Journal
NATURE
Volume 522, Issue 7554, Pages 89-U221Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature14319
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Funding
- Rett Syndrome Research Trust
- National Institutes of Health (NIH) [1RO1NS048276]
- Damon Runyon Cancer Research Foundation [DRG-2048-10]
- William Randolf Hearst fund
- NIH [T32GM007753]
- HHMI
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Disruption of the MECP2 gene leads to Rett syndrome (RTT), a severe neurological disorder with features of autism(1). MECP2 encodes a methyl-DNA-binding protein(2) 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(3-9). 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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