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DNA methylation is implicated in neuronal biology via the protein MeCP2, the mutation of which causes Rett syndrome. MeCP2 recruits the NCOR1/2 co-repressor complexes to methylated cytosine in the CG dinucleotide, but also to sites of non-CG methylation, which are abundant in neurons. To test the biological significance of the dual-binding specificity of MeCP2, we replaced its DNA binding domain with an orthologous domain from MBD2, which can only bind mCG motifs. Knockin mice expressing the domain-swap protein displayed severe Rett-syndrome-like phenotypes, indicating that normal brain function requires the interaction of MeCP2 with sites of non-CG methylation, specifically mCAC. The results support the notion that the delayed onset of Rett syndrome is due to the simultaneous post-natal accumulation of mCAC and its reader MeCP2. Intriguingly, genes dysregulated in both Mecp2 null and domain-swap mice are implicated in other neurological disorders, potentially highlighting targets of relevance to the Rett syndrome phenotype.

Original publication

DOI

10.1016/j.molcel.2021.01.011

Type

Journal article

Journal

Molecular cell

Publication Date

03/2021

Volume

81

Pages

1260 - 1275.e12

Addresses

Wellcome Centre for Cell Biology, University of Edinburgh, The Michael Swann Building, King's Buildings, Max Born Crescent, Edinburgh EH9 3BF, UK.

Keywords

Neurons, Hela Cells, NIH 3T3 Cells, Animals, Mice, Transgenic, Humans, Mice, Rett Syndrome, DNA Methylation, CpG Islands, Mutation, Male, Methyl-CpG-Binding Protein 2, Gene Knock-In Techniques, Protein Domains