Genome-wide profiling of transcribed enhancers during macrophage activation
Background Macrophages are sentinel cells that play essential role in tissue homeostasis and host defence. Owing to their plasticity, macrophages acquire a range of functional phenotypes in response to microenvironmental stimuli, of which M1 (IFNγ) and M2 (IL-4/IL-13) phenotypes 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, with recent studies highlighting their importance in macrophages.
Results Using cap analysis of gene expression (CAGE) and epigenetic data, we identify on a 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 cytokine-initiated M1 and M2 macrophage polarization and demonstrate stimuli-specificity of the 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.
Conclusions Our study provides new insights into genome-wide enhancer-mediated transcriptional control of macrophage genes, including those implicated in macrophage M1 and M2 polarization, and offers a detailed genome-wide catalogue to further elucidate enhancer regulation in macrophages.