Leveraging the mendelian disorders of the epigenetic machinery to systematically map functional epigenetic variation
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.
-
ATAC-Seq dataNCBI Gene Expression Omnibus, GSE162181.
-
RNA-Seq dataNCBI Gene Expression Omnibus, GSE162181.
Article and author information
Author details
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.
Reviewing Editor
- Job Dekker, University of Massachusetts Medical School, United States
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).
Version history
- Preprint posted: November 8, 2020 (view preprint)
- Received: December 17, 2020
- Accepted: August 27, 2021
- Accepted Manuscript published: August 31, 2021 (version 1)
- 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.
Metrics
-
- 1,617
- views
-
- 232
- downloads
-
- 11
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Computational and Systems Biology
Imputing data is a critical issue for machine learning practitioners, including in the life sciences domain, where missing clinical data is a typical situation and the reliability of the imputation is of great importance. Currently, there is no canonical approach for imputation of clinical data and widely used algorithms introduce variance in the downstream classification. Here we propose novel imputation methods based on determinantal point processes (DPP) that enhance popular techniques such as the multivariate imputation by chained equations and MissForest. Their advantages are twofold: improving the quality of the imputed data demonstrated by increased accuracy of the downstream classification and providing deterministic and reliable imputations that remove the variance from the classification results. We experimentally demonstrate the advantages of our methods by performing extensive imputations on synthetic and real clinical data. We also perform quantum hardware experiments by applying the quantum circuits for DPP sampling since such quantum algorithms provide a computational advantage with respect to classical ones. We demonstrate competitive results with up to 10 qubits for small-scale imputation tasks on a state-of-the-art IBM quantum processor. Our classical and quantum methods improve the effectiveness and robustness of clinical data prediction modeling by providing better and more reliable data imputations. These improvements can add significant value in settings demanding high precision, such as in pharmaceutical drug trials where our approach can provide higher confidence in the predictions made.
-
- Computational and Systems Biology
Interacting molecules create regulatory architectures that can persist despite turnover of molecules. Although epigenetic changes occur within the context of such architectures, there is limited understanding of how they can influence the heritability of changes. Here, I develop criteria for the heritability of regulatory architectures and use quantitative simulations of interacting regulators parsed as entities, their sensors, and the sensed properties to analyze how architectures influence heritable epigenetic changes. Information contained in regulatory architectures grows rapidly with the number of interacting molecules and its transmission requires positive feedback loops. While these architectures can recover after many epigenetic perturbations, some resulting changes can become permanently heritable. Architectures that are otherwise unstable can become heritable through periodic interactions with external regulators, which suggests that mortal somatic lineages with cells that reproducibly interact with the immortal germ lineage could make a wider variety of architectures heritable. Differential inhibition of the positive feedback loops that transmit regulatory architectures across generations can explain the gene-specific differences in heritable RNA silencing observed in the nematode Caenorhabditis elegans. More broadly, these results provide a foundation for analyzing the inheritance of epigenetic changes within the context of the regulatory architectures implemented using diverse molecules in different living systems.