SWI/SNF in ultraviolet radiation-induced chromatin alterations - Cutaneous malignant melanoma, the most lethal form of skin cancer, originates from the transformation of epidermal melanocytes. The primary environmental risk factor for melanoma is exposure to ultraviolet radiation (UVR) from sunlight. UVR induces DNA damage, inflammation, and various cellular alterations that culminate in the conversion of melanocytes into melanoma cells. Under normal circumstances, melanocytes respond to UVR by orchestrating genomic changes that facilitate a photo-protective response. This includes crucial processes such as melanin synthesis, modifications to the cell cycle, activation of DNA repair mechanisms, and initiation of cell death pathways. The development of melanoma can arise from deficiencies in the photo-protective response. This underscores the significance of comprehending the regulatory mechanisms at play. Proper gene expression, epigenetic regulation, and the maintenance of genome integrity hinge on the regulation of chromatin structure. In melanomas, mutations in genes encoding components of the SWI/SNF Chromatin Remodeling Complex occur in 34% of cases. However, the epigenetic consequences of the loss of SWI/SNF function following exposure to UVR remain unclear. This proposal posits that the absence of BRG1, a catalytic subunit of the SWI/SNF complex, disrupts the normal response of melanocytes to UVR. This leads to the deregulation of gene expression and chromatin structure, compromising the photo-protective response and exacerbating the inflammatory and other detrimental effects of UVR. To validate this hypothesis, BRG1 will be inactivated in the melanocyte compartment of adult mice, and the mice will be exposed to UVR. Our investigation will determine (Aim 1) the effects on gene expression and (Aim 2) alterations in chromatin structure. This innovative study represents the first to elucidate the impact of BRG1 loss in UVR-exposed melanocytes in vivo.
