Leveraging the mendelian disorders of the epigenetic machinery to systematically map functional epigenetic variation
- Johns Hopkins University, United States
- Stanford University, United States
- Bloomberg School of Public Health, United States
Abstract
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) types 1&2 and Rubinstein-Taybi (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.
Data availability
Sequencing data have been deposited in GEO under accession code GSE162181.
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ATAC-Seq dataNCBI Gene Expression Omnibus, GSE162181.
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RNA-Seq dataNCBI Gene Expression Omnibus, GSE162181.
Article and author information
Author details
Allison Kalinousky
Funding
National Institutes of Health (R01GM121459)
- Kasper Daniel Hansen
Icelandic Centre for Research (195835-051)
- Hans T Bjornsson
Icelandic Centre for Research (206806-051)
- Hans T Bjornsson
Icelandic Centre for Research (2010588-0611)
- Hans T Bjornsson
Louma G Private Foundation (KS grant)
- Teresa R Luperchio
- Hans T Bjornsson
Johns Hopkins University (Discovery grant)
- Leandros Boukas
- Kasper Daniel Hansen
- Hans T Bjornsson
Burroughs Wellcome Fund (MD-GEM grant)
- Leandros Boukas
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: We performed all mouse experiments in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and all were approved by the Animal Care and Use Committee of the Johns Hopkins University. (protocol number: MO18M112).
Copyright
© 2021, Luperchio et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Leveraging the mendelian disorders of the epigenetic machinery to systematically map functional epigenetic variation
eLife 10:e65884.
https://doi.org/10.7554/eLife.65884
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