The Heme-regulated transcriptional repressor, BACH1 safeguards macrophage enhancer selection, activation andtissue adaptation [ATAC-seq_muscle]

Transcriptional master regulators of the myeloid lineage (like PU.1, Cebpa/b, etc.) are believed to be the main drivers of chromatin reprogramming during differentiation and polarization. Such developmental transcription factors act via their pioneer ability to open chromatin de novo and bookmark genomic regulatory sites (enhancers and promoters) to later recruit signal-dependent TFs, co-factors, and the basal transcriptional machinery. However, recent studies by us and others challenged this “developmental TF-centric” mode as they suggested that signal-dependent TFs, particularly repressors, can also have a pioneer and thus safeguarding role in the MF epigenome at baseline and during acute inflammation. Such an expanded model predicts that active transcriptional repression and chromatin bookmarking by signal-dependent master regulators are key mechanisms for safeguarding the enhancer repertoire and proper priming, deployment, and resolution of an inflammatory response. Here, we show that BACH1, a heme-sensitive transcriptional repressor, acts as such a pervasive epigenomic safeguard to regulate tissue macrophage identity. We show that BACH1 is part of the core hardwired transcriptional program of ground-state macrophages shaping the chromatin accessibility of thousands of distal regulatory elements. Furthermore, BACH1 cistrome is extensive, not static but dynamic, and expanding upon different inflammatory stimuli and correlates with pre-formed and de novo formed enhancer-promoter networks. We further show that myeloid BACH1 is indispensable in vivo for tissue regeneration upon injury as it regulates the kinetics of Ly6C+ to Ly6C- transition of inflammatory macrophages and regulates the onset, the kinetics and magnitude of expression of critical inflammatory and repair-related genes. Finally, BACH1 was found to be required in vivo for competitive fitness and tissue adaptation of several tissue-resident macrophage populations (eg. lung, peritoneal macrophages), further supporting its pervasive role in acquiring and maintaining the functional specificity and diversity of tissue macrophages. Taken together, our data suggest that BACH1 acts as a signal-dependent master regulator that directly controls key transcriptional circuits during tissue macrophage subtype function, specification and inflammatory responses in vivo.