Niche-Specific Re-Programming of Epigenetic Landscapes Drives Myeloid Cell Diversity in NASH [ChIP-seq]

Tissue resident macrophages and recruited monocyte-derived macrophages contribute to host defense but also play pathological roles in a diverse range of human diseases. Multiple macrophage phenotypes are often represented in a diseased tissue, but we lack a deep understanding of the mechanisms that control diversification. Here we use a combination of genetic, genomic, and imaging approaches to investigate the origins and epigenetic trajectories of hepatic myeloid cells during a diet-induced model of nonalcoholic steatohepatitis (NASH). We provide evidence that distinct microenvironments within the NASH liver induce strikingly divergent transcriptomes of resident and infiltrating cells. Myeloid cell diversification results from both remodeling open chromatin landscapes of recruited monocytes and altering activities of preexisting enhancers of resident Kupffer cells. These findings provide evidence that niche-specific combinations of disease-associated environmental signals instruct resident and recruited macrophages to acquire distinct programs of gene expression and corresponding phenotypes. RNA-seq, ATAC-seq, H3K27ac ChIP-seq and LXR alpha + beta ChIP-seq on liver and peripheral myeloid cells in healthy and NASH model diet mice.