Oral Presentation Epigenetics 2013

Global epigenomic reconfiguration during mammalian brain development (#2)

Ryan Lister 1
  1. School of Molecular Sciences, and the Harry Perkins Institute of Medical Research, University of Western Australia, Perth, WA, Australia

Several lines of evidence point to a key role for dynamic epigenetic changes during brain development, maturation and learning. DNA methylation (mC) is a stable covalent modification that persists in post-mitotic cells throughout their lifetime, defining their cellular identity. The methylation status at each of the ~1 billion cytosines in the genome is potentially an information-rich and flexible substrate for epigenetic modification that can be altered by cellular activity. Indeed, DNA methylation changes have been implicated in learning and memory, as well as in age-related cognitive decline. However, little is known about the cell type-specific patterning of DNA methylation and its dynamics during mammalian brain development. Here, we have performed genome-wide single-base resolution profiling of the composition, patterning, cell-specificity and dynamics of DNA methylation in the frontal cortex of humans and mice throughout their lifespan, revealing profound changes during frontal cortex development in both species. In this period, coincident with synaptogenesis, highly-conserved non-CG methylation (mCH) accumulates in neurons, but not glia, to become the dominant form of methylation in the human neuronal genome. We uncovered surprisingly complex features of brain cell DNA methylation at multiple scales. First, we identified intragenic methylation patterns in neurons and glia that distinguish genes with cell-type specific activity. Second, we report a novel mCH signature that identifies genes escaping X-chromosome inactivation in neurons. Third, we find >100,000 developmentally dynamic and cell-type specific differentially CG-methylated regions that are enriched at putative regulatory regions of the genome. Finally, whole-genome detection of 5-hydroxymethylcytosine (hmC) at single-base resolution revealed that this mark is present in fetal brain cells at locations that lose CG methylation and become activated during development, and CG-demethylation at these hmC-poised loci depends on Tet2 and Tet3 activity. These results extend our knowledge of the unique role of DNA methylation in brain development and function, offering a new framework for testing the role of the epigenome in healthy function and in pathological disruptions of neural circuits.