Journal
GENOME RESEARCH
Volume 31, Issue 12, Pages 2185-2198Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gr.264705.120
Keywords
-
Categories
Funding
- National Institutes of Health (NIH) [R01 HG010730, R01 NS099068, R01 GM055479]
- NIH Office of Research Infrastructure Programs [U01 AI150748, R01 AR073228, P01 AI150585, R01 DK107502, P30 AR070549, U01 AI130830, U01 HG008666, R01 AI024717, R01 AI148276, I01 BX001834]
- Ohio Supercomputing Center
- Cincinnati Children's Research Foundation Academic and Research Committee (ARC)
- Center for Pediatric Genomics (CpG) awards
- Cincinnati Children's Research Foundation (CCRF) Endowed Scholar Award
Ask authors/readers for more resources
The interplay between environmental and genetic factors is crucial in the development of autoimmune diseases, with Epstein-Barr virus (EBV) being identified as a contributor. EBV nuclear antigen 2 (EBNA2) plays a significant role in chromatin alteration events and gene regulation, with autoimmune genetic risk loci highly enriched at these sites. This study highlights the interaction between host genetic variation and EBNA2-driven disease mechanisms, emphasizing the importance of EBNA2 in reshaping human gene regulatory programs and its impact on autoimmune disease risk.
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available