DNA Methylation-Related Chromatin Remodeling in Activity-Dependent <i>Bdnf</i> Gene Regulation

TLDR

DNA methylation, together with histone modifications, regulates gene silencing through chromatin remodeling, and its dysregulation—such as mutations in MeCP2—impairs neuronal function and is linked to Rett syndrome. Neuronal depolarization elevates BDNF expression by reducing CpG methylation at the Bdnf promoter and releasing the MeCP2–HDAC–mSin3A repression complex, indicating that methylation‑dependent chromatin remodeling drives activity‑dependent gene regulation essential for neural plasticity.

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.