Mechanisms Underlying the Selection and Function of Macrophage-Specific Enhancers

Abstract

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.

Figure 1

Schematic overview of a ‘collaborative/hierarchical’ model for macrophage enhancer selection and function. Panel A. Enhancers are initially selected by ‘collaborative’ interactions of lineage-determining transcription factors (LDTFs) at regions of the genome that contain closely spaced binding sites for these factors. The term collaborative is meant to indicate that each factor requires the other to effectively compete with nucleosomes and establish a nucleosome-free region. Panel B. Pre-existing enhancers are primary sites of action of signal-dependent transcription factors (SDTFs), here illustrated for the p65 component of NFκB following macrophage activation by LPS. The dependence of SDTFs on pre-existing binding of LDTFs establishes a hierarchical relationship that enables cell-specific functions of widely expressed transcription factors.

Figure 2

Schematic overview of the interplay between primed enhancers established by lineage-determining transcription factors (LDTF) and activation by signals from the environment. Environment-specific signals activate a subset of enhancers that are primed in all macrophages. This leads to the expression of environment-induced genes, a subset of which encode collaborative transcription factors (TFs). These TFs in turn drive the establishment of tissue-specific enhancers in collaboration with already expressed LDTFs, such as PU.1. The combination of direct and indirect responses contributes to the identity and function of macrophages residing in that particular tissue environment.

Figure 3

Implications of mechanisms of enhancer selection and function for interpretation of genome-wide association studies (GWAS). Panel A. Schematic overview illustrating how SNPs identified in GWAS and associated with expression quantitative trait loci (eQTL) can affect enhancers in a cell-type specific manner. Panel B. Schematic overview how studies identifying disease-associated genomic variations in mouse can be helpful in understanding human disease through conserved sequence.