Unknown,Transcriptomics,Genomics,Proteomics

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Transcription profiling of mouse wild type vs Dnmt1 hypomethylated forebrain

ABSTRACT: DNA methylation is a major epigenetic factor regulating genome reprogramming, cell differentiation, developmental gene expression. To understand the role DNA methylation in CNS neurons, we generated conditional Dnmt1 mutant mice that possess ~90% hypomethylated cortical and hippocampal cells in the dorsal forebrain from E13.5 on. The mutant mice were viable with a normal lifespan, but displayed severe neuronal cell death between E14.5 to 3-weeks postnatally. Accompanied with the striking cortical and hippocampal degeneration, adult mutant mice exhibited neurobehavioral defects in learning and memory in adulthood. Unexpectedly, a fraction of Dnmt1-/- cortical neurons survived through postnatal development, so that the residual cortex in mutant mice contained 20-30% of hypomethylated neurons throughout the life. Hypomethylated excitatory neurons exhibited multiple defects in postnatal maturation including abnormal dendritic arborization and impaired neuronal excitability. The mutant phenotypes are coupled with deregulation of those genes involved in neuronal layer-specification, cell death, and the function of ion channels. Our results suggest that DNA methylation, through its role in modulating neuronal gene expression, plays multiple roles in regulating cell survival, neuronal migration and maturation in the CNS. Experiment Overall Design: We compared gene expression patterns in Wildtype and DNA methylation deficient (Emx1-cre; Dnmt1 mutant) mouse dorsal cortex. We performed 3 replicates using different each individual mouse strain. The Sample GSM350992 table is the average log ratio for the 3 replicatesArrays were performed in triplicate.

ORGANISM(S): Mus musculus

SUBMITTER: Masakazu Namihira

PROVIDER: E-GEOD-14216 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:X chromosome inactivation (XCI) is a dosage compensation mechanism in female cells to regulate X-linked gene expression. We report here that subcultures from established lines of female hESCs displayed variations (0-100%) in the expression of XCI markers such as XIST RNA coating and enrichment of histone H3 lysine 27 trimethylation (H3K27me3) on inactive X chromosome. Surprisingly, regardless of the presence or absence of XCI markers in different cultures, all female hESCs we examined (H7, H9, and HSF6 cells) exhibit a mono-allelic expression pattern for a majority of X-linked genes. Our results suggest that these established female hESCs have completed XCI during the process of derivation and/or propagation, and the XCI pattern of lines we investigated is already non-random. However, XIST gene expression in subsets of female hESCs is unstable and subject to epigenetic silencing through DNA methylation. Concomitant with the loss of XCI markers including XIST expression and H3K27me3, approximately 12% of X-linked CpG islands become hypomethylated and a subset of previously silenced X-linked alleles are reactivated, resulting a significant elevation of gene expression dosage. Because changes in dosage compensation of X-linked genes could impair somatic cell function, we propose that XCI status should be routinely checked in subcultures of female hESCs, with cultures displaying XCI markers better suited for use in regenerative medicine. Keywords: Genotyping, gene expression and DNA methylation We used Affymetrix Genotyping array for looking for X-linked SNPs with HSF6, H7 and H9 genomic DNA, Agilent Gene expression array for comparing gene expression patten changes between HSF6 hESCs with X-inactiation and HSF6 hESCs without X-inactivation (3 repeats). Finally, mDIP-Chip method was used to detect X-linked CpG island methylation changes differences between hESCs with X-inactivation and hESCs without X-inactivation using Agilent CpG island array (3 repeats, and one of them has dye swap)

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Transcription profiling of mouse wild type vs Dnmt1 hypomethylated forebrain

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