Trevor W. Siggers, PhD
BS, Simon Fraser University
PhD, Columbia University
Gene Regulation in the Immune System. Broadly, our lab studies gene regulatory specificity in the immune system. We employ systems-level approaches that integrate genome-wide datasets (e.g. ChIP-seq, RNA-seq), high-throughput biochemical assays (e.g., protein-binding microarrays, PBMs) and computational genomics to study how transcription factors specify their target genes.
Interferon Regulatory Factors (IRFs). IRFs regulate a range of functions in the immune system. We are examining how IRF3, IRF5 and IRF7 – critical regulators of the anti-viral response – discriminate their overlapping yet distinct target gene sets. We have recently shown that distinct DNA binding specificities of these factors contribute to their specific target gens. We are now characterizing their genome-wide binding and examining the role of DNA-based allostery in discriminating functional from non-functional binding throughout the genome.
Nuclear Receptors. The type II nuclear receptors (NRs) regulate and integrate diverse aspects of metabolism and immune-system signaling. We are examining how NRs discriminate their unique target genes sets despite widely overlapping binding profiles in the genome. We have recently used PBMs to characterize the DNA-binding or twelve NR heterodimers, revealing considerable overlap in the DNA-binding specificities of NRs while also highlighting key differences between factors. We are currently integrating this our biophysical data genomic datasets to understand how specific NR-dependent gene expression is achieved in macrophages.
Lineage factors and Enhancers (PU.1, IRF8 and C/EBPa). We are working to understand how lineage factors in macrophages establish the enhancer landscape and cooperative with signal-dependent factors (i.e., NF-kB and IRFs) to coordinate gene expression responses. We are integrating ChIP-seq data (transcription factors and histone marks) in wild-type and CRISPR/Cas9-based gene knockout cell lines, with high-throughput PBM-based binding data to understand biophysical mechanisms that establish enhancers in macrophages.
Technology development. Our lab has years of experience using protein-binding microarrays (PBMs) to study the DNA-binding of transcription factors (TFs). We are now working to develop PBM-based methods to study both cooperative TF binding and cofactor recruitment to enable the study of higher-order mechanisms of regulatory specificity at the genome scale.