Back to Search
Start Over
MeCP2 recognizes cytosine methylated tri-nucleotide and di-nucleotide sequences to tune transcription in the mammalian brain
- 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.
- Subjects :
- Male
Methyl-CpG-Binding Protein 2
Oligonucleotides
Biochemistry
Epigenesis, Genetic
Database and Informatics Methods
Mice
Trinucleotide Repeats
Medicine and Health Sciences
Dinucleotide Repeats
DNA methylation
Mammalian Genomics
Nucleotides
Brain
Genomics
Chromatin
Nucleic acids
Epigenetics
Anatomy
DNA modification
Sequence Analysis
Chromatin modification
Research Article
Chromosome biology
Protein Binding
congenital, hereditary, and neonatal diseases and abnormalities
Cell biology
lcsh:QH426-470
Bioinformatics
Hypothalamus
Research and Analysis Methods
Transfection
Cytosine
Sequence Motif Analysis
mental disorders
Genetics
Rett Syndrome
Animals
Molecular Biology Techniques
Molecular Biology
DNA sequence analysis
Biology and life sciences
DNA
Settore FIS/07 - Fisica Applicata(Beni Culturali, Ambientali, Biol.e Medicin)
nervous system diseases
Mice, Inbred C57BL
lcsh:Genetics
Animal Genomics
CpG Islands
Gene expression
Subjects
Details
- Language :
- English
- ISSN :
- 15537404 and 15537390
- Volume :
- 13
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- PLoS Genetics
- Accession number :
- edsair.pmid.dedup....ac3b608b2871b7da9453a5cf60e8bc1a