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Steroid receptors are hormone-activated transcription factors. Sex steroids play a central role in the growth and maintenance of a number of tissues and the tumors originating from these tissues. Steroids of the glucocorticoid class control many aspects of metabolism and homeostasis. They have potent anti-inflammatory activities and are widely used in medicine. Steroid hormones achieve these wide ranging actions by regulating gene expression. The hormones bind to specific receptors, which, via a series of events, become active transcription factors. The receptors for progesterone, a sex steroid, and cortisol, a glucocorticoid, are related. Indeed, the two receptors bind to the same target sequences in DNA. Thus, a fundamental issue is how the two receptors mediate the regulation of distinct sets of genes in tissues that contain both receptors.

How do two transcription factors that recognized the same DNA site regulate different genes? One of the major areas of work in the laboratory investigates this conundrum. One set of studies has developed a novel cre-lox based enhancer trap system to identify genes differentially induced by glucocorticoids and progestins. In parallel, microarray analyses have identified a set of differentially regulated genes. Current studies are investigating the mechanisms that underlie the differential regulation by the two receptors. Other studies have shown that a steroid-regulated promoter, the mouse mammary tumor virus promoter, can be regulated very differently by glucocorticoids and progestins depending on the site of integration of the promoter in the genome. Thus, integration of the mouse mammary tumor virus promoter into one site results in a transcription unit that can be regulated by both hormone receptors. However, when integrated into another site in the same cell, the same promoter retains its glucocorticoid responsiveness while being nearly refractory to progestins. Glucocorticoids can elicit remodeling of mouse mammary tumor virus chromatin at both loci whereas progestins only promote remodeling and chromatin modification at the responsive locus. This implies that the surrounding chromatin can impose differential regulation on the transcription control elements of this promoter in such a way as to distinguish two closely related receptors.

Chromatin and gene regulation. We are currently employing a variety of methodologies to investigate the mechanisms that underlie the role of chromatin in regulating the steroid response. Current studies are analyzing transcription factor loading and histone acetylation at target genes using chromatin immunoprecipitation assays. These studies have found, contrary to prevailing assumptions, that histone acetylation is not required for hormone-receptor mediated gene induction. More recently we have begun to employ a newly developed in vitro transcription system using chromatin-assembled templates to elucidate mechanisms of regulation of gene expression by estrogen and progesterone receptors. A focus in these in vitro studies is the role of chromatin remodeling, coactivators, and histone acetylation in the activation of gene expression by steroid receptors in the reconstituted system.

Glucocorticoid-induced cell death. Additional research endeavors in the laboratory seek to identify glucocorticoid-induced genes that mediate the hormonal induction of apoptosis in T-cells. A candidate gene has been identified and a multifaceted approach is being applied to test whether the manipulation of expression of the candidate gene has the functional consequences expected of a gene that serves as a central mediator of hormone-induced cell death.​​​​​