Unknown,Transcriptomics,Genomics,Proteomics

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Cell type specific expression data from Mecp2 null mice

ABSTRACT: Human methyl-CpG-binding protein 2 (MeCP2) disruption causes Rett syndrome, an autistic disease prevalent in females. Previous microarray expression profiling studies using tissue homogenate samples from mouse model of the Rett syndrome revealed only modest changes in expression caused by the loss of Mecp2, making it difficult to identify etiology of the Rett syndrome. Here, we carried out cell type specific genome wide expression profiling of Mecp2 null mice in three neuronal cell types. We found a hot spot of Mecp2 affected genes in chromosome 11B3 syntenic to human chromosome 17p13 which has known associations to mental retardation. We also found Mecp2 affected genes are almost non-overlapping between cell types. Cell-adhesion category of genes, however, are commonly overrepresented, suggesting a possible etiology of Rett syndrome Keywords: cell type comparison, disease state analysis, genetic modification Transgenic mice lines which label subpopulations of neurons (G42: fast spiking Parvarbumin positive interneurons, YFPH: layer 5 thick tufted pyramidal neurons, TH: tyrosine hydroxylase positive locus coeruleus neurons) were used to obtain cell type specific expression profiles on Affymetrix microarrays. Females which carry Mecp2 null alleles (and one of the fluorescent alleles) were crossed with males (which may or may not carry one of the fluorescent alleles depending on whether the female has one or not). Male offsprings at around age P40 which carry fluorescent allele and Mecp2 null allele were used for experiments. Littermate males which carry fluorescent allele but not Mecp2 null allele were used for controls. 3 or 4 biological replicates were done for each condition.

ORGANISM(S): Mus musculus

SUBMITTER: Ken Sugino

PROVIDER: E-GEOD-8720 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Mutations in methyl-CpG-binding protein 2 (MeCP2), a major epigenetic regulator, are the predominant cause of Rett syndrome, an X-linked neurodevelopmental disorder. We previously found that Mecp2-null microglia are functionally impaired, and that engraftment of wild-type monocytes into the brain of Mecp2-deficient mice attenuates pathology. In this study we show that Mecp2 is expressed in macrophage and monocyte populations throughout the body, and is indispensable for their transcriptional regulation in multiple contexts. We demonstrate that Mecp2-null mice progressively lose or are chronically deficient in several macrophage populations and resident monocytes. Postnatal re-expression of Mecp2 driven by a tamoxifen-inducible CX3CR1 promoter significantly increased the lifespan of otherwise Mecp2-null mice, suggesting that epigenetic regulation of macrophage function by Mecp2 significantly contributes to pathology. RNA-Seq of acutely isolated microglia and peritoneal macrophages (to our knowledge, the first cell-specific RNA-Seq analysis comparing Mecp2-null and wild type cells of any kind) revealed significantly increased transcription of glucocorticoid- and hypoxia-signaling genes in Mecp2-null cells compared to that in their wild-type counterparts, suggesting that Mecp2 functions as a repressor of these pathways. Furthermore, in-vitro and in vivo validation studies demonstrated that the absence of Mecp2 is associated with cell-intrinsic dysfunction of signaling underlying inflammatory activation, suggesting that Mecp2 is important for regulation of specific macrophage gene-expression programs in response to stimuli and stressors. Our findings demonstrate a fundamental role for Mecp2 in the regulation of macrophage functions, which may provide a link to pathologies in Rett syndrome across multiple organs. Mecp2-null microglia and resident peritoneal macrophages from 10-12 week old mice were acutely isolated via AutoMACS, total RNA collected, and analyzed via RNA-Seq to compare for transcriptional differences in microglia and macrophages in the absence of Mecp2.

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Cell type specific expression data from Mecp2 null mice

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