Widespread promoter methylation of synaptic plasticity genes in long-term potentiation in the adult brain in vivo.

Abstract

Background: DNA methylation is a key modulator of gene expression in mammalian development and cellular differentiation, including neurons. To date, the role of DNA modifications in long-term potentiation (LTP) has not been explored. Results: To investigate the occurrence of DNA methylation changes in LTP, we undertook the first detailed study to describe the methylation status of all known LTP-associated genes during LTP induction in the dentate gyrus of live rats. Using a methylated DNA immunoprecipitation (MeDIP)-array, together with previously published matched RNA-seq and public histone modification data, we discover widespread changes in methylation status of LTP-genes. We further show that the expression of many LTP-genes is correlated with their methylation status. We show that these correlated genes are enriched for RNA-processing, active histone marks, and specific transcription factors. These data reveal that the synaptic activity-evoked methylation changes correlates with pre-existing activation of the chromatin landscape. Finally, we show that methylation of Brain-derived neurotrophic factor (Bdnf) CpG-islands correlates with isoform switching from transcripts containing exon IV to exon I. Conclusions: Together, these data provide the first evidence of widespread regulation of methylation status in LTP-associated genes.