Transcription factors dynamically bind to chromatin and are essential for the regulation of genes. While a large percentage of these proteins appear to self-associate to form dimers or higher-order oligomers, the stoichiometry of DNAbound transcription factors has been poorly characterized in vivo. The glucocorticoid receptor (GR) is a ligand regulated transcription factor and its oligomerization state has been implicated in clinical outcome of therapy. Although widely believed to act as a dimer, we have shown that GR is predominantly a tetramer when bound to its target DNA. Using a unique set of imaging techniques coupled with a cell line containing an array of DNA binding elements, we found that DNA binding triggers an inter-domain allosteric regulation of the GR, followed by a change in its oligomeric state. These findings demonstrate a new step in steroid receptor activation an open new doors to the rational design of novel GR ligands. We discovered that a mutation in the GR DBD causes the receptor to constitutively adopt a tetrameric form of the receptor. When expressed in GR knock out cells, all nuclear receptor is in the tetrameric state. We performed genome-wide studies using the GR knock-out cell line with reintroduced wild-type GR or reintroduced GRtetra. GRtetra acts as a super receptor by binding to response elements not accessible to wild-type receptor, and both induces and represses more genes than GRwt. These results argue that DNA binding induces a structural transition to the tetrameric state, forming a transient higher order structure that penetrates chromatin and drives both the activating and repressive actions of glucocorticoids.
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