The majority of nuclear receptors (NRs) signal as heterodimers (HDs) with the promiscuous retinoid X receptors (RXRs). Heterodimerization introduces several key regulatory features to the RXR family,as it specifies response element recognition and allows dual ligand input in a HD-specific manner. Together these features allow the large family of RXR heterodimerizing NRs to establish a plethora of cognate ligand-dependent gene networks that regulate major aspects of cell and organ function during embryoge nesis and in the adult. Importantly, NRs are drugable and play central roles in major diseases like cancer, diabetes and atherosclerosis. HD target gene regulation has only been investigated by a gene-by-gene approach. Thus, key aspects of this regulator y network, e.g. identity of primary targets and their response dynamics, sharing of targets by different HDs, NR subtype and ligand dependency, are entirely unknown. The main objective of X-TRA-NET is to develop and employ chromatin-immunoprecipitation ( ChIP) microarray technology to explore the complex transcriptional network of RXR and its partners. X-TRA-NET will use these unique microarrays to investigate the impact of position and binding site diversity on the mechanisms of RXR target gene activati on. The complex interplay between cellular context, target site diversity and receptor subtype specificity will also be addressed. The microarrays will be used to investigate how treatment of cell culture and animal models with different ligands targeti ng the heterodimerization partner, or RXR itself, differentially affects recruitment of the NRs and their associated co-factors to target sites. Thus, X-TRA-NET aims to provide the first proof of concept for the use of ChIP-chip technology in NR ligand p rofiling. This would represent a major leap forward in NR pharmacogenomics by providing the missing link between in vitro ligand binding studies and testing these putative drugs in animals.
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