MeCP2, a member of the MBD (methyl-CpG binding domain) protein family, silences genes when it is bound to methylated upstream CpG regions, by recruiting histone deacetylases (HDAC). Mutations in MeCP2 are associated to the Rett syndrome, and studies have shown that its expression is not homogeneous between different brain areas. To assess the spatio- temporal effects of MeCP2 regulation in nervous cells, Cassel et al. (2006) evaluated the influence of some serotonin (5-HT)- elevating agents, such as fluoxetine (an antidepressant, inhibitor of the serotonin- reuptake) and cocaine, using immuno- histochemistry and real- time PCR in normal adult rat brains. They found that after repeated doses of both drugs, there was an increase of the number of cells that immuno- reacted more for MeCP2 and another member of the methyl-CpG binding domain protein family, MBD1; but not concurrent HDAC1 or HDAC2 increase was seen, suggesting a different epigenetic regulation pathway for these cells. Quantitative analyses of the expression of both MBDs and HDACs in different serotonin- responsive brain regions, showed that the serotonergic system (particularly GABA-ergic neurons) was involved in this regulation pathway indeed because both drugs employed are 5-HT uptake and transport inhibitors, and this was later confirmed using other inhibitors of dopamine and noradrenaline transporters, obtaining the same pattern of MBD expression. In short, this research indicates that there is a relationship between epigenetic regulation (via the stimulus of MeCP2 and MBD1 expression) and the mode of action of these serotonin- elevating agents. This could be important not only for the control of depression but besides it gives more clues to understand the symptoms of the Rett syndrome.
Cassel S. et al. 2006. Mol Pharmacol 70(2):487-492
epigeneticsComment on the same issue of Molecular Pharmacology
