Human Molecular Genetics Advance Access published online on March 9, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi097
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1 Department of Cellular Biochemistry and Human Genetics, The Hebrew University--Hadassah Medical School, Jerusalem, Israel 91120
* To whom correspondence should be addressed. Rett syndrome (RS) is a severe and progressive neurodevelopmental disorder, caused by heterozygous mutations in the X-linked methyl CpG binding protein 2 gene (MeCP2). MeCP2 is a nuclear protein that binds specifically to methylated DNA and functions as a general transcription repressor in the context of chromatin remodeling complexes. Rett syndrome shares clinical features with those of Angelman syndrome (AS) an imprinting neurodevelopmental disorder. In AS patients, the maternally expressed copy of UBE3A that codes for the ubiquitin protein ligase 3A (E6-AP) is repressed. The similar phenotype of these two syndromes led us to hypothesize that part of the RS phenotype is due to MeCP2 associated silencing of UBE3A. Indeed, UBE3A mRNA and protein are shown here to be significantly reduced in human and mouse MECP2 deficient brains. This reduced UBE3A level was associated with biallelic production of the UBE3A antisense RNA. In addition, MeCP2 deficiency resulted in elevated acetylation of histone H3 and H3(K4) methylation and reduced H3(K9) methylation at the PWS/AS imprinting center with no effect on DNA methylation or SNRPN expression. We conclude therefore that MeCP2 deficiency causes epigenetic aberrations at the PWS imprinting center. These changes in histone modifications result in loss of imprinting (LOI) of the UBE3A antisense gene in the brain, increase in UBE3A antisense RNA level and consequently reduction in UBE3A production.
Article
MeCP2 deficiency in Rett syndrome causes epigenetic aberrations at the PWS/AS imprinting center that affect UBE3A expression
Ruth Shemer, E-mail: shemer{at}md2.huji.ac.il
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