Macrophages populate every tissue of the body and play vital roles in homeostasis, pathogen elimination, and tissue healing. These cells possess the ability to adapt to a multitude of abruptly changing and complex environments. Furthermore, different populations of resident tissue macrophages each show their own defining gene signatures. The enhancer repertoire of these cells underlies both the cellular identity of a given subset of resident macrophage population and their ability to dynamically alter, in an efficient manner, their gene expression programs in response to internal and external signals. Notably, transcription is pervasive at active enhancers and enhancer RNAs, or eRNAs, are tightly correlated to regulated transcription of protein-coding genes. Furthermore, selection and establishment of enhancers is a dynamic and plastic process in which activation of intracellular signaling pathways by factors present in a macrophage's environment play a determining role. Here, we review recent studies providing insights into the distinct mechanisms that contribute to the selection and function of enhancers in macrophages and the relevance of studying these mechanisms to gain a better understanding of complex human diseases.
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