Genome-wide identification and analysis of transcribed enhancers during macrophage polarization
Macrophages are sentinel cells essential for tissue homeostasis and host defence. Owing to their plasticity, macrophages acquire a range of functional phenotypes in response to microenvironmental stimuli, of which M(IFN-{gamma}) and M(IL-4/IL-13) are well-known for their opposing pro- and anti-inflammatory roles. Enhancers have emerged as regulatory DNA elements crucial for transcriptional activation of gene expression. Using cap analysis of gene expression and epigenetic data, we identify on large-scale transcribed enhancers in mouse macrophages, their time kinetics and target protein-coding genes. We observe an increase in target gene expression, concomitant with increasing numbers of associated enhancers and find that genes associated to many enhancers show a shift towards stronger enrichment for macrophage-specific biological processes. We infer enhancers that drive transcriptional responses of genes upon M(IFN-{gamma}) and M(IL-4/IL-13) macrophage activation and demonstrate stimuli-specificity of regulatory associations. Finally, we show that enhancer regions are enriched for binding sites of inflammation-related transcription factors, suggesting a link between stimuli response and enhancer transcriptional control. Our study provides new insights into genome-wide enhancer-mediated transcriptional control of macrophage genes, including those implicated in macrophage activation, and offers a detailed genome-wide catalogue to further elucidate enhancer regulation in macrophages.