An EGR1-dependent cascade modulates genome architecture at the CSF1R locus

The organization and dynamics of chromatin are key to regulating gene expression during myeloid cell differentiation. Sequence-specific transcription factors initiate and maintain a complex network of enhancer-promoter contacts, which is supported by insulating elements and genome folding organizers such as CTCF and Cohesin. The spatial arrangement of enhancers and promoters, as well as their epigenetic state, drives cell and tissue-specific transcriptomes. Here we dissect the spatial, transcriptional, and epigenetic landscape of the colony stimulating factor 1 receptor (CSF1R) locus in monocytes and macrophages. CSF1R is a receptor tyrosine kinase that triggers the signaling cascade required for macrophage differentiation. Previous work showed that CSF1R expression is regulated by multiple enhancers, including the fms-intronic regulatory element (FIRE). Here, we find that a single EGR-1 binding motif dictates activation of CSF1R. We also discover that the CSF1R entire locus folds into a hub of gene regulation, affecting an extended network of myeloid and inflammatory genes. Globally, EGR1 may have an expanded role as a macrophage-specific boundary element, supporting enhancer-promoter looping at several genes. In sum, we describe a novel 3D chromatin network that is critical for macrophage development and function.