Disruption of DNA-methylation-dependent long gene repression in Rett syndrome

Nature
Harrison W GabelMichael E Greenberg

Abstract

Disruption of the MECP2 gene leads to Rett syndrome (RTT), a severe neurological disorder with features of autism. MECP2 encodes a methyl-DNA-binding protein that has been proposed to function as a transcriptional repressor, but despite numerous mouse studies examining neuronal gene expression in Mecp2 mutants, no clear model has emerged for how MeCP2 protein regulates transcription. Here we identify a genome-wide length-dependent increase in gene expression in MeCP2 mutant mouse models and human RTT brains. We present evidence that MeCP2 represses gene expression by binding to methylated CA sites within long genes, and that in neurons lacking MeCP2, decreasing the expression of long genes attenuates RTT-associated cellular deficits. In addition, we find that long genes as a population are enriched for neuronal functions and selectively expressed in the brain. These findings suggest that mutations in MeCP2 may cause neurological dysfunction by specifically disrupting long gene expression in the brain.

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Datasets Mentioned

BETA
GSE52584

Methods Mentioned

BETA
electrophoretic mobility shift assay
immunoprecipitation
ChIP-seq
ChIP
histone
RNA-seq
PCR
electrophoresis
Methyl-Seq
genotyping

Software Mentioned

Genespring
BWA
annotatePeaks
Geo2R
Nanostring nCounter
Affymetrix Power Tools
Bowtie
Cufflinks
Hypergeometric Optimization of Motif EnRichment ( HOMER )
Spliced Transcripts Alignment to a Reference ( STAR )

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