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



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.



Together, these data provide the first evidence of widespread regulation of methylation status in LTP-associated genes.
Division of Genomics and Epigenetics, Garvan Institute of Medical Research, Sydney, Australia.|St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, 370 Victoria Street, Darlinghurst, Sydney, NSW, 2010, Australia.
Jesper L V
JL
Maag
Division of Genomics and Epigenetics, Garvan Institute of Medical Research, Sydney, Australia.
Dominik C
DC
Kaczorowski
Department of Biomedicine and K.G. Jebsen Centre for Neuropsychiatric Disorders, University of Bergen, Bergen, Norway.
Debabrata
D
Panja
Division of Genomics and Epigenetics, Garvan Institute of Medical Research, Sydney, Australia.
Timothy J
TJ
Peters
Department of Biomedicine and K.G. Jebsen Centre for Neuropsychiatric Disorders, University of Bergen, Bergen, Norway.
Clive R
CR
Bramham
Department of Biomedicine and K.G. Jebsen Centre for Neuropsychiatric Disorders, University of Bergen, Bergen, Norway.
Karin
K
Wibrand
Division of Genomics and Epigenetics, Garvan Institute of Medical Research, Sydney, Australia. m.dinger@garvan.org.au.|St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, 370 Victoria Street, Darlinghurst, Sydney, NSW, 2010, Australia. m.dinger@garvan.org.au.
Marcel E
ME
Dinger
D000328:Adult; D001921:Brain / Q000378:metabolism / Q000502:physiology*; D002843:Chromatin / Q000378:metabolism; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D005786:Gene Expression Regulation; D056426:Genetic Loci / Q000235:genetics; D006657:Histones / Q000378:metabolism; D006801:Humans; D017774:Long-Term Potentiation / Q000235:genetics*; D008568:Memory / Q000502:physiology; D009473:Neuronal Plasticity / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics*
D002843:Chromatin; D006657:Histones
DNA-methylation; Epigenetics; LTP; Long-term potentiation; MeDIP; Neuroepigenetics; Synaptic plasticity