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

Authors :
Lagger, Sabine
Connelly, John C.
Schweikert, Gabriele
Webb, Shaun
Selfridge, Jim
Ramsahoye, Bernard H.
Yu, Miao
He, Chuan
Sanguinetti, Guido
Sowers, Lawrence C.
Walkinshaw, Malcolm D.
Bird, Adrian
Source :
PLoS Genetics, 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, vol. 13, no. 5, e1006793 . https://doi.org/10.1371/journal.pgen.1006793, PLoS Genetics, Vol 13, Iss 5, p e1006793 (2017)
Publication Year :
2017
Publisher :
Public Library of Science, 2017.

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.<br />Author summary Rett Syndrome is a severe neurological disorder found in approximately 1:10.000 female births. The gene causing most cases of Rett Syndrome has been identified as methyl-CG binding protein 2 (MeCP2) which is an epigenetic reader protein, classically characterized as binding to CpG methylated (mCG) di-nucleotides. Although much research has focused on the binding capacities of MeCP2, its exact mode of action is still controversial. Here we show, that in addition to the classical mCG motif, frequently occurring mCAC tri-nucleotides are also bound by MeCP2. We additionally discover large genomic regions of high mCG + mCAC density that contain neuro-disease relevant genes sensitive to MeCP2 loss or overexpression. Our results re-emphasize MeCP2’s original proposed function as a transcriptional repressor whose purpose is to maintain the delicate balance of neuronal gene expression.

Details

Language :
English
ISSN :
15537404 and 15537390
Volume :
13
Issue :
5
Database :
OpenAIRE
Journal :
PLoS Genetics
Accession number :
edsair.pmid.dedup....ac3b608b2871b7da9453a5cf60e8bc1a