MeCP2 recognizes cytosine methylated tri-nucleotide and di-nucleotide sequences to tune transcription in the mammalian brain

Sabine Lagger, John C. Connelly, Gabriele Schweikert, Shaun Webb, Jim Selfridge, Bernard H. Ramsahoye, Miao Yu, Chuan He, Guido Sanguinetti, Lawrence C. Sowers, Malcolm D. Walkinshaw, Adrian Bird

    Research output: Contribution to journalArticle

    38 Scopus citations

    Abstract

    Mutations in the gene encoding the methyl-CG binding protein MeCP2 cause several neurological disorders including Rett syndrome. The di-nucleotide methyl-CG (mCG) is the classical MeCP2 DNA recognition sequence, but additional methylated sequence targets have been reported. Here we show by in vitro and in vivo analyses that MeCP2 binding to non-CG methylated sites in brain is largely confined to the tri-nucleotide sequence mCAC. MeCP2 binding to chromosomal DNA in mouse brain is proportional to mCAC + mCG density and unexpectedly defines large genomic domains within which transcription is sensitive to MeCP2 occupancy. Our results suggest that MeCP2 integrates patterns of mCAC and mCG in the brain to restrain transcription of genes critical for neuronal function.

    Original languageEnglish (US)
    Article numbere1006793
    JournalPLoS genetics
    Volume13
    Issue number5
    DOIs
    StatePublished - May 2017

    ASJC Scopus subject areas

    • Ecology, Evolution, Behavior and Systematics
    • Molecular Biology
    • Genetics
    • Genetics(clinical)
    • Cancer Research

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    Lagger, S., Connelly, J. C., Schweikert, G., Webb, S., Selfridge, J., Ramsahoye, B. H., Yu, M., He, C., Sanguinetti, G., Sowers, L. C., Walkinshaw, M. D., & Bird, A. (2017). MeCP2 recognizes cytosine methylated tri-nucleotide and di-nucleotide sequences to tune transcription in the mammalian brain. PLoS genetics, 13(5), [e1006793]. https://doi.org/10.1371/journal.pgen.1006793