Genome-wide antagonism between 5-hydroxymethylcytosine and DNA methylation in the adult mouse brain

Abstract

Mounting evidence points to critical roles for DNA modifications, including 5-methylcytosine (5mC) and its oxidized forms, in the development, plasticity and disorders of the mammalian nervous system. The novel DNA base 5-hydroxymethylcytosine (5hmC) is known to be capable of initiating passive or active DNA demethylation, but whether and how extensively 5hmC functions in shaping the post-mitotic neuronal DNA methylome is unclear. Here we report the genome-wide distribution of 5hmC in dentate granule neurons from adult mouse hippocampus in vivo. 5hmC in the neuronal genome is highly enriched in gene bodies, especially in exons, and correlates with gene expression. Direct genome-wide comparison of 5hmC distribution between embryonic stem cells and neurons reveals extensive differences, reflecting the functional disparity between these two cell types. Importantly, integrative analysis of 5hmC, overall DNA methylation and gene expression profiles of dentate granule neurons in vivo reveals the genome-wide antagonism between these two states of cytosine modifications, supporting a role for 5hmC in shaping the neuronal DNA methylome by promoting active DNA demethylation.

Keywords

dentate granule neuron / active DNA demethylation / TET / methylome

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Acknowledgments

We thank Cheryl Strauss and Kimberley Christian for critical reading of the manuscript. This study was supported in part by the National Institutes of Health (NS051630 and MH076090 to P.J.; NS047344, MH087874, ES021957 to H.S., HD0679184 and NS048271 to G.L.M.), the Emory Genetics Discovery Fund (P.J.), the Simons Foundation Autism Research Initiative (P.J. and H.S.), Dr. Miriam & Sheldon G. Adelson Medical Research Foundation (G.L.M.), Maryland Stem Cell Research Foundation (G.L.M.), and John Hopkins Brain Science Institute (G.L.M.). J.U.G. is a Damon Runyon fellow supported by the Damon Runyon Cancer Research Foundation. Y.S. was supported by a postdoctoral fellowship from Maryland Stem Cell Research Foundation.

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