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 (Lead / Corresponding author)

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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
Article numbere1006793
JournalPLoS Genetics
Volume13
Issue number5
DOIs
Publication statusPublished - 12 May 2017

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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