MeCP2 deficiency in Rett syndrome causes epigenetic aberrations at the PWS/AS imprinting center that affects UBE3A expression

Makedonski, Kirill; Abuhatzira, Liron; Kaufman, Yotam; Razin, Aharon; Shemer, Ruth

doi:10.1093/hmg/ddi097

Cited by 115 publications

(97 citation statements)

References 37 publications

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“…As expected from the mouse studies, a significant defect in GABRB3 transcript was observed in RTT brain compared to control ( Figure 3A). Although conflicting data have been reported on the dysregulation of Ube3a in Mecp2-deficient mouse (13,31,32), a significant decrease in UBE3A expression was found in RTT brain ( Figure 3B), consistent with the decreased protein observed previously (13). Even though MeCP2 binds to the promoter of SNRPN (13,26), no difference in SNRPN transcript was observed ( Figure 3C), consistent with maintenance of normal imprinting of SNRPN in RTT (33), and normal expression in Mecp2-deficient mouse brain (13,34).…”

Section: Resultsmentioning

confidence: 99%

15q11-13 GABAA receptor genes are normally biallelically expressed in brain yet are subject to epigenetic dysregulation in autism-spectrum disorders

Hogart

Nagarajan

Patzel

et al. 2007

Human Molecular Genetics

218

173

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Human chromosome 15q11-13 is a complex locus containing imprinted genes as well as a cluster of three GABA A receptor subunit (GABR) genes, GABRB3, GABRA5, and GABRG3. Deletion or duplication of 15q11-13 GABR genes occurs in multiple human neurodevelopmental disorders including Prader-Willi syndrome (PWS), Angelman syndrome (AS), and autism. GABRB3 protein expression is also reduced in Rett syndrome (RTT), caused by mutations in MECP2 on Xq28. Although Gabrb3 is biallelically expressed in mouse brain, conflicting data exist regarding the imprinting status of the 15q11-13 GABR genes in humans. Using coding single nucleotide polymorphisms we show that all three GABR genes are biallelically expressed in 21 control brain samples, demonstrating that these genes are not imprinted in normal human cortex. Interestingly, four of eight autism and one of five RTT brain samples showed monoallelic or highly skewed allelic expression of one or more GABR gene, suggesting that epigenetic dysregulation of these genes is common to both disorders. Quantitative real-time RT-PCR analysis of PWS and AS samples with paternal and maternal 15q11-13 deletions revealed a paternal expression bias of GABRB3, while RTT brain samples showed a significant reduction in GABRB3 and UBE3A. Chromatin immunoprecipitation and bisulfite sequencing in SH-SY5Y neuroblastoma cells demonstrated that MeCP2 binds to methylated CpG sites within GABRB3. Our previous studies demonstrated that homologous 15q11-13 pairing in neurons was dependent on MeCP2 and was disrupted in RTT and autism cortex. Combined these results suggest that MeCP2 acts as a chromatin organizer for optimal expression of both alleles of GABRB3 in neurons.

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Section: Resultsmentioning

confidence: 99%

15q11-13 GABAA receptor genes are normally biallelically expressed in brain yet are subject to epigenetic dysregulation in autism-spectrum disorders

Hogart

Nagarajan

Patzel

et al. 2007

Human Molecular Genetics

218

173

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“…64 Given the possible contribution of epigenetic factors to autism, researchers have examined interactions involving genes from imprinted regions of chromosome 15q. There has been some evidence that Mecp2 regulates Ube3A and Gabrb3 expression in the mouse model for Rett syndrome, 87,344 but this finding has been inconsistent. 345 There are also reports that Mecp2 plays a role in the regulation of Bdnf levels.…”

Section: Discussionmentioning

confidence: 99%

Advances in behavioral genetics: mouse models of autism

2007

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Autism is a neurodevelopmental syndrome with markedly high heritability. The diagnostic indicators of autism are core behavioral symptoms, rather than definitive neuropathological markers. Etiology is thought to involve complex, multigenic interactions and possible environmental contributions. In this review, we focus on genetic pathways with multiple members represented in autism candidate gene lists. Many of these pathways can also be impinged upon by environmental risk factors associated with the disorder. The mouse model system provides a method to experimentally manipulate candidate genes for autism susceptibility, and to use environmental challenges to drive aberrant gene expression and cell pathology early in development. Mouse models for fragile X syndrome, Rett syndrome and other disorders associated with autistic-like behavior have elucidated neuropathology that might underlie the autism phenotype, including abnormalities in synaptic plasticity. Mouse models have also been used to investigate the effects of alterations in signaling pathways on neuronal migration, neurotransmission and brain anatomy, relevant to findings in autistic populations. Advances have included the evaluation of mouse models with behavioral assays designed to reflect disease symptoms, including impaired social interaction, communication deficits and repetitive behaviors, and the symptom onset during the neonatal period. Research focusing on the effect of gene-by-gene interactions or genetic susceptibility to detrimental environmental challenges may further understanding of the complex etiology for autism.

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“…In addition, association of methyl-CpG-binding domain (MBD) proteins to the methylated allele could be involved in somatic maintenance, as well as the recruitment of enzymatic complexes that regulate histone modifications linked to the differential DNA methylation. (9,39,40) When do the aberrant epigenetic alterations occur in SRS and BWS? Several observations suggest that these arise after fertilisation, at some point early in development.…”

Section: Introductionmentioning

confidence: 99%