The long-term goals of this research are to understand the mechanisms responsible for the establishment and maintenance of tissue-specific patterns of transcription in mammalian cells. Using cultured hepatoma cells and hepatoma hybrids as a model system, trans-acting genetic loci that regulate expression of sets of liver genes have been defined. To determine the mechanisms by which these tissue-specific extinguisher (TSE) loci function and to assess their roles in cellular development, three main areas of research will be pursued. First, microcell hybrids retaining specific donor chromosomes will be used to complete the genetic analysis of extinction, the process by which tissue-specific gene activity is repressed in intertypic hybrid cells. Second, cDNA and genomic clones from two human TSE loci will be isolated and characterized. Third, the functions of TSE gene products will be studied by in vitro mutagenesis of cloned sequences and gene transfer. In particular, the potential roles of these products in regulating transcription factor expression will be assessed. These studies should help define regulatory networks involved in eukaryotic gene control, and may provide insights into perturbation of those controls that underlie abnormal development and neoplasia.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Mammalian Genetics Study Section (MGN)
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Fred Hutchinson Cancer Research Center
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Zhao, Hui; Friedman, Richard D; Fournier, R E K (2007) The locus control region activates serpin gene expression through recruitment of liver-specific transcription factors and RNA polymerase II. Mol Cell Biol 27:5286-95
Marsden, Mark D; Fournier, R E K (2005) Organization and expression of the human serpin gene cluster at 14q32.1. Front Biosci 10:1768-78
Baxter, Euan W; Cummings, W Jason; Fournier, R E K (2005) Formation of a large, complex domain of histone hyperacetylation at human 14q32.1 requires the serpin locus control region. Nucleic Acids Res 33:3313-22
Namciu, Stephanie J; Friedman, Richard D; Marsden, Mark D et al. (2004) Sequence organization and matrix attachment regions of the human serine protease inhibitor gene cluster at 14q32.1. Mamm Genome 15:162-78
Namciu, Stephanie J; Fournier, R E K (2004) Human matrix attachment regions are necessary for the establishment but not the maintenance of transgene insulation in Drosophila melanogaster. Mol Cell Biol 24:10236-45
Marsden, Mark D; Fournier, R E K (2003) Chromosomal elements regulate gene activity and chromatin structure of the human serpin gene cluster at 14q32.1. Mol Cell Biol 23:3516-26
Antes, T J; Namciu, S J; Fournier, R E et al. (2001) The 5' boundary of the human apolipoprotein B chromatin domain in intestinal cells. Biochemistry 40:6731-42
Rollini, P; Fournier, R E (2000) Differential regulation of gene activity and chromatin structure within the human serpin gene cluster at 14q32.1 in macrophage microcell hybrids. Nucleic Acids Res 28:1767-77
Rollini, P; Xu, L; Fournier, R E (1999) Partial activation of gene activity and chromatin remodeling of the human 14q32.1 serpin gene cluster by HNF-1 alpha and HNF-4 in fibroblast microcell hybrids. Somat Cell Mol Genet 25:207-21
Rollini, P; Fournier, R E (1999) The HNF-4/HNF-1alpha transactivation cascade regulates gene activity and chromatin structure of the human serine protease inhibitor gene cluster at 14q32.1. Proc Natl Acad Sci U S A 96:10308-13

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