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Review
. 2015 Jun 2;112(22):6800-6.
doi: 10.1073/pnas.1411269112. Epub 2015 Mar 4.

Reading the unique DNA methylation landscape of the brain: Non-CpG methylation, hydroxymethylation, and MeCP2

Benyam Kinde  1 , Harrison W Gabel  2 , Caitlin S Gilbert  1 , Eric C Griffith  1 , Michael E Greenberg  2
Affiliations
Review

Reading the unique DNA methylation landscape of the brain: Non-CpG methylation, hydroxymethylation, and MeCP2

Benyam Kinde et al. Proc Natl Acad Sci U S A. .

Abstract

DNA methylation at CpG dinucleotides is an important epigenetic regulator common to virtually all mammalian cell types, but recent evidence indicates that during early postnatal development neuronal genomes also accumulate uniquely high levels of two alternative forms of methylation, non-CpG methylation and hydroxymethylation. Here we discuss the distinct landscape of DNA methylation in neurons, how it is established, and how it might affect the binding and function of protein readers of DNA methylation. We review studies of one critical reader of DNA methylation in the brain, the Rett syndrome protein methyl CpG-binding protein 2 (MeCP2), and discuss how differential binding affinity of MeCP2 for non-CpG and hydroxymethylation may affect the function of this methyl-binding protein in the nervous system.

Keywords: MeCP2; Rett syndrome; hydroxymethylation; non-CpG methylation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Cytosine methylation and hydroxymethylation. The DNA methyltransferases Dnmt1, Dnmt3a, and Dnmt3b methylate the five-position carbon on cytosine. The maintenance methyltransferase Dnmt1 predominantly methylates hemimethylated CpG dinucleotides (mCG:CG), whereas the de novo methyltransferases Dnmt3a and Dnmt3b catalyze the methylation of cytosines in CN (in which N = G, A, C, or T) dinucleotides (1, 8, 9, 22). Methylcytosine can be modified to hydroxymethylcytosine by the Tet family of dioxygenases, Tet1–3. Current evidence demonstrates that the oxidative conversion of methylcytosine to hydroxymethylcytosine by the Tet enzymes occurs at CG dinucleotides, as is consistent with the overwhelming proportion of hydroxymethylation occurring as hmCG rather than hmCH (8, 37). Additionally, Tet enzymes are capable of catalyzing further oxidation of hmC to formylcytosine and carboxylcytosine to yield substrates for Tdg, ultimately resulting in the generation of a nonmethylated cytosine (10, 11).
Fig. 2.
Fig. 2.
Summary of MeCP2 mC and hmC binding-affinity studies.
See this image and copyright information in PMC

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