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Sex-biased and parental allele-specific gene regulation by KDM6A [ATAC-seq]

ABSTRACT: KDM6A, which regulates gene expression by demethylation of the repressive histone mark H3K27me3, has a higher level in mammalian females than in males because the Kdm6a gene escapes X chromosome inactivation. Here, we report that maternal and paternal alleles of a number of genes throughout the genome are differentially regulated by KDM6A. Knockout of KDM6A in male and female embryonic stem cells derived from F1 hybrid mice results in downregulation of maternal alleles more frequently than paternal alleles. This parent-of-origin preference for regulation of gene expression by KDM6A was observed for subsets of maternally expressed non-imprinted and imprinted genes. By ATAC-seq downregulated genes showed a concomitant loss of chromatin accessibility on maternal but not on paternal alleles. Surprisingly, enrichment in H3K27me3 was observed on downregulated paternal but not maternal alleles. These results suggest parent-of-origin mechanisms of gene regulation by KDM6A, which may be histone demethylation-dependent and -independent.

ORGANISM(S): Mus musculus musculus x Mus musculus castaneus

PROVIDER: GSE209786 | GEO | 2022/07/26

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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Sex-biased and parental allele-specific gene regulation by KDM6A [ATAC-seq]

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