CpG methylation and the methyl CpG binding protein 2 (MeCP2) are required for restraining corticotropin releasing hormone (CRH) gene expression

Abstract

The hypothalamic-pituitary-adrenal (HPA) axis plays a critical role in mounting a stress response and maintaining homeostasis. A dysregulated HPA axis and elevated levels of CRH are associated with a number of disorders. Although extensive research has been devoted to understanding molecular events associated with stimulated CRH gene, less is known about the mechanisms that restrain CRH expression. Using a cell culture system, we report here two molecular aspects of CRH gene regulation that are required for maintenance of basal level of CRH gene expression. These are a specific CpG methylation at a single CpG, and adequate levels of the methyl CpG binding protein 2 (MeCP2). The single site methylation allows the recruitment of MeCP2 to the CRH gene promoter region, and MeCP2 knockdown leads to increased expression of CRH gene. Taken together, the results indicate that site-specific methylation and MeCP2 are required for maintenance of basal levels of CRH gene expression.