This is a proposal to investigate the control of cell-type-specific gene expression in mammalian cells. Using highly differentiated rat hepatoma cells growing in vitro as a model system, an integrated genetic/molecular biological approach will be applied to study the regulation of expression of liver-specific genes. Genetic analyses will be performed with the use of a novel monochromosomal hybrid panel (MHP). This panel consists of twenty nine hepatoma clones, each retaining a single, specific mouse fibroblast chromosome. Studies of the type have defined a novel class of mammalian genes, the Tissue-specific extinguisher (Tse) loci, that regulate expression of unlinked structural genes in trans. The goals of this project will be to further define the Tse loci and their phenotypic effects, to isolate a particular locus (Tse-2) by molecular cloning to study its structure and function in detail, and to define the cis sequences in tissue-specific structural genes that are required for Tse control. Ultimately, we hope to precisely determine the role of Tse regulatory loci in differentiation and development, and to understand in molecular detail the mechanisms by which they function. These studies should provide important insights into perturbations of cellular regulatory controls that underlie abnormal developmental situations and neoplasia.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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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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