Repressor Element Silencing Transcription Factor/Neuron-restrictive Silencing Factor (REST/NRSF) Can Act as an Enhancer as Well as a Repressor of Corticotropin-releasing Hormone Gene Transcription

Abstract

The repressor element-1/neuron-restrictive silencing element (RE-1/NRSE) mediates transcriptional repression by the repressor element silencing transcription factor/neuron-restrictive silencing factor (REST/NRSF) in many neuron-specific genes. REST/NRSF is expressed most highly in non-neural tissues, where it is thought to repress gene transcription, but is also found in developing neurons and at low levels in the brain. Its null mutation in vivo results in embryonic lethality in mice. While the RE-1/NRSE-mediated repressive influence of REST/NRSF is well established, results in transgenic studies have suggested that the action of the system is more complex. Here, we report that transcription of the corticotropin releasing hormone (CRH) gene is regulated by REST/NRSF, in part through the RE-1/NRSE. Expression of transfected Crh-luciferase constructs was down-regulated by REST/NRSF in a RE-1/NRSE-dependent fashion in both muscle-derived L6 and REST/NRSF co-transfected neuronal PC12 cells. Treatment of L6 cells with trichostatin A revealed that REST/NRSF repression depends, in part, on histone deacetylase activity in these cells. In another neuronal cell line, NG108, REST/NRSF also repressed expression from constructs containing an intact RE-1/NRSE. However, unexpectedly, REST/NRSF up-regulated expression levels of constructs lacking an intact RE-1/NRSE. These results suggest that REST/NRSF can act as both a repressor of Crh transcription, via the Crh RE-1/NRSE, and an enhancer of Crh transcription, via a mechanism independent of the Crh RE-1/NRSE.