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

View ORCID ProfileTeresa R. Luperchio, View ORCID ProfileLeandros Boukas, Li Zhang, View ORCID ProfileGenay O. Pilarowski, Jenny Jiang, Allison Kalinousky, View ORCID ProfileKasper D. Hansen, View ORCID ProfileHans T. Bjornsson
doi: https://doi.org/10.1101/2020.11.08.373456
Teresa R. Luperchio
1Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Leandros Boukas
1Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
2Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
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Li Zhang
1Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Genay O. Pilarowski
1Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Jenny Jiang
1Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Allison Kalinousky
1Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Kasper D. Hansen
1Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
2Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
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  • For correspondence: hbjorns1@jhmi.edu khanse10@jhu.edu
Hans T. Bjornsson
1Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
3Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland
4Landspitali University Hospital, Reykjavik, Iceland
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  • For correspondence: hbjorns1@jhmi.edu khanse10@jhu.edu
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Abstract

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. Therefore, we seek to identify abnormalities shared across multiple MDEMs, in order to pinpoint locations where epigenetic variation is causally related to disease phenotypes. To this end, 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 463 loci and 249 genes with shared disruption across all three MDEMs. As an example of how widespread dysregulation leads to specific phenotypes, we show that subtle expression alterations of multiple, IgA-relevant genes, collectively contribute to IgA deficiency in KS1 and RT1. In contrast, we predict that KS2 does not have IgA deficiency, and confirm this observation in vivo. We propose that the joint study of MDEMs offers a principled approach for systematically mapping functional epigenetic variation in mammals.

Competing Interest Statement

The authors have declared no competing interest.

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  • Minor changes and writing clarification.

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Posted January 01, 2021.
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Leveraging the Mendelian Disorders of the Epigenetic Machinery to Systematically Map Functional Epigenetic Variation
Teresa R. Luperchio, Leandros Boukas, Li Zhang, Genay O. Pilarowski, Jenny Jiang, Allison Kalinousky, Kasper D. Hansen, Hans T. Bjornsson
bioRxiv 2020.11.08.373456; doi: https://doi.org/10.1101/2020.11.08.373456
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Leveraging the Mendelian Disorders of the Epigenetic Machinery to Systematically Map Functional Epigenetic Variation
Teresa R. Luperchio, Leandros Boukas, Li Zhang, Genay O. Pilarowski, Jenny Jiang, Allison Kalinousky, Kasper D. Hansen, Hans T. Bjornsson
bioRxiv 2020.11.08.373456; doi: https://doi.org/10.1101/2020.11.08.373456

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