CSB Departmental Seminar – Professor Christopher Glass, UCSD

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. These observations raise the question of the roles of distinct environments in determining patterns of gene expression required for such specialized functions and the underlying mechanisms. 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. 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. Natural genetic variation alters the selection and function of these enhancers in a tissue-specific manner and can be used as a ‘mutagenesis’ screen, to identify key transcription factors that are dependent on environmental signals and direct tissue specific macrophage phenotypes. These findings provide insights into molecular mechanisms by which nature (genomic sequence) and nurture (tissue environment) influence macrophage phenotypes and provide a basis for understanding how noncoding natural genetic variation in humans influences disease risk. Current efforts focus on roles of tissue environment and genetic variation in controlling the functions of macrophage populations in the liver and brain under homeostatic and pathologic conditions.