Publication Date:
2015-03-13
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 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4480648/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4480648/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gabel, Harrison W -- Kinde, Benyam -- Stroud, Hume -- Gilbert, Caitlin S -- Harmin, David A -- Kastan, Nathaniel R -- Hemberg, Martin -- Ebert, Daniel H -- Greenberg, Michael E -- 1R01NS048276/NS/NINDS NIH HHS/ -- P30 HD018655/HD/NICHD NIH HHS/ -- R01 NS048276/NS/NINDS NIH HHS/ -- T32 GM007753/GM/NIGMS NIH HHS/ -- T32GM007753/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Jun 4;522(7554):89-93. doi: 10.1038/nature14319. Epub 2015 Mar 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Department of Ophthalmology, Children's Hospital Boston, Center for Brain Science and Swartz Center for Theoretical Neuroscience, Harvard University, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25762136" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Base Sequence
;
Brain/metabolism
;
DNA (Cytosine-5-)-Methyltransferase/metabolism
;
DNA Methylation/*genetics
;
Disease Models, Animal
;
Female
;
Gene Expression Regulation
;
Humans
;
Male
;
Methyl-CpG-Binding Protein 2/deficiency/*genetics/*metabolism
;
Mice
;
Molecular Sequence Data
;
Mutation/*genetics
;
Neurons/metabolism
;
Rett Syndrome/*genetics
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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