Title | Disruption of DNA-methylation-dependent long gene repression in Rett syndrome. |
Publication Type | Journal Article |
Year of Publication | 2015 |
Authors | Gabel HW, Kinde B, Stroud H, Gilbert CS, Harmin DA, Kastan NR, Hemberg M, Ebert DH, Greenberg ME |
Journal | Nature |
Volume | 522 |
Issue | 7554 |
Pagination | 89-93 |
Date Published | 2015 Jun 04 |
ISSN | 1476-4687 |
Keywords | Animals, Base Sequence, Brain, Disease Models, Animal, DNA (Cytosine-5-)-Methyltransferases, DNA Methylation, Female, Gene Expression Regulation, Humans, Male, Methyl-CpG-Binding Protein 2, Mice, Molecular Sequence Data, Mutation, Neurons, Rett Syndrome |
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. |
DOI | 10.1038/nature14319 |
Alternate Journal | Nature |
PubMed ID | 25762136 |
PubMed Central ID | PMC4480648 |
Grant List | 1R01NS048276 / NS / NINDS NIH HHS / United States T32 GM007753 / GM / NIGMS NIH HHS / United States P30 HD018655 / HD / NICHD NIH HHS / United States / / Howard Hughes Medical Institute / United States T32GM007753 / GM / NIGMS NIH HHS / United States R01 NS048276 / NS / NINDS NIH HHS / United States |
Submitted by api_import on December 20, 2019 - 1:39pm