DNA Methylation-Related Chromatin Remodeling in Activity-Dependent Bdnf Gene Regulation

Abstract

In conjunction with histone modifications, DNA methylation plays critical roles in gene silencing through chromatin remodeling. Changes in DNA methylation perturb neuronal function, and mutations in a methyl-CpG-binding protein, MeCP2, are associated with Rett syndrome. We report that increased synthesis of brain-derived neurotrophic factor (BDNF) in neurons after depolarization correlates with a decrease in CpG methylation within the regulatory region of the Bdnf gene. Moreover, increased Bdnf transcription involves dissociation of the MeCP2-histone deacetylase-mSin3A repression complex from its promoter. Our findings suggest that DNA methylation-related chromatin remodeling is important for activity-dependent gene regulation that may be critical for neural plasticity.

The mood stabilizers lithium and valproate selectively activate the promoter IV of brain-derived neurotrophic factor in neurons

“…44 On the other hand, BDNF promoter IV binds the transcriptional repressor, MeCP2 (a methyl-CpG-binding domain protein), in complex with the corepressor sin3a and HDACs. [45][46][47] Inhibition of HDAC by VPA or other inhibitors could cause dissociation of the repressor-corepressor complex from the promoter, resulting in transcriptional disinhibition. It is noteworthy that the antidepressant effect of imipramine is largely reversed by HDAC5 overexpression in the hippocampus of mice subjected to chronic defeat stress, which per se induces downregulation of BDNF III and IV mRNA.…”

Regulation of myofibroblast transdifferentiation by DNA methylation and MeCP2: implications for wound healing and fibrogenesis

“…32 There is therefore an emerging concept for a more gene selective role for MeCP2 involving regulation of a smaller number of key regulatory genes such as brain-derived neurotrophic factor (BDNF), a bona fida MeCP2 target. 33,34 However, this concept does not exclude gene selective or global regulatory functions for MeCP2 in non-neuronal cell types of the fully developed adult. Absence of MeCP2 expression in normal adult human and rodent liver demonstrated in the present study helps to explain the lack of hepatic phenotype for Mecp2 À/À mice.…”

Advances in behavioral genetics: mouse models of autism

“…345 There are also reports that Mecp2 plays a role in the regulation of Bdnf levels. 134,201,202 Reduction in the levels of Bdnf exacerbates the phenotype of both the Rett syndrome-model mouse 346 and the Sert deletion line. [208][209][210] In the Rett syndrome-model mouse, Bdnf overexpression with an inducible Bdnf transgene leads to partial correction of abnormalities linked to loss of Mecp2 function.…”

“…[192][193][194] Work with mouse lines characterized by deficient Bdnf has shown that these trophic effects are important for normal serotonergic neurotransmission. [195][196][197][198][199][200] In addition, several lines of evidence have provided support for a role of Mecp2 in the regulation of activity-dependent transcription of Bdnf, 134,201,202 suggesting that alterations in 5-HT signaling could arise from deficient Mecp2 function, through dysregulation of Bdnf. Bdnf-null mice die soon after birth, but mutants have been developed with conditional disruption of Bdnf, limited to either the prenatal or postnatal period.…”