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Leveraging the Mendelian Disorders of the Epigenetic Machinery to Systematically Map Functional Epigenetic Variation

ABSTRACT: Leveraging the Mendelian Disorders of the Epigenetic Machinery to Systematically Map Functional Epigenetic Variation

PROVIDER: PRJNA680795 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13143400_1.fastq.gz	Fastqsanger.gz
	SRR13143400_2.fastq.gz	Fastqsanger.gz
	SRR13143500_1.fastq.gz	Fastqsanger.gz
	SRR13143500_2.fastq.gz	Fastqsanger.gz
	SRR13144600_1.fastq.gz	Fastqsanger.gz

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Leveraging the Mendelian Disorders of the Epigenetic Machinery to Systematically Map Functional Epigenetic Variation - RNA-seq

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Leveraging the Mendelian Disorders of the Epigenetic Machinery to Systematically Map Functional Epigenetic Variation - ATAC-seq

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Leveraging the Mendelian Disorders of the Epigenetic Machinery to Systematically Map Functional Epigenetic Variation - ATAC-seq

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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Leveraging the Mendelian Disorders of the Epigenetic Machinery to Systematically Map Functional Epigenetic Variation - RNA-seq

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Leveraging the Mendelian disorders of the epigenetic machinery to systematically map functional epigenetic variation.

Project description:Although each Mendelian Disorder of the Epigenetic Machinery (MDEM) has a different causative gene, there are shared disease manifestations. We hypothesize that this phenotypic convergence is a consequence of shared epigenetic alterations. To identify such shared alterations, we interrogate chromatin (ATAC-seq) and expression (RNA-seq) states in B cells from three MDEM mouse models (Kabuki [KS] type 1 and 2 and Rubinstein-Taybi type 1 [RT1] syndromes). We develop a new approach for the overlap analysis and find extensive overlap primarily localized in gene promoters. We show that disruption of chromatin accessibility at promoters often disrupts downstream gene expression, and identify 587 loci and 264 genes with shared disruption across all three MDEMs. Subtle expression alterations of multiple, IgA-relevant genes, collectively contribute to IgA deficiency in KS1 and RT1, but not in KS2. We propose that the joint study of MDEMs offers a principled approach for systematically mapping functional epigenetic variation in mammals.

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Leveraging the Mendelian Disorders of the Epigenetic Machinery to Systematically Map Functional Epigenetic Variation

Project description:This SuperSeries is composed of the SubSeries listed below.

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Olfactory Malformations in Mendelian Disorders of the Epigenetic Machinery.

Project description:Usually overlooked by physicians, olfactory abnormalities are not uncommon. Olfactory malformations have recently been reported in an emerging group of genetic disorders called Mendelian Disorders of the Epigenetic Machinery (MDEM). This study aims to determine the prevalence of olfactory malformations in a heterogeneous group of subjects with MDEM. We reviewed the clinical data of 35 patients, 20 females and 15 males, with a mean age of 9.52 years (SD 4.99). All patients had a MDEM and an already available high-resolution brain MRI scan. Two experienced neuroradiologists reviewed the MR images, noting abnormalities and classifying olfactory malformations. Main findings included Corpus Callosum, Cerebellar vermis, and olfactory defects. The latter were found in 11/35 cases (31.4%), of which 7/11 had Rubinstein-Taybi syndrome (RSTS), 2/11 had CHARGE syndrome, 1/11 had Kleefstra syndrome (KLFS), and 1/11 had Weaver syndrome (WVS). The irregularities mainly concerned the olfactory bulbs and were bilateral in 9/11 patients. With over 30% of our sample having an olfactory malformation, this study reveals a possible new diagnostic marker for MDEM and links the epigenetic machinery to the development of the olfactory bulbs.

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