GROWTH HORMONE GENE EXPRESSION AND HISTONE ACETYLATION

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The human growth hormone (hGH) gene cluster encompasses pituitary and placenta specific genes that are essential for normal growth and physiology during development and in adulthood. Misregulation of the hGH gene cluster results in severe pathological consequences and illustrates the importance of the hGH genes in postnatal growth, metabolic control, and gestational physiology. A set of distal hGH regulatory elements, termed the locus control region (LCR), has been identified and shown to be essential for the appropriate expression of the hGH in the pituitary and placenta. However, the mechanism(s) underlying the functions of remote elements in general, and LCR elements in particular, are not well defined. Defining the mechanisms underlying LCR activity is of particular importance in the case of the hGH LCR as it is closely linked to other genes with at least 4 distinct tissue specificities. The various elements of the LCR involved in the appropriate tissue-specific expression of the hGH gene cluster in the pituitary and placenta were identified by their DNase I hypersensitivity (HS). In the pituitary nuclei, a subset of 4 regulatory determinants in the hGH LCR were detected in the 5'-flanking region remote from the gene cluster (designated HSI,II,III,V) and in the placenta syncytiotrophoblastic nuclei, a subset of 3 regulatory determinants were detected (designated HSIII,IV,V). The focus of this proposal will be to elucidate the mechanism(s) underlying HS activity in the pituitary and placenta by investigating the role of histone acetylation in HS function/gene activation. Aim I will test the hypothesis that histone acetylation at critical control determinants (HS) within the LCR will correlate with tissue specific gene activation from the hGH gene cluster. Aim II will test the hypothesis that the CBP/p300 histone acetylase mediates the tissue-specific and targeted hyperacetylation of histone proteins at these specific HS. The outcome of this research will provide a novel insight into the mechanism(s) underlying LCR function and how appropriate gene expression profiles are established, regulated and maintained in specific cell lineages during development.