RT Journal
A1 Hong, Ted
A1 Parameswaran, Sreeja
A1 Donmez, Omer A.
A1 Miller, Daniel
A1 Forney, Carmy
A1 Lape, Michael
A1 Saint Just Ribeiro, Mariana
A1 Liang, Jun
A1 Edsall, Lee E.
A1 Magnusen, Albert F.
A1 Miller, William
A1 Chepelev, Iouri
A1 Harley, John B.
A1 Zhao, Bo
A1 Kottyan, Leah C.
A1 Weirauch, Matthew T.
T1 Epstein–Barr virus nuclear antigen 2 extensively rewires the human chromatin landscape at autoimmune risk loci
JF Genome Research 
JO Genome Research 
YR 2021 
FD December 01 
VO 31 
IS 12 
SP 2185 
OP 2198 
DO 10.1101/gr.264705.120 
UL http://genome.cshlp.org/content/31/12/2185.abstract 
AB 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.