Abstract
Macrophages are myeloid-lineage cells that reside in nearly all tissues of the body and play key roles in innate and adaptive immune responses. Distinct populations of tissue macrophages also acquire context-specific functions that are important for normal tissue homeostasis and organ function. We find that distinct tissue environments drive divergent programs of gene expression by acting on common enhancer elements as well as by directing the selection and activation of large sets of enhancers and super-enhancers that are unique to each tissue-resident macrophage population. In addition, natural genetic variation influences the responses of these cells to internal and external signals. These observations raise questions regarding gene by environment interactions in determining tissue-specific patterns of macrophage gene expression required for such specialized functions. As one approach to this question, we are systematically analyzing the transcriptomes and enhancer landscapes of different macrophage populations derived from a panel of inbred strains of mice providing more than 60 million single nucleotide variants. Natural genetic variation alters the selection and function of these enhancers and can be used as a ‘mutagenesis’ screen, to identify key transcription factors that direct tissue specific macrophage phenotypes. These studies are providing insights into molecular mechanisms by which nature (genomic sequence) and nurture (tissue environment) influence macrophage phenotypes and provide a basis for understanding how non-coding natural genetic variation in human influences disease risk.