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RNA-Seq of MADM induced UPDs of Chr. 7, 11, 12 (QuantSeq)

ABSTRACT: In mammalian genomes a subset of genes is regulated by genomic imprinting resulting in silencing of one parental allele. Imprinting is essential for cerebral cortex development but prevalence and functional impact in individual cells is unclear. Here we determined allelic expression in cortical cell types and established a quantitative platform to interrogate imprinting in single cells. We created cells with uniparental disomy (UPD) containing either two copies of the maternal or paternal chromosome hence imprinted genes will be twofold overexpressed or not expressed. By genetic labeling of UPD we determined cellular phenotypes and transcriptional responses to deregulated imprinted gene expression at unprecedented single cell resolution. We discovered an unexpected degree of cell type specificity and a novel function of imprinting in the regulation of cortical astrocyte survival. More generally our results suggest functional relevance of imprinted gene expression in glial astrocyte lineage and thus for generating cortical cell type diversity.

ORGANISM(S): Mus musculus

PROVIDER: GSE154468 | GEO | 2020/07/16

REPOSITORIES: GEO

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Project description:Genomic imprinting is a mechanism in which the expression of genes varies depending on their parent-of-origin. Imprinting occurs through differential DNA methylation and histone modifications on the two parental alleles, with most imprinted genes marked by CpG-rich differentially methylated regions (DMRs). DNA methylation profiling in cases of uniparental disomy (UPD) provides a unique system permitting the study of DNA derived from a single parent (PMID: 20631049). Approximately 70 human imprinted genes have been described, and imprinted loci have been associated with diseases such as diabetes and cancer. We profiled parent of origin DNA methylation marks to find novel imprinted loci. Methods: We have an unprecedented collection of whole blood DNA from XX patients with UPD covering 18 different chromosomes, allowing for the efficient detection of DMRs associated with imprinted genes for 84% of the human genome. Our study is complimented with Ovarian Teratoma DNA (maternal DNA) and Complete hydatidiform Mole (paternal DNA). DNA methylation was profiled using Illumina Infinium 450K Methylation BeadArrays. Imprinted DMRs were defined by sites at which the maternal and paternal methylation levels diverged significantly from the biparental average. We confirmed novel DMRs by bisulfite sequencing of informative trios and SequenomEpiTYPER assays. Allelic specific gene expression studies were also performed by RNA sequencing in independent biparental controls. Findings: Our results provide for the first comprehensive map of the human imprintome, doubling the number of known imprinted regions. We identified a total of 71 DMRs, 41 of which were novel. 27 novel DMRs were maternally methylated and 14 were paternally methylated. We identified DMRs on chromosomes 5, 21 and 22 previously considered devoid of imprinting, highlighting potential parent-of-origin effects in chromosomal aneuploidies such as Down syndrome. We also found DMRs in genes associated with Schizophrenia and epilepsy. Interpretation: Our data provide the first comprehensive genome-wide map of imprinted sites in the human genome, and provide novel insights into potential parent-of-origin effects in human disorders. 66 UPD samples analyzed in total, From each individual, whole bllod DNA was extracted and global DNA methylation levels were assessed using Illumina Infinium HumanMethylation450 BeadChip.

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RNA-Seq of MADM induced UPDs of Chr. 7, 11, 12 (QuantSeq)

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