Interplay between Histone and DNA Methylation Seen through Comparative Methylomes in Rare Mendelian Disorders
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PROVIDER: PRJNA703961 | ENA |
REPOSITORIES: ENA
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Project description:According to Mendel's laws, each parent makes an equal genetic contribution to an offspring in sexually reproducing organisms. The bipolar mitotic spindle controls the equal segregation of paternal and maternal chromosomes during the first cell division. By overexpression of a single protein, GPR-1, in the maternal strain we changed the structure of the mitotic spindle from bipolar to two monopolar spindles to segregate maternal and paternal chromosomes into different cell lineages, resulting in non-mendelian segregation for entire genomes. To follow maternal and paternal segregation of the chromosomes we used red and green histone markers respectively. By mating gpr-1-overexpressing hermaphrodites with wild-type males, mendelian F1 worms that express both markers simultaneously in all tissues and non-mendelian F1 worms that express red and green markers in different tissues will be produced representing embryos with bipolar and embryos with two monopolar spindles. Thus, we show that the rules of genetic inheritance can be changed, which may inspire the formation of a new field of synthetic zoology. Transcriptional profiling was done to investigate the differences in gene expression between mendelian and non-mendelian offspring.
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Project description:The Mendelian Disorders of the Epigenetic Machinery (MDEMs) have emerged as a class of Mendelian disorders caused by loss-of-function variants in epigenetic regulators. Although each MDEM has a different causative gene, they exhibit several overlapping disease manifestations. Here, we hypothesize that this phenotypic convergence is a consequence of common abnormalities at the epigenomic level, which directly or indirectly lead to downstream convergence at the transcriptomic level. This implies that identifying abnormalities shared across multiple MDEMs could pinpoint locations where epigenetic variation is causally related to disease phenotypes. To test our hypothesis, we perform a comprehensive interrogation of chromatin (ATAC-Seq) and expression (RNA-Seq) states in B cells from mouse models of three MDEMs (Kabuki types 1&2 and Rubinstein-Taybi syndromes). We build on recent work in covariate-powered multiple testing to develop a new approach for the overlap analysis, which enables us to find extensive overlap primarily localized in gene promoters. We show that disruption of chromatin accessibility at promoters often leads to disruption of downstream gene expression, and identify a total of 463 loci and 249 genes commonly disrupted across the three MDEMs. As an example of how widespread dysregulation leads to specific phenotypes, we show that subtle expression alterations of multiple, directly relevant genes, collectively contribute to IgA deficiency in KS1 and RT. In contrast, we predict that KS2 does not have IgA deficiency, and confirm this pattern in mice. We propose that the joint study of MDEMs offers a principled approach for systematically mapping functional epigenetic variation in mammals.
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Project description:The Mendelian Disorders of the Epigenetic Machinery (MDEMs) have emerged as a class of Mendelian disorders caused by loss-of-function variants in epigenetic regulators. Although each MDEM has a different causative gene, they exhibit several overlapping disease manifestations. Here, we hypothesize that this phenotypic convergence is a consequence of common abnormalities at the epigenomic level, which directly or indirectly lead to downstream convergence at the transcriptomic level. This implies that identifying abnormalities shared across multiple MDEMs could pinpoint locations where epigenetic variation is causally related to disease phenotypes. To test our hypothesis, we perform a comprehensive interrogation of chromatin (ATAC-Seq) and expression (RNA-Seq) states in B cells from mouse models of three MDEMs (Kabuki types 1&2 and Rubinstein-Taybi syndromes). We build on recent work in covariate-powered multiple testing to develop a new approach for the overlap analysis, which enables us to find extensive overlap primarily localized in gene promoters. We show that disruption of chromatin accessibility at promoters often leads to disruption of downstream gene expression, and identify a total of 463 loci and 249 genes commonly disrupted across the three MDEMs. As an example of how widespread dysregulation leads to specific phenotypes, we show that subtle expression alterations of multiple, directly relevant genes, collectively contribute to IgA deficiency in KS1 and RT. In contrast, we predict that KS2 does not have IgA deficiency, and confirm this pattern in mice. We propose that the joint study of MDEMs offers a principled approach for systematically mapping functional epigenetic variation in mammals.
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