title: A role for CaV1 and calcineurin signaling in depolarization-induced changes in neuronal DNA methylation.
abstract: Direct manipulations of neuronal activity have been shown to induce changes in DNA methylation (DNAm), although little is known about the cellular signaling pathways involved. Using reduced representation bisulfite sequencing, we identify DNAm changes associated with moderate chronic depolarization in dissociated rat hippocampal cultures. Consistent with previous findings, these changes occurred primarily in the vicinity of loci implicated in neuronal function, being enriched in intergenic regions and underrepresented in CpG-rich promoter regulatory regions. We subsequently used 2 pharmacological interventions (nifedipine and FK-506) to test whether the identified changes depended on 2 interrelated signaling pathways known to mediate multiple forms of neuronal plasticity. Both pharmacological manipulations had notable effects on the extent and magnitude of depolarization-induced DNAm changes indicating that a high proportion of activity-induced changes are likely to be mediated by calcium entry through L-type CaV1 channels and/or downstream signaling via the calcium-dependent phosphatase calcineurin.
authors.affiliation: University of Exeter Medical School, University of Exeter, Exeter, UK.
authors.forename: Eilis
authors.initials: E
authors.lastname: Hannon
authors.affiliation: MRC Centre for Developmental Neurobiology, King's College London, London, UK.
authors.forename: Annisa N
authors.initials: AN
authors.lastname: Chand
authors.affiliation: MRC Centre for Developmental Neurobiology, King's College London, London, UK.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Evans
authors.affiliation: MRC Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London UK.
authors.forename: Chloe C Y
authors.initials: CC
authors.lastname: Wong
authors.affiliation: MRC Centre for Developmental Neurobiology, King's College London, London, UK.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Grubb
authors.affiliation: University of Exeter Medical School, University of Exeter, Exeter, UK ; MRC Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Mill
keywords: Calcium channels; DNA methylation; Hippocampal; Neuronal activity; Pharmacological manipulation; Reduced representation bisulfite sequencing