Cis- and trans-regulation of Irf8 enhancers during dendritic cell development

Dendritic cells (DCs) are mononuclear phagocytes that play a crucial role in the immune system by mediating innate and adaptive immunity. DC differentiation requires the establishment of DC-specific gene expression regulated by lineage-specific transcription factors. Recent studies have reported a series of transcription factors essential for DC differentiation, as well as the regulatory circuit composed of these transcription factors. Among these transcription factors, interferon regulatory factor 8 (IRF8) is pivotal for the differentiation of type 1 classical DCs (cDC1s). IRF8 establishes the enhancer landscape at the progenitor stage and also regulates the higher-order chromatin structure of cDC1-specific genes. Furthermore, the cell fate within the myeloid lineages is determined in an IRF8 dose-dependent manner. The enhancers that govern Irf8 expression have been identified and extensively studied. Notably, Irf8 expression is regulated by a complex interplay among 3' enhancers, each of which has a differentiation stage-specific effect. In this review, we discuss recent advances in our understanding of the regulatory mechanisms of IRF8 expression underlying cDC1 development.