Transcription factor IRF8 governs enhancer landscape dynamics during mononuclear phagocyte development

Abstract

Abstract Monocytes and dendritic cells (DCs) are mononuclear phagocytes essential for innate and adaptive immunity. These phagocytes develop from hematopoietic stem cells via intermediate progenitors, such as granulocyte-monocyte progenitors (GMPs), monocyte-DC progenitors (MDPs), and common monocyte progenitors (cMoPs) or common DC progenitors (CDPs). However, the molecular mechanism underlying their differentiation potential remains incompletely understood. Recent studies suggest that promoter-distal enhancers are key for cell fate decision. In this study, we performed chromatin immunoprecipitation-sequencing (ChIP-seq) analysis of enhancer-related histone modifications in GMPs, MDPs, cMoPs, CDPs, monocytes, DCs, and neutrophils. We found that monocyte- and DC-specific enhancers were gradually established at progenitor stages before the expression of associated genes. Of the transcription factors predicted to bind to these enhancers, IRF8, essential for monocyte and DC development, was found to be required for the establishment of these enhancers, particularly those common to both monocyte and DC lineages. Somewhat unexpectedly, global gene expression patterns were comparable between the remaining Irf8−/− progenitors and their wild-type counterparts. Nevertheless, the enhancer landscapes of Irf8−/− progenitors were significantly distinct from those of wild-type cells, with the enhancer landscapes of Irf8−/− GMPs, MDPs, and cMoPs all remaining similar to that of wild-type GMPs. Our results illustrate the dynamic process by which key transcription factors regulate enhancer formation and thereby direct future gene expression to achieve mononuclear phagocyte development.