Gene Expression Profiling in Postmortem Rett Syndrome Brain: Differential Gene Expression and Patient Classification

Colantuoni, Carlo; Jeon, Ok Hee; Hyder, Karim; Chenchik, Alex; Khimani, Anis H.; Narayanan, Vinodh; Hoffman, Eric P.; Kaufmann, Walter E.; Naidu, Sakku Bai; Pevsner, Jonathan

doi:10.1006/nbdi.2001.0428

Cited by 185 publications

(152 citation statements)

References 90 publications

(90 reference statements)

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“…Although traditionally viewed as a transcriptional repressor (44,45), MeCP2 has recently been shown indirectly to positively regulate the target gene Bdnf (46) and genome-wide expression profiling analyses have demonstrated many potentially down-regulated genes with MeCP2 deficiency (47)(48)(49). In our model (Figure 6), we suggest that binding of MeCP2 to brain-specific methylated CpG sites within GABRB3 positively influences expression by promoting trans interactions between homologues and by positively organizing chromatin in cis.…”

Section: Discussionmentioning

confidence: 61%

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

219

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: Discussionmentioning

confidence: 61%

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

219

173

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“…14) does not markedly affect the expression of the remainder of the transcript (not shown), we could not use differences in Mecp2 levels as a positive control for gene-expression changes in our studies. Genes that could tangentially be considered as candidates for expression changes based on published studies (31,32) were individually inspected and confirmed to be unchanged in our experiments (not shown).…”

Section: Resultsmentioning

confidence: 69%

“…Amplification primers added 10-15 nt of nonhomologous (T3 promoter sequence) to the 3Ј end of probes. T7 RNA polymerase promoters were added to the PCR products by using the Lig'n Scribe kit (Ambion; the adapter adds another 10-12 nucleotides of nonhomologous sequence to the 5Ј end of probes), and probes were transcribed by using the Maxiscript kit (Ambion) as described, except that reactions were carried out for 3 h. To equalize intensities of bands in the RNase protection assay, the probes were synthesized at different specific activities by diluting the UTP␣P 32 Probes were gel-purified, and 1,000 cpm each eluted probe was used for each assay. An amount of 10 g of total RNA was used for each assay (using the Ambion RPA III kit), the samples were precipitated with the probes, resuspended in 9 l of hybridization buffer, denatured, and hybridized overnight at 56°C.…”

Section: Methodsmentioning

confidence: 99%

Transcriptional profiling of a mouse model for Rett syndrome reveals subtle transcriptional changes in the brain

Tudor

Akbarian

Chen

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

318

214

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The Mecp2 gene has been shown to be mutated in most cases of human Rett syndrome, and mouse models deleted for the ortholog have been generated. Lineage-specific deletion of the gene indicated that the Rett-like phenotype is caused by Mecp2 deficiency in neurons. Biochemical evidence suggests that Mecp2 acts as a global transcriptional repressor, predicting that mutant mice should have genome-wide transcriptional deregulation. We tested this hypothesis by comparing global gene expression in wild-type and Mecp2 mutant mice. The results of numerous microarray analyses revealed no dramatic changes in transcription even in mice displaying overt disease symptoms, although statistical power analyses of the data indicated that even a small number of relatively subtle changes in transcription would have been detected if present. However, a classifier consisting of a combined small set of genes was able to distinguish between mutant and wild-type samples with high accuracy. This result suggests that Mecp2 deficiency leads to subtle gene expression changes in mutant brains which may be associated with the phenotypic changes observed.

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“…MeCP2 deficiency in neurons may therefore lead to expression of genes that are normally astrocytespecific. Indeed, many glial gene transcripts, including gfap, were found to be up-regulated in the brains of Rett syndrome patients with a mutation in mecp2 (29). However, no major phenotype related to cellular differentiation in MeCP2-deficient mice is known, probably due to functional redundancy and overlapping expression among MBDs (25) (Fig.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic regulation of neural cell differentiation plasticity in the adult mammalian brain

Kohyama

Kojima

Takatsuka

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Neural stem/progenitor cells (NSCs/NPCs) give rise to neurons, astrocytes, and oligodendrocytes. It has become apparent that intracellular epigenetic modification including DNA methylation, in concert with extracellular cues such as cytokine signaling, is deeply involved in fate specification of NSCs/NPCs by defining cell-type specific gene expression. However, it is still unclear how differentiated neural cells retain their specific attributes by repressing cellular properties characteristic of other lineages. In previous work we have shown that methyl-CpG binding protein transcriptional repressors (MBDs), which are expressed predominantly in neurons in the central nervous system, inhibit astrocyte-specific gene expression by binding to highly methylated regions of their target genes. Here we report that oligodendrocytes, which do not express MBDs, can transdifferentiate into astrocytes both in vitro (cytokine stimulation) and in vivo (ischemic injury) through the activation of the JAK/STAT signaling pathway. These findings suggest that differentiation plasticity in neural cells is regulated by cell-intrinsic epigenetic mechanisms in collaboration with ambient cell-extrinsic cues.glia ͉ JAK/STAT

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Gene Expression Profiling in Postmortem Rett Syndrome Brain: Differential Gene Expression and Patient Classification

Cited by 185 publications

References 90 publications

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

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

Transcriptional profiling of a mouse model for Rett syndrome reveals subtle transcriptional changes in the brain

Epigenetic regulation of neural cell differentiation plasticity in the adult mammalian brain

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