LOCUS CONTROL REGION HSI,II AND HGH EXPRESSION

University Of Pennsylvania, Philadelphia PA

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Abstract

The pituitary- and placenta-specific genes of the human growth hormone (hGH) gene cluster are vital to normal growth and physiology during development and in the adult. Misregulation of the hGh gene leads to significant pathological consequences that illustrate its importance in postnatal development. Furthermore, the organization of genes in the cluster and its association with a dominant distal regulatory element, the locus control region (LCR), make it a valuable model for the study of genes in higher eukaryotes that are organized into discrete genomic regulatory domains. The work proposed here will address important questions about the modulation of gene expression during in utero development with a focus on the mechanisms by which LCRs are involved as major determinants in this process. The aims of the proposed research are to study the organization and identity of a subset of regulatory determinants in the hGH LCR ( HSI, II) and their role in the establishment ant maintenance of an hGH transgene in a transcriptionally active state during pituitary development. The region of the LCR involved in the transcriptional activation of the hGH gene in the pituitary has been identified by its DnaseI hypersensitivity (HSI,II) and is the focus of this proposal. In aim I, using a transgenic mouse system, the precise locations of LCR activity will be mapped in the HSI, II region. In Aim II, the discrete elements involved in HSI,II region. In Aim II, the discrete elements involved in HSI,II activity and their corresponding protein factors will be identified and characterized using in vitro protein binding and foot printing assays. There is a strong potential for the discovery of novel regulatory proteins in this Aim, as there are no recognition sequences for known factors in the HSI,II region. Finally, Aim III will determine whether HSI,II is required the maintenance as well as the initial activation of hGH gene expression during pituitary somatotrope cell lineage progression in a transgenic mouse system using a developmentally-regulated conditional deletion of HSI,II. The outcome of this research, if successful , will result in novel insight into the developmental control of human growth hormone gene cluster, the mechanism by which LCRs function, and how gene expression profiles are established and maintained in specific cell lineages during development.