1. Computational and Systems Biology
  2. Genetics and Genomics

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

  1. Teresa R Luperchio
  2. Leandros Boukas
  3. Li Zhang
  4. Genay Opal Pilarowski
  5. Jenny Jiang
  6. Allison Kalinousky
  7. Kasper Daniel Hansen
  8. Hans T Bjornsson  Is a corresponding author
  1. Johns Hopkins University, United States
  2. Stanford University, United States
  3. Bloomberg School of Public Health, United States
https://doi.org/10.7554/eLife.65884
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Cite this article
  1. Teresa R Luperchio
  2. Leandros Boukas
  3. Li Zhang
  4. Genay Opal Pilarowski
  5. Jenny Jiang
  6. Allison Kalinousky
  7. Kasper Daniel Hansen
  8. Hans T Bjornsson
(2021)
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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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

Article and author information

Author details

  1. Teresa R Luperchio

    Department of Biological Chemistry, Johns Hopkins University, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. 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.

  3. Li Zhang

    McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Genay Opal Pilarowski

    Pathology, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Jenny Jiang

    Pediatrics and Genetics, Johns Hopkins University, Stafford, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8310-298X

  6. Allison Kalinousky

    Pediatrics and Genetics, Johns Hopkins University, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7292-8500

  7. Kasper Daniel Hansen

    Biostatistics, Bloomberg School of Public Health, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.

  8. 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.
    ORCID icon "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).

Reviewing Editor

  1. Job Dekker, University of Massachusetts Medical School, United States

Version history

  1. Preprint posted: November 8, 2020 (view preprint)
  2. Received: December 17, 2020
  3. Accepted: August 27, 2021
  4. Accepted Manuscript published: August 31, 2021 (version 1)
  5. Version of Record published: September 15, 2021 (version 2)

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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  1. Teresa R Luperchio
  2. Leandros Boukas
  3. Li Zhang
  4. Genay Opal Pilarowski
  5. Jenny Jiang
  6. Allison Kalinousky
  7. Kasper Daniel Hansen
  8. Hans T Bjornsson
(2021)
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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