Gene Regulation in Health and Disease

Associate Professor Matthew T. Weirauch, Centre for Autoimmune Genomics and Etiology, Divisions of Biomedical Informatics and Development Biology, Cincinnati Children's Hospital, Cincinnati, Ohio, USA

Gene regulation is the carefully orchestrated process controlling the expression of genes in all organisms and cell types. Transcription factors (TFs), a key component of gene regulatory systems, recognize specific DNA sequences and control chromatin and transcription. I will present two large-scale computational projects aimed at understanding TF function on a global scale. First, TF DNA sequence preferences direct their regulatory activity, but are currently known for only ~1% of all eukaryotic TFs.  Broadly sampling DNA-binding domain (DBD) types from multiple eukaryotic clades, we determined DNA sequence preferences for >1,000 TFs encompassing 54 different DBD classes from 131 diverse eukaryotes, forming the basis of our widely used Cis-BP database. Dr Weirauch will demonstrate how these data are invaluable for the interpretation of disease-associated non-coding genetic variants, which largely localize to regulatory regions. Second, using a novel computational algorithm called RELI, we have discovered that particular TFs occupy multiple loci of individual complex genetic disorders. Strikingly, nearly half of the systemic lupus erythematosus risk loci are occupied by the Epstein-Barr virus EBNA2 protein and many co-clustering human TFs, revealing gene-environment interaction. Similar EBNA2-anchored associations exist in multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes, juvenile idiopathic arthritis, and celiac disease. Instances of allele-dependent DNA binding and downstream effects on gene expression at plausibly causal variants support genetic mechanisms dependent upon EBNA2, and hence Epstein-Barr virus. Collectively, these results nominate mechanisms that operate across risk loci within disease phenotypes, suggesting new paradigms for disease origins.

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.