| Psoriasis is a chronic, inflammatory skin disease characterized by hyperproliferation and altered differentiation of keratinocytes, and infiltration of activated immune cells in the epidermis. Array based genome-wide expression studies by our lab and others have revealed over 1,300 alterations in mRNA transcript levels in psoriatic skin. microRNAs (miRNAs) are a class of short, regulatory RNAs that play critical roles in human development and disease. I hypothesized that differential expression of miRNAs might underlie some of the gene expression changes in psoriatic skin. Thus, I sought to characterize the global landscape of miRNA expression in human skin, and to investigate the functional roles of miRNAs with respect to psoriasis pathogenesis. I profiled small RNAs in human skin with Next Generation sequencing, and detected known miRNAs, variants of known miRNAs, and novel miRNAs with unprecedented sequencing depth. Eighty known and 18 novel miRNAs were two- to 42-fold differentially expressed in psoriatic skin. Computational and experimental analysis of miRNA targets revealed that three differentially expressed miRNAs directly regulate components of the skin barrier, and that these regulatory interactions have recent evolutionary origins. I also identified other species of small RNAs, such as endogenous small interfering RNAs (siRNAs) in skin, but determined that they are typically less abundant than miRNAs. Like miRNAs, some of these are differentially expressed in psoriasis, and may function as regulators of gene expression. Overall, this work has greatly increased our understanding of the depth and breadth of small RNA species expressed in human skin, and implicated a large number of small RNAs in psoriasis pathogenesis. |
