5-hmC–mediated epigenetic dynamics during postnatal neurodevelopment and aging

Abstract

DNA methylation in the context of epigenetics occurs on the 5' position of cytosine, which can be further oxidized by enzymes from the Ten-eleven translocation (Tet) family, resulting in 5-hydroxymethylcytosine (5-hmC). In the context of embryonic stem cells, Tet and 5-hmC DNA act in an alternate epigenetic state that regulates epigenetic programming and stem cell differentiation. Here, the authors describe the epigenomic profiling of 5-hmC in mouse and human brain across different time periods during development and aging. DNA methylation dynamics influence brain function and are altered in neurological disorders. 5-hydroxymethylcytosine (5-hmC), a DNA base that is derived from 5-methylcytosine, accounts for ∼40% of modified cytosine in the brain and has been implicated in DNA methylation–related plasticity. We mapped 5-hmC genome-wide in mouse hippocampus and cerebellum at three different ages, which allowed us to assess its stability and dynamic regulation during postnatal neurodevelopment through adulthood. We found developmentally programmed acquisition of 5-hmC in neuronal cells. Epigenomic localization of 5-hmC–regulated regions revealed stable and dynamically modified loci during neurodevelopment and aging. By profiling 5-hmC in human cerebellum, we found conserved genomic features of 5-hmC. Finally, we found that 5-hmC levels were inversely correlated with methyl-CpG–binding protein 2 dosage, a protein encoded by a gene in which mutations cause Rett syndrome. These data suggest that 5-hmC–mediated epigenetic modification is critical in neurodevelopment and diseases.