Epstein–Barr virus nuclear antigen 2 extensively rewires the human chromatin landscape at autoimmune risk loci
- Ted Hong1,2,11,12,
- Sreeja Parameswaran1,11,
- Omer A. Donmez1,
- Daniel Miller1,
- Carmy Forney1,
- Michael Lape1,3,
- Mariana Saint Just Ribeiro1,
- Jun Liang4,
- Lee E. Edsall1,
- Albert F. Magnusen5,
- William Miller6,
- Iouri Chepelev1,7,
- John B. Harley1,7,8,
- Bo Zhao4,
- Leah C. Kottyan1,7,9 and
- Matthew T. Weirauch1,3,7,10
- 1Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA;
- 2Department of Pharmacology and Systems Physiology, University of Cincinnati, College of Medicine, Cincinnati, Ohio 45229, USA;
- 3Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA;
- 4Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA;
- 5Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA;
- 6Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, College of Medicine, Cincinnati, Ohio 45267, USA;
- 7Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, Ohio 45229, USA;
- 8US Department of Veterans Affairs Medical Center, Cincinnati, Ohio 45229, USA;
- 9Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA;
- 10Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA
Abstract
The interplay between environmental and genetic factors plays a key role in the development of many autoimmune diseases. In particular, the Epstein–Barr virus (EBV) is an established contributor to multiple sclerosis, lupus, and other disorders. Previously, we showed that the EBV nuclear antigen 2 (EBNA2) transactivating protein occupies up to half of the risk loci for a set of seven autoimmune disorders. To further examine the mechanistic roles played by EBNA2 at these loci on a genome-wide scale, we globally examined gene expression, chromatin accessibility, chromatin looping, and EBNA2 binding in a B cell line that was (1) uninfected, (2) infected with a strain of EBV lacking EBNA2, or (3) infected with a strain that expresses EBNA2. We identified more than 400 EBNA2-dependent differentially expressed human genes and more than 5000 EBNA2 binding events in the human genome. ATAC-seq analysis revealed more than 2000 regions in the human genome with EBNA2-dependent chromatin accessibility, and HiChIP data revealed more than 1700 regions where EBNA2 altered chromatin looping interactions. Autoimmune genetic risk loci were highly enriched at the sites of these EBNA2-dependent chromatin-altering events. We present examples of autoimmune risk genotype–dependent EBNA2 events, nominating genetic risk mechanisms for autoimmune risk loci such as ZMIZ1. Taken together, our results reveal important interactions between host genetic variation and EBNA2-driven disease mechanisms. Further, our study highlights a critical role for EBNA2 in rewiring human gene regulatory programs through rearrangement of the chromatin landscape and nominates these interactions as components of genetic mechanisms that influence the risk of multiple autoimmune diseases.
Footnotes
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↵11 Co-first authors.
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at https://www.genome.org/cgi/doi/10.1101/gr.264705.120.
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Freely available online through the Genome Research Open Access option.
- Received April 15, 2020.
- Accepted October 7, 2021.
This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
