EGR1 is a gatekeeper of inflammatory enhancers in human macrophages.
Monocytes and monocyte-derived macrophages originate through a multistep differentiation process. First, hematopoietic stem cells generate lineage-restricted progenitors that eventually develop into peripheral, postmitotic monocytes. Second, blood-circulating monocytes undergo differentiation into macrophages, which are specialized phagocytic cells capable of tissue infiltration. While monocytes mediate some level of inflammation and cell toxicity, macrophages boast the widest set of defense mechanisms against pathogens and elicit robust inflammatory responses. Here, we analyze the molecular determinants of monocytic and macrophagic commitment by profiling the EGR1 transcription factor. EGR1 is essential for monopoiesis and binds enhancers that regulate monocytic developmental genes such as CSF1R However, differentiating macrophages present a very different EGR1 binding pattern. We identify novel binding sites of EGR1 at a large set of inflammatory enhancers, even in the absence of its binding motif. We show that EGR1 repressive activity results in suppression of inflammatory genes and is mediated by the NuRD corepressor complex.