Leveraging the mendelian disorders of the epigenetic machinery to systematically map functional epigenetic variation

Abstract
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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.

The following data sets were generated

(2020) ATAC-Seq data
NCBI Gene Expression Omnibus, GSE162181.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE162181
(2020) RNA-Seq data
NCBI Gene Expression Omnibus, GSE162181.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE162181

Article and author information

Author details

Teresa R Luperchio

Department of Biological Chemistry, Johns Hopkins University, Baltimore, United States

Competing interests
The authors declare that no competing interests exist.
Leandros Boukas

Predoctoral Training Program in Human Genetics, McKusick-Nathans Institute of Genetic Medicine, Department of Biostatistics, Johns Hopkins University, Baltimore, United States

Competing interests
The authors declare that no competing interests exist.
Li Zhang

McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, United States

Competing interests
The authors declare that no competing interests exist.
Genay Opal Pilarowski

Pathology, Stanford University, Stanford, United States

Competing interests
The authors declare that no competing interests exist.
Jenny Jiang

Pediatrics and Genetics, Johns Hopkins University, Stafford, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-8310-298X
Allison Kalinousky

Pediatrics and Genetics, Johns Hopkins University, Baltimore, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-7292-8500
Kasper Daniel Hansen

Biostatistics, Bloomberg School of Public Health, Baltimore, United States

Competing interests
The authors declare that no competing interests exist.
Hans T Bjornsson

Pediatrics and Genetics, Johns Hopkins University, Baltimore, United States

For correspondence
hbjorns1@jhmi.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-6635-6753

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

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.