Steroid hormone receptors (SR) are hormone-regulated transcription factors belonging to the nuclear receptor family. Upon binding hormone, SR bind to specific enhancer or silencer elements on DNA, recruit many coregulators which remodel chromatin, regulate assembly of the transcription complex, and regulate transcription of the neighboring promoters. Defining the specific molecular functions of the many coregulators and how their recruitment and actions are coordinated are key to understanding how transcription is regulated. Among the many coregulators identified, three complexes are known to have critical roles: the steroid receptor coactivators (SRC) bind directly to SRs and anchor histone modifying enzymes and other coregulators to the promoter;the SWI/SNF complex remodels chromatin in an ATP-dependent manner;and the Mediator complex recruits RNA polymerase II. We have recently discovered two SRC-associated coregulators which are required for recruitment of the SWI/SNF and Mediator complexes to steroid hormone-regulated promoters. With this knowledge we can now progress from coactivator discovery and characterization, which has occupied us and the field for the past 15 years, to the definition of what each coregulator contributes to the process of hormone- stimulated transcription activation and how the recruitment and activities of many of the coregulators are coordinated. This will be done by using RNA interference to systematically deplete the endogenous levels of selected coregulators, followed by chromatin immunoprecipitation assays to examine the effects of coregulator depletion on the stepwise modification of histones and assembly of the transcription complex, which occur on endogenous SR target genes in response to the hormone. This study will go beyond the simple cataloguing of promoter occupancy by defining the stepwise requirements for chromatin modifications and transcription factor assembly and by establishing the functional relationships among the various coregulators, histone modifications, and transcription complex components. We will also define the functions of specific coregulator domains by testing the effect of specific mutations (which disrupt coregulator interactions or functions) on the hormone-dependent regulation of endogenous target genes of SRs. To complement these mechanistic studies, we will also define the physiological gene programs controlled by individual coregulators. We and others have shown that individual coregulators are required for the hormonal regulation of some, but not all, of the target genes of a particular SR in a particular cell line. We will use microarray and bioinformatics analyses to define the subset of SR target genes that require individual coregulators. Then we will examine the specific cellular properties or programs (such as growth and migration) controlled by coregulator-specific subsets of steroid hormone regulated genes. This comprehensive analysis will provide the information necessary to assess whether coregulators are reasonable targets for intervention in breast and prostate cancer and in other steroid hormone-related diseases.
The proposed project will generate a new level of understanding for the molecular mechanism of regulation of genes and cellular activities by steroid hormones. Steroid hormones control normal development and play important roles in diseases such as cancer, diabetes, and autoimmune diseases. The new basic knowledge obtained in this project will identify new potential targets for therapeutic intervention in these diseases.
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