KANSAS U COBRE: REGULATION OF GENE EXPRESSION IN THE TH2 CYTOKINE LOCUS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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 overall scientific 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 following aims are designed to create a model system in which the role that various cis-elements play in transcriptional regulation within the Th2 cytokine locus can be examined. Their completion will lay the groundwork for successfully addressing the overall scientific goal. The first aim is to identify trans-factor binding sites serving structural or functional roles in mediating transcriptional activity in the locus. We will specifically focus on binding sites for two important Th2-related factors, GATA3 and STAT6. Biochemical and molecular biological approaches will be used to fulfill the objectives of this aim. The second aim is to generate a reporter system to evaluate the role of elements within the Th2 cytokine locus in regulating coordinated expression of IL4, IL5, and IL13. 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. 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.