Project description:Studies of the zinc finger transcription factors Slug and Snail have largely focused on their important role in modulating epithelial-mesenchymal transition during embryonic development and tumor progression. However, these transcription factors also appear to regulate local inflammation. In previous studies, we showed that Slug knockout mice were resistant to sunburn, an acute cutaneous inflammatory response, compared to wild type mice. In the present studies, we used Slug knockout, chimeric Slug knockout/wild type, conditional Slug knockout, and Slug transgenic mice to study the role of Slug in ultraviolet radiation (UVR)-induced cutaneous inflammation. We demonstrated, using immunohistochemistry, in vivo imaging, and neutrophil migration studies, that it was Slug expression in the epidermis rather than in neutrophils that modulated the UVR response. Microarray analysis indicated that this modulation was effected by the production of epidermal cytokines, including CCL3, CCL4, oncostatin, and interleukin-1β, that recruited neutrophils to UVR-exposed skin. The pattern of pro-inflammatory gene regulation by Slug suggested a central role for NF-κB in mediating gene induction. Immunohistochemical analysis of UVR-induced NF-κB activation demonstrated reduced activation in Slug knockout and enhanced activation in Slug transgenic epidermis. Slug thus appears to modulate NF-κB activation in response to UVR.
Project description:To characterize the genetic basis of hybrid male sterility in detail, we used a systems genetics approach, integrating mapping of gene expression traits with sterility phenotypes and QTL. We measured genome-wide testis expression in 305 male F2s from a cross between wild-derived inbred strains of M. musculus musculus and M. m. domesticus. We identified several thousand cis- and trans-acting QTL contributing to expression variation (eQTL). Many trans eQTL cluster into eleven ‘hotspots,’ seven of which co-localize with QTL for sterility phenotypes identified in the cross. The number and clustering of trans eQTL - but not cis eQTL - were substantially lower when mapping was restricted to a ‘fertile’ subset of mice, providing evidence that trans eQTL hotspots are related to sterility. Functional annotation of transcripts with eQTL provides insights into the biological processes disrupted by sterility loci and guides prioritization of candidate genes. Using a conditional mapping approach, we identified eQTL dependent on interactions between loci, revealing a complex system of epistasis. Our results illuminate established patterns, including the role of the X chromosome in hybrid sterility.
