As major determents of homeostasis and development, the steroid receptors are particularly important targets for environmental endocrine disruptors that have many human health consequences. While these agents are extremely diverse in structure, activity and bioavailability, many if not all activities are mediated via these receptors. The chromatin and gene expression sections primary scientific focus is the mechanisms by which gene expression is initiated in response to physiological and environmental signals and how those signals are mediated by steroid receptors. Consequently a molecular description of the mechanism of action of these receptors will provide a precise underpinning to evaluate their physiological and clinical impact with a specific interest in breast cancer. ? ? To this end we have pursued two highly interactive objectives as part of two specific aims. The first is to provide a molecular definition of the relationship between nuclear receptors, chromatin remodeling machines and promoter chromatin structure in the regulation of steroid receptor activity. Within this objective we will continue to make use of the Mouse Mammary Tumor Virus (MMTV) system, see below, as the preeminent model for a steroid hormone activated promoter in the context of chromatin. The wealth of prior information, extensive reagents and resources allow us pursue a series of goals that are not possible in other systems. The second objective is the development of additional model systems to understand glucocorticoid, progesterone and estrogen receptors (GR, PR, ER). This objective has resulted in initial characterization of the human P21, PLZF and Inhibitor of Nuclear Kappa B alpha genes. More recently we have begun to develop mouse models that interrogate the specific role played by chromatin remodeling proteins focusing on a member of the human SWI/SNF complex, BRG1 associated factors.? ? Our efforts are informed by the overwhelming evidence that a full understanding of transcriptional control requires an appreciation for roles played by the chromatin structure of target genes and the molecular machines that are required to unleash the regulatory potential of steroid receptors. The approach has been bidirectional with efforts geared to understanding transacting proteins and the protein architecture of chromatin that is subject to post-translational modifications. To achieve this we have focused our attention on the mammalian BRG1 chromatin remodeling complex that is the homologue of the yeast SWI/SNF complex and its interactions and regulation by the glucocorticoid and progesterone receptors. The activity of this complex has been evaluated in the context of the chromatin within human and mouse cells. Using the MMTV promoter as our primary model system, we have paid particular attention to the phosphorylation of histone H1 and the acetylation/methylation of the core histones.? ? The nature of many of our models, human and mouse beast cancer cells, is also indicative of our active interest in women's health and breast cancer specifically. We have, via collaborations, maintained a strong interest in the epigenetic regulation of the human breast cancer susceptibility gene BRCA1 that was initially identified at the NIEHS. We continue to view the estrogen receptor regulated genes that are associated with a poor clinical outcome for patients with breast cancer as a major focus of our group. Finally, we are very excited about studies that begin to use mouse models for chromatin regulatory proteins, which directly link these research objectives. ? ? In pursuit of our second specific aim my group has recently embarked on an exciting new area of research that examines the fundamental nature of human embryonic stem cells. We have begun to characterize the chromatin remodeling and chromatin modifying complexes that are present in these cells. This is complimented by analyses of the master regulatoryproteins OCT4 and Nanog to determine the genetic and epigenetic targets that underlie the biological program for stem cells. ? ? Our research plan is to assess the contributions that chromatin remodeling proteins, receptors and promoter chromatin architecture make to regulate the transcriptional response to endogenous and environmental signals.
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