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 显示荷尔蒙、发育和组织特异性调节。S 小鼠主要组织相容性复合体的基因包括 C4(补体第四组分)和S1P(性限制蛋白)。S1P是 受雄激素调控，而其同源邻近基因C4不受 荷尔蒙控制。这两个基因都存在调节性突变，影响 表达水平以及S1P对雄激素的依赖性。因此， 对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 监管。这项建议的具体目标是： 1)小鼠C4和S1P基因克隆的鉴定 单倍型。 2)几种单倍型小鼠S基因座基因的比较。 3)体内分析S1P的激素调节和组织特异性 C4的调节。 4)通过转基因基因的表达鉴定顺式作用的DNA 涉及荷尔蒙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，对于各种C4和S1P等位基因。 6)可能涉及的反式作用调节因子的特征 在基因表达的承诺事件中。 7)雄激素受体蛋白质-核酸相互作用的检测，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。 一般作用，尤其是类固醇激素作用。这些研究将是 通过C4/S1P系统的遗传学增强，在该系统中，各种等位基因 不同的调控可以在分子水平上进行对比。

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.