Our objective is to elucidate the molecular basis of steroid hormone regulation of gene expression. We are pursuing this in a model system that displays hormonal, developmental and tissue-specific regulation. The S locus of the murine major histocompatibility complex includes the genes for C4 (fourth component of complement) and S1p (sex-limited protein). S1p is regulated by androgens while its homologous neighbor gene, C4, is not under hormonal control. Regulatory mutations exist in both genes, affecting levels of expression as well as S1p's dependence on androgen. Thus characterization of the structure and expression of these genes should allow us to correlate differences in DNA sequence with differences in regulation.
The specific aims of this proposal are: 1) Characterization of cDNA clones for C4 and S1p from mice of two haplotypes. 2) Comparison of S locus genes from mice of several haplotypes. 3) In vivo analysis of hormonal regulation of S1p and tissue-specific regulation of C4. 4) Identification, by expression of transfected genes, of cis-acting DNA sequences involved in hormonal and tissue-specific regulation. 5) Correlation of specific chromatin configurations with patterns of gene expression, for a variety of C4 and S1p alleles. 6) Characterization of trans-acting regulatory factors that may be involved in committment events in gene expression. 7) Examination of androgen receptor protein-nucleic acid interactions, and study of regulation of expression of the receptors. Our long-term goal is to understand regulation of gene expression in general and steroid hormone action in particular. These studies will be enhanced by the genetics of the C4/S1p system in which a variety of alleles differing in regulation can be contrasted, at a molecular level.
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