Decoding Environmentally Driven Gene Regulatory Networks in Hepatic Macrophages

The following work uses multi-level genomics approaches coupled with mouse models to study the gene regulatory networks in hepatic macrophages during both healthy conditions and liver disease. Chapter 1 will serve as an introduction, reviewing what is currently known about regulation of gene expression by sequence specific transcription factors and enhancers, how niche specific environmental signals are relayed through this regulatory machinery to produce the unique phenotypes of different populations of tissue resident macrophages, and how Kupffer cells and recruited macrophages function in the liver during nonalcoholic steatohepatitis. Chapter 2 utilizes a model system of experimental Kupffer cell ablation and repopulation to dissect the pathways that allow bone marrow derived monocytes to differentiate into Kupffer cell-like macrophages. Using this system, we found that TGF/SMAD, Notch/RBPJ, and LXR are critical pathways underlying Kupffer cell identity. Chapter 3 investigates the changes that occur to macrophages during experimentally induced fatty liver disease in mice. Bone marrow derived monocytes were recruited to both liver sinusoids (the Kupffer cell niche) and large diameter vessels and displayed divergent patterns of open chromatin and gene expression based on their destination. Further, embryonically derived Kupffer cells lost enhancer activity disproportionately at regulatory regions important for Kupffer cell identity. This loss of enhancer activity correlated with a selective loss of LXR binding at these regions. Liver disease also selectively resulted in apoptosis of embryonically derived Kupffer cells and their replacement with bone marrow derived precursors. Chapter 4 will discuss the broader implications of these studies