MOLECULAR CONTROL OF HORMONALLY RESPONSIVE GENES

我们的目标是阐明类固醇激素的分子基础 基因表达的调控。 我们正在一个模型系统中追求这一点， 显示激素、发育和组织特异性调节。 的S 鼠主要组织相容性复合体的基因座包括以下基因 C4（补体第四成分）和S1 p（限性蛋白）。 S1 P是 受雄激素调节，而其同源相邻基因C4不受雄激素调节。 荷尔蒙控制 两种基因都存在调节突变， 表达水平以及S1 p对雄激素的依赖性。 因此 这些基因的结构和表达的表征应该 使我们能够将DNA序列的差异与 调控 这项建议的具体目标是： 1)两种小鼠C4和S1 p cDNA克隆的特征 单倍型。 2)几种单倍型小鼠S位点基因的比较。 3)S1 p和组织特异性的激素调节的体内分析 C4的调节。 4)通过转染基因的表达鉴定顺式作用DNA 参与激素和组织特异性调节的序列。 5)特定染色质构型与基因模式的相关性 表达，为各种C4和S1 p等位基因。 6)可能涉及的反式作用调节因子的表征 在基因表达的承诺事件中。 7)雄激素受体蛋白-核酸相互作用的检查，以及 受体表达调控的研究。 我们的长期目标是了解基因表达的调控， 一般和类固醇激素的作用特别。 这些研究报告将 通过C4/S1 p系统的遗传学增强，其中多种等位基因 在分子水平上，调节的不同可以形成对比。

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.