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E-GEOD-60062 - Length-dependent gene misregulation in Rett syndrome (Bisulfite-seq)

Status
Released on 12 March 2015, last updated on 21 March 2015
Organism
Mus musculus
Samples (2)
Protocols (3)
Description
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 is proposed to function as a transcriptional repressor, but, despite numerous studies examining neuronal gene expression in MeCP2 mutants, no coherent model has emerged for how MeCP2 regulates transcription. Here we identify a genome-wide length-dependent increase in the expression of long genes in neurons lacking MeCP2. This gene misregulation occurs in human RTT brains and correlates with onset and severity of phenotypes in Mecp2 mutant mice, suggesting that the disruption of long gene expression contributes to RTT pathology. We present evidence that MeCP2 represses long genes by binding to brain-enriched, methylated CA dinucleotides within genes and show that loss of methylated CA in the brain recapitulates gene expression defects observed in MeCP2 mutants. We find that long genes encode proteins with neuronal functions, and overlap substantially with genes that have been implicated in autism and Fragile X syndrome. Reversing the overexpression of long genes in neurons lacking MeCP2 can improve some RTT-associated cellular deficits. These findings suggest that a function of MeCP2 in the mammalian brain is to temper the expression of genes in a length-dependent manner, and that mutations in MeCP2 and possibly other autism genes may cause neurological dysfunction by disrupting the expression of long genes in the brain. Bisulfite-seq from mouse cortex and cerebellum
Experiment type
methylation profiling by high throughput sequencing 
Contacts
Harrison Wren Gabel <harrison_gabel@hms.harvard.edu>, Benyam Z Kinde, Harrison W Gabel, Hume Stroud, Michael E Greenberg
MINSEQE
Exp. designProtocolsVariablesProcessedSeq. reads
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