SciLifeLab The Svedberg seminar series 2014-05-14 EXTRA SEMINAR!
Professor of Neurology and Neuroscience, Director of Stem Cell Biology Program Johns Hopkins University School of Medicine, Baltimore, US
Activity-induced active DNA modifications of neuronal methylome
Epigenetic modifications of chromatin molecules, including the genomic DNA and histone proteins, play critical roles in orchestrating transcriptomes of all cell types and their developmental potentials. Emerging evidence suggests important roles for epigenetic regulation in activity-dependent brain functions, including synaptic plasticity, learning and memory, circadian rhythm, drug addiction, and adult neurogenesis. We have found that neuronal stimulation induces DNA demethylation at specific promoters of brain-derived neurotrophic factor and fibroblast growth factor 1 in a Gadd45b- and TET1-dependent fashion in the adult mouse dentate gyrus (Ma et al. Science 2009; Guo et al. Cell 2011). Our genome-wide analysis at a single-nucleotide resolution further showed that 1.4% of all CpGs measured exhibit rapid active demethylation or de novo methylation in adult mouse dentate granule neurons in vivo after synchronous neuronal activation (Guo et al. Nat. Neurosci. 2011). These activity-modified CpGs exhibit a broad genomic distribution with significant enrichment in low-CpG density regions, and are associated with brain-specific genes related to neuronal plasticity. More recently, our single-base methylome analysis revealed discovered significant nonCpG methylation in these neurons and further identified DNMT3A and MeCP2 as a writer and a reader for nonCpG methylation, respectively (Guo et al. Nat. Neurosci. 2013). Our study implicates novel modification of the neuronal DNA methylome as a previously under-appreciated mechanism for activity-dependent epigenetic regulation in the adult nervous system.
Host: Georgy Bakalkin