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Astrocyte transcriptome from Mecp2-deficient mice

ABSTRACT: Mutations in the gene encoding the transcriptional modulator methyl-CpG binding protein 2 (MeCP2) are responsible for the neurodevelopmental disorder Rett syndrome that is one of the most frequent sources of intellectual disability in women. It has been shown that mutant astrocytes contribute to neuronal defects, probably as a result of aberrant secretion of soluble factor(s). Based on the hypothesis that this irregular secretion of soluble factor is the result of abnormal transcription of those factors, we have compared the gene expression profiles of wild type and mutant astrocytes from Mecp2 308/y mice by using Affymetrix mouse 2.0 microarrays. P0 newborns from pregnant Mecp2 308/+ heterozygous mice were used for the preparation of dissociated cortical astrocyte cultures. Four wild-type and four mutant confluent astrocytes cultures were used for total RNA extraction with the Qiagen RNeasy kit (Qiagen, Courtaboeuf, France) as described by the manufacturer. The gene expression profiles of wild type and mutant astrocytes from Mecp2 308/y mice have been assayed by using Affymetrix mouse 2.0 microarrays.

ORGANISM(S): Mus musculus

SUBMITTER: Florent Dumont

PROVIDER: E-GEOD-56709 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Astrocyte transcriptome from Mecp2-deficient mice

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Project description:Rett syndrome (RTT) is one of the most prevalent female mental disorders. De novo mutations in methyl CpG binding protein 2 (MeCP2) are a major cause of RTT. MeCP2 regulates gene expression as a transcription regulator as well as through long-range chromatin interaction. Because MeCP2 is present on the X chromosome, RTT is manifested in a X-linked dominant manner. Investigation using murine MeCP2 null models and post-mortem human brain tissues has contributed to understanding the molecular and physiological function of MeCP2. In addition, RTT models using human induced pluripotent stem cells derived from RTT patients (RTT-iPSCs) provide novel resources to elucidate the regulatory mechanism of MeCP2. Previously, we obtained clones of female RTT-iPSCs that express either wild type or mutant MECP2 due to the inactivation of one X chromosome. Reactivation of the X chromosome also allowed us to have RTT-iPSCs that express both wild type and mutant MECP2. Using these unique pluripotent stem cells, we investigated the regulation of gene expression by MeCP2 in pluripotent stem cells by transcriptome analysis. We found that MeCP2 regulates genes encoding mitochondrial membrane proteins. In addition, loss of function in MeCP2 results in de-repression of genes on the inactive X chromosome. Furthermore, we showed that each mutation in MECP2 affects a partly different set of genes. These studies suggest that fundamental cellular physiology is affected by mutations in MECP2 from very early fetal development and that a therapeutic approach targeting to unique forms of mutant MeCP2 is needed.

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