Regulation of Gene Expression in the Th2 Cytokine Locus

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DESCRIPTION (provided by applicant): During Th2 differentiation, the Th2 cytokine locus undergoes changes in chromatin structure that facilitate coordinated cytokine gene expression. A variety of positive and negative regulatory elements work cooperatively to bring about these changes in a lineage-specific fashion. The principal goal of this study is to understand the functional interplay among cis-elements that coordinates gene expression within this locus. We also want to understand the mechanism by which transcription factors initiate and maintain transcriptional activity of the cytokine genes. The first aim is to generate a reporter system to evaluate the role of elements within the Th2 cytokine locus in regulating coordinated expression of IL-4, IL-5, and IL-13. This reporter will be utilized to assess transcription of the genes simultaneously as well as assess the role of cis-elements, individually and in combination, on their regulation. The second aim is to create a system by which the reporter in Aim 1 can be rapidly introduced into mouse ES cells. Recombinase-mediated cassette exchange (RMCE) will be used to fulfill the goals of this aim. Appropriate Th2 differentiation is critical for proper immune homeostasis and antigen responsiveness. Dysregulated T cell polarization has been implicated in a number of pathological states, including allergic diseases and autoimmunity. Information gleaned from these studies will contribute to our understanding of Th2 differentiation and hopefully enable the ultimate goal, to intervene in this process and to avoid or correct these pathological manifestations. PUBLIC HEALTH RELEVANCE: The study of the regulation of Th2 cytokine gene expression is crucial in order to understand the development and treatment of immune-mediated dysfunction such as asthma or autoimmune disease. In this exploratory grant, we propose to develop a novel system to study Th2 cytokine gene expression that will enable for the first time a comprehensive analysis of regulatory element function in the Th2 cytokine locus. The development of this system will provide a much more detailed understanding of the control of Th2 cytokine gene expression and will eventually enable the development of therapeutic modalities that can specifically target and modulate the expression of these genes.