androgens. While female-pattern hair loss is characterized by a diffuse thinning of the scalp, male pattern can be induced upon elevation of testosterone levels. What confers regional susceptibility vs. refractivity on different regions of the scalp is unknown. Donor Dominance refers to the phenomenon by which hair follicles retain the characteristics of the donor site when transplanted to a recipient site. This property forms the basis for the success of hair transplantation. Since the calvarium begins to develop shortly prior to hair follicle induction, this suggests that the craniofacial dermis epigenetically/differentially influences hair follicle patterning and development. We noticed that the hair pattern in AGA overlaps precisely with the demarcations of scalp dermis/underlying bones, which have a dual origin (neuroectoderm for parietal bone), vs. mesoderm (for occipital bone). Computational analyses of RNA seq from parietal and occipital scalp of matching control and AGA affected volunteers revealed a striking differential gene expression profile along the cranial-caudal axis defining two distinct biosignatures that reflect: 1) the developmental origins of the skin and 2) the susceptibility to develop AGA. Functional annotation of the differentially expressed genes shows enriched pathways in AGA samples, including genes implicated in cartilage-ECM interaction (ADAMTS4), in immunity (CD300c, FCGR1A), and epigenetic factors. Using the ARACNe algorithm, we identified transcription factors or master regulators (MRs) that govern the molecular mechanisms of AGA. This list of MRs was used to perform functional studies. Altogether, we present novel insights into the genetic, epigenetic, and developmental factors required for temporal specification of the skin and the interdependence of hair follicle, skull and craniofacial development.