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The estrogen-related receptors: orphans orchestrating myriad functions

Coordinated and tight regulation of gene expression in metazoans is essential for cellular homeostasis and functions. Tissue- and cell-specific regulatory factors are indispensable and a wide variety of them exist to regulate genes. A family of transcriptional factors was identified in the past two decades through gene cloning studies and was informally referred as “orphan receptors”, as appropriate endogenous ligands for such receptors were unknown. One of the subclasses of such receptors is known as the estrogen-related receptors (ERRs), which include three isoforms, namely ERRα, ERRβ and ERRγ. Over the past one decade, unprecedented knowledge about the ERRs biology has been generated, indicating their vital roles in various metabolic and physiological activities in animals. The ERRs cellular action is largely attributed to its interaction with a wide variety of other nuclear receptors, including some orphan nuclear receptors, and thereby can modulate diverse array of genes involved in metabolism and animal physiology. Studies using genome-wide location analyses, microarray and functional genomics, including ERR-specific null mice have revealed a number of pathways controlled by the ERRs. In this context, new and recent information on the biological functions of ERRs are being reviewed.