Répression transcriptionnelle : glucocorticoïdes et proopiomélanocortine

Abstract

In contrast to the wealth of information on the mechanisms responsible for activation of transcription by nuclear receptors, little is known about molecular mechanisms involved in repression of gene expression by the same nuclear receptors. Various mechanisms have been proposed and they are reviewed here, including those which require direct interaction between nuclear receptor and DNA and those which do not require such interaction but rather result from protein/protein interactions. The gene encoding pro-opiomelanocortin (POMC) provides an interesting model to study repression of transcription by the glucocorticoid receptor (GR), as POMC transcription is specifically repressed by glucocorticoids in anterior pituitary corticotroph cells. We have identified an in vitro binding site for the GR within the POMC promoter and it appears to be required for glucocorticoid repression. This receptor binding site has only limited homology with positive glucocorticoid response elements (GRE). Detailed in vitro analysis of receptor-DNA interactions revealed that three molecules of GR bind this site whereas receptor homodimers were previously shown to interact with positive GREs. Mutagenesis experiments have correlated formation of these complexes with glucocorticoid repression. Current data are consistent with a model of repression by interference in which receptor binding in the proximal region of the POMC promoter interferes with the action of other transcription factors binding upstream and/or downstream of GR. This interference could be due to steric hindrance or to an effect on the local conformation of DNA. The demonstration of novel receptor-DNA complexes associated with glucocorticoid regulation of POMC suggests new mechanisms through which nuclear receptors might act to modulate gene transcription.