Novel parent-of-origin specific differentially methylated loci on chromosome 16
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE125589 | GEO | 2019/04/16
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.
2016-06-01 | E-GEOD-64244 | biostudies-arrayexpress
Project description:Utilizing reciprocal genome-wide uniparental disomy samples presenting with Beckwith-Wiedemann and Silver-Russell syndrome-like phenotypes, we have analyzed ~0.1% of CpG dinucleotides present in the human genome for imprinted differentially methylated regions (DMRs) using the Illumina Infinium HumanMethylation27 BeadChip microarray. This approach identified 15 imprinted DMRs associated with previously characterized imprinted domains, and confirmed the maternal methylation of the RB1 DMR. In addition, we discovered two novel DMRs: a maternally methylated region overlapping the FAM50B promoter CpG island, which results in paternal expression of this retrotransposon, and a paternally methylated region located between maternally expressed ZNF597 and NAT15 genes. We analyzed reciprocal genome-wide uniparental disomy samples (one maternal UPD and three paternal UPD samples) and six different normal somatic tissues derived from the three germinal layers (lymphocytes, buccal cells, placenta, brain, muscle, and fat) .
2011-05-26 | E-GEOD-28525 | biostudies-arrayexpress
Project description:The maternal and paternal copies of the genome are both required for mammalian development and this is primarily due to imprinted genes, those that are mono-allelically expressed based on parent-of-origin. Typically, this pattern of expression is regulated by differentially methylated regions (DMRs) that are established in the germline and maintained after fertilisation. There are a large number of germline DMRs that have not yet been associated with imprinting and their function in development is unknown. In this study, we developed a genome-wide approach to identify novel imprinted DMRs, specifically in the human placenta, and investigated the dynamics of imprinted DMRs during development in somatic and extra-embryonic tissues. DNA methylation was evaluated using the Illumina HumanMethylation450 array in 116 human tissue samples, publically available reduced representation bisulfite sequencing in the human embryo and germ cells, and targeted bisulfite sequencing in term placentas. 43 known and 101 novel imprinted DMRs were identified in the human placenta, by comparing methylation between diandric and digynic triploids and female and male gametes. 72 novel DMRs showed a pattern consistent with placental-specific imprinting and this mono-allelic methylation was entirely maternal in origin. Strikingly, these DMRs exhibited polymorphic imprinted methylation specifically in placenta. These data suggest that imprinting in human development is far more extensive and dynamic than previously reported and that the placenta preferentially maintains maternal germline-derived DNA methylation
2015-12-22 | GSE74738 | GEO
Project description:The maternal and paternal copies of the genome are both required for mammalian development and this is primarily due to imprinted genes, those that are mono-allelically expressed based on parent-of-origin. Typically, this pattern of expression is regulated by differentially methylated regions (DMRs) that are established in the germline and maintained after fertilisation. There are a large number of germline DMRs that have not yet been associated with imprinting and their function in development is unknown. In this study, we developed a genome-wide approach to identify novel imprinted DMRs, specifically in the human placenta, and investigated the dynamics of imprinted DMRs during development in somatic and extra-embryonic tissues. DNA methylation was evaluated using the Illumina HumanMethylation450 array in 116 human tissue samples, publically available reduced representation bisulfite sequencing in the human embryo and germ cells, and targeted bisulfite sequencing in term placentas. 43 known and 101 novel imprinted DMRs were identified in the human placenta, by comparing methylation between diandric and digynic triploids and female and male gametes. 72 novel DMRs showed a pattern consistent with placental-specific imprinting and this monoallelic methylation was entirely maternal in origin. Strikingly, these DMRs exhibited polymorphic imprinted methylation specifically in placenta. These data suggest that imprinting in human development is far more extensive and dynamic than previously reported and that the placenta preferentially maintains maternal germline-derived DNA methylation.
2015-12-23 | GSE76273 | GEO
Project description:Imprinted genes are critical for normal human growth and neurodevelopment. We developed a strategy to identify new DNA differentially methylated regions (DMRs), a hallmark of imprinted genes. Using genome-wide methylation profiling, candidate DMRs were selected by identifying CpGs with putative allelic differential methylation in normal biparental tissues. In parallel, we looked for parent of origin-specific DNA methylation patterns in paternally derived human androgenetic complete hydatidiform mole (AnCHM), and maternally derived mature cystic ovarian teratoma (MCT). Using this approach, we found known DMRs associated with imprinted genomic regions as well as new DMRs for known imprinted genes, NAP1L5 and ZNF597. Most importantly, novel candidate imprinted genes were identified. The paternally methylated DMR for one candidate, AXL, a receptor tyrosine kinase, was validated by methylation analyses in humans. Further validation in mouse embryos showed that Axl was expressed preferentially from the maternal allele in a DNA methylation–dependent manner. We have analyzed 3 androgenetic complete hydatidiform mole (AnCHM), 16 white blood cell (WBC), 1 mature cystic ovarian teratoma (MCT), 5 placenta, and 1 lymphoblastoid cell line paternal UPD4 sample
2011-01-26 | E-GEOD-22091 | biostudies-arrayexpress
Project description:Methylation profiles of chr12-16 were generated by meDIP and array hybridisation in 3 cases with maternal uniparental disomy of chromosome 15, and three cases of paternal uniparental disomy of chromosome 15. Comparison of these profiles reveals differentially methylated (imprinted) regions on chromosome 15.
2010-06-12 | GSE22188 | GEO
Project description:The maternal and paternal copies of the genome are both required for mammalian development and this is primarily due to imprinted genes, those that are mono-allelically expressed based on parent-of-origin. Typically, this pattern of expression is regulated by differentially methylated regions (DMRs) that are established in the germline and maintained after fertilisation. There are a large number of germline DMRs that have not yet been associated with imprinting and their function in development is unknown. In this study, we developed a genome-wide approach to identify novel imprinted DMRs, specifically in the human placenta, and investigated the dynamics of imprinted DMRs during development in somatic and extra-embryonic tissues. DNA methylation was evaluated using the Illumina HumanMethylation450 array in 116 human tissue samples, publically available reduced representation bisulfite sequencing in the human embryo and germ cells, and targeted bisulfite sequencing in term placentas. 43 known and 101 novel imprinted DMRs were identified in the human placenta, by comparing methylation between diandric and digynic triploids and female and male gametes. 72 novel DMRs showed a pattern consistent with placental-specific imprinting and this mono-allelic methylation was entirely maternal in origin. Strikingly, these DMRs exhibited polymorphic imprinted methylation specifically in placenta. These data suggest that imprinting in human development is far more extensive and dynamic than previously reported and that the placenta preferentially maintains maternal germline-derived DNA methylation For the identification of imprinted DMRs in the placenta, chorionic villous samples from 5 diandric and 5 digynic triploids pregnancies were assayed, along with a pooled sample of complete hydatiform moles (CHM). Placental chorionic villous samples (n=63) included 29 control pregnancies delivered at term, while the remaining 34 were delivered preterm or miscarried, or had abnormal MSS results, IUGR or LOPET. The preterm births were associated with one or more of: preterm labour, premature rupture of membranes (PROM), chorioamnionitis, placental abruption, and incompetent cervix. All samples were determined to be chromosomally normal using standard karyotyping or comparative genome hybridization, as previously described (Robinson et al. 2010). Two to four independent sites were taken from each placenta and after DNA extraction from chorionic villous, the DNA was pooled before being utilized in this study. Thirty-three fetal tissues, including brain (n=8), spinal cord (n=7), muscle (n=9), and kidney (n=9) were collected from second trimester foetuses, as previously described (Price et al. 2012). Adult female whole blood samples (n=10) were collected from control women. Extra-embryonic cell types (n=19), including cord blood (embryonic), cord, amniotic membrane, chorionic membrane, 1st, 2nd and 3rd trimester trophoblast and mesenchyme, and decidua (maternal), were isolated from control placental samples.
2015-12-22 | E-GEOD-74738 | biostudies-arrayexpress
Project description: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.
2020-07-16 | GSE153878 | GEO
Project description: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.
2020-07-16 | GSE153362 | GEO
Project description: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.
2020-07-16 | GSE153356 | GEO