Systems Biology Group Meeting

Date & Time

Presenter: Matthew Weirauch, Ph.D., Cincinnati Children’s Hospital Medical Center

Title: Autoimmune risk allele-dependent human gene regulation by Epstein-Barr Virus EBNA2

Decades of research has implicated an etiologic role for the Epstein-Barr Virus (EBV) in several autoimmune diseases, with patients displaying increased infection rates, viral loads, and immune responses. However, the underlying molecular mechanisms behind these associations have remained elusive. We developed an unbiased approach employing a novel computational method called RELI (Regulatory Element Locus Intersector) for cross-referencing publically available Genome-Wide Association Study (GWAS) and ChIP-seq data. Using RELI, we discovered that the EBV transactivator protein EBNA2 occupies up to half of the genetic risk loci for a set of seven autoimmune diseases, along with dozens of particular human transcription factors (TFs) and co-factors. Application of a second new computational tool called MARIO (Measurement of Allelic Ratios Informatics Operator) revealed over 20 examples of autoimmune risk allele-dependent co-binding of EBNA2 with human TFs. To further examine the mechanisms underlying these phenomena, we performed RNA-seq, ATAC-seq, and EBNA2 ChIP-seq in Ramos B cell lines that are uninfected, infected with a strain of EBV that carries EBNA2 (B95-8), or infected with a strain that lacks EBNA2 (P3HR-1). Global analysis of these data reveals hundreds of regions of the human genome showing EBNA2-dependent human gene expression and chromatin accessibility, many of which correspond to autoimmune risk loci and display risk allele-dependent behavior. Allele-dependent behavior is also observed in experiments performed in cells derived from multiple sclerosis and systemic lupus erythematosus patients. Collectively, these results implicate a critical mechanistic role for EBNA2 in the etiology of multiple autoimmune diseases. More generally, they illustrate an important and relatively unexplored mechanism through which environmental influences (viral infection) and human genetics can synergize to influence human disease.

About the Speaker

Dr. Weirauch is a computational biologist. His lab seeks to understand the mechanisms of gene transcriptional regulation. Current projects focus on characterizing transcription factor binding specificities, and developing methods for modeling their interactions with DNA, both in vitro and in vivo. His lab applies insights from basic research on transcription factor-DNA interactions to study the mechanisms underlying complex diseases.

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