Unmasking Silenced DNA in Neurons

Abstract

Methylation of DNA is thought to be important for long-term silencing of gene expression. Chen et al. and Martinowich et al. now show that DNA methylation is a critical regulator of acute neuronal gene expression in response to depolarization (see the Perspective by Klose and Bird). In both studies, MeCP2, a protein that specifically binds methylated DNA, associated with the promotor of the gene encoding brain-derived neurotrophic factor (BDNF) in unstimulated neurons, but was released once depolarization-induced signaling occurred. Chen et al. show that such release correlates with increased expression of the BDNF gene and appears to be associated with regulated phosphorylation of MeCP2. Martinowich et al. suggest that activity-dependent expression of the BDNF gene may result from release of a repression complex that contains MeCP2, histone deacetylase 1, and the corepressor mSin3A. The proposed role of MeCP2 in learning and memory may help to explain why mutations in MeCP2 lead to Rett syndrome, a human disease that causes abnormal brain development and progressive neurological decline. W. G. Chen, Q. Chang, Y. Lin, A. Meissner, A. E. West, E. C. Griffith, R. Jaenisch, M. E. Greenberg, Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2. Science 302 , 885-889 (2003). [Abstract] [Full Text] K. Martinowich, D. Hattori, H. Wu, S. Fouse, F. He, Y. Hu, G. Fan, Y. E. Sun, DNA methylation-related chromatin remodeling in activity-dependent Bdnf gene regulation. Science 302 , 890-893 (2003). [Abstract] [Full Text] R. Klose, A. Bird, MeCP2 repression goes nonglobal. Science 302 , 793-795 (2003). [Summary] [Abstract]