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 Sowers, Malcolm D. Walkinshaw, Adrian Bird

Research output: Contribution to journalArticle

23 Citations (Scopus)

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 1 2017

Fingerprint

cytosine
Cytosine
brain
Nucleotides
transcription (genetics)
nucleotides
nucleotide sequences
Brain
Rett Syndrome
DNA
nervous system diseases
gene
Nervous System Diseases
Genes
binding proteins
mutation
genomics
Carrier Proteins
genes
Mutation

ASJC Scopus subject areas

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

Cite this

Lagger, S., Connelly, J. C., Schweikert, G., Webb, S., Selfridge, J., Ramsahoye, B. H., ... 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

MeCP2 recognizes cytosine methylated tri-nucleotide and di-nucleotide sequences to tune transcription in the mammalian brain. / Lagger, Sabine; Connelly, John C.; Schweikert, Gabriele; Webb, Shaun; Selfridge, Jim; Ramsahoye, Bernard H.; Yu, Miao; He, Chuan; Sanguinetti, Guido; Sowers, Lawrence; Walkinshaw, Malcolm D.; Bird, Adrian.

In: PLoS Genetics, Vol. 13, No. 5, e1006793, 01.05.2017.

Research output: Contribution to journalArticle

Lagger, S, Connelly, JC, Schweikert, G, Webb, S, Selfridge, J, Ramsahoye, BH, Yu, M, He, C, Sanguinetti, G, Sowers, L, Walkinshaw, MD & Bird, A 2017, 'MeCP2 recognizes cytosine methylated tri-nucleotide and di-nucleotide sequences to tune transcription in the mammalian brain', PLoS Genetics, vol. 13, no. 5, e1006793. https://doi.org/10.1371/journal.pgen.1006793
Lagger, Sabine ; Connelly, John C. ; Schweikert, Gabriele ; Webb, Shaun ; Selfridge, Jim ; Ramsahoye, Bernard H. ; Yu, Miao ; He, Chuan ; Sanguinetti, Guido ; Sowers, Lawrence ; Walkinshaw, Malcolm D. ; Bird, Adrian. / MeCP2 recognizes cytosine methylated tri-nucleotide and di-nucleotide sequences to tune transcription in the mammalian brain. In: PLoS Genetics. 2017 ; Vol. 13, No. 5.
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