MafB is a conserved transcriptional regulator of macrophage development and identity across tissues and species [CUT&Run]

Resident tissue macrophages (RTM) are characterized by a remarkable diversity but also share common features that are thought to be driven by conserved transcriptional programs. While the transcription factor MafB is highly expressed in the macrophage lineage, little is known about its role in establishing RTM identities. Here, we show that the absence of MafB results in a profound imbalance across many RTM populations and in a disruption of global and tissue-specific RTM signatures in mice. Furthermore, we found that MafB was required for the differentiation of bone-marrow-derived macrophages (BMDMs) ex vivo and of RTM populations from monocytes in vivo. Mechanistically, epigenetic profiling of MafB binding sites in BMDMs revealed that MafB directly regulated expression of key RTM differentiation and identity genes, including Csf1r and Fcgr1. Finally, in silico analyses showed that MafB binding sites were highly conserved across vertebrates. Our findings demonstrate the crucial and evolutionarily conserved role of MafB as regulator of RTM development and identity, connecting MafB-dependent transcriptional programs with unique defining features of RTM. Overall design: To identify MafB binding sites we performed CUT&RUN for MafB on wild-type BMDM.