Mapping the chromatin and RNA expression landscapes of human macrophages to interrogate the function of disease-associated genetic polymorphisms

Macrophages are known to show highly dynamic responses to diverse stimuli, and have been implicated in metabolic syndrome and related diseases. Genome-wide association studies have identified many single-nucleotide polymorphisms (SNPs) associated with these common conditions, largely in non-coding regions; how these SNPs influence disease processes remains largely unknown. We hypothesized that examining RNA expression and chromatin state in macrophages across diverse activation conditions would elucidate the roles of macrophages in mediating the effects of disease-linked SNPs on the development of disease. We measured gene expression via RNAseq and histone 3 lysine 27 acetylation via ChIPseq as an indicator of promoter/enhancer activity in human blood monocyte-derived macrophages stimulated in vitro with a range of inflammatory and disease-relevant stimuli. Over 11,000 genes and 43,000 regulatory elements show condition-dependent activity in this dataset. Functional enrichment in modules of co-expressed transcripts confirmed expected stimuli-specific biology and reveal potentially novel relationships between distinct stimulation states. Correlation of regulatory element activity with module gene expression shows broad inflammatory/anti-inflammatory separation, and metabolic-trait associated SNPs tend to be embedded within regulatory elements whose activity is associated with both non-inflammatory and, surprisingly, some anti-viral macrophage gene modules. Ongoing work includes using these data to infer the transcriptional networks underlying these states. This study was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH.