Significance
Dendritic cells (DCs), essential for immune responses, originate from bone marrow hematopoietic stem cells via intermediate progenitors. In eukaryotic nuclei, DNA is packaged into 3D chromatin structures that have been implicated in gene regulation. However, the chromatin structure reorganization dynamics during DC differentiation remain unknown. Here, we analyzed 3D chromatin structures in DCs and their progenitors. In genomic regions at DC-specific genes, the 3D chromatin structures were reorganized upon DC differentiation. The transcription factor IRF8 promoted chromatin structure changes in DC progenitors, leading to DC-specific gene induction. Strikingly, the chromatin structures of infection-inducible genes were preestablished in unstimulated DCs. Our findings advance the understanding of DC biology and basic principles of gene regulation for cell differentiation and host defense. Abstract
Classical dendritic cells (cDCs) are essential for immune responses and differentiate from hematopoietic stem cells via intermediate progenitors, such as monocyte−DC progenitors (MDPs) and common DC progenitors (CDPs). Upon infection, cDCs are activated and rapidly express host defense-related genes, such as those encoding cytokines and chemokines. Chromatin structures, including nuclear compartments and topologically associating domains (TADs), have been implicated in gene regulation. However, the extent and dynamics of their reorganization during cDC development and activation remain unknown. In this study, we comprehensively determined higher-order chromatin structures by Hi-C in DC progenitors and cDC subpopulations. During cDC differentiation, chromatin activation was initially induced at the MDP stage. Subsequently, a shift from inactive to active nuclear compartments occurred at the cDC gene loci in CDPs, which was followed by increased intra-TAD interactions and loop formation. Mechanistically, the transcription factor IRF8, indispensable for cDC differentiation, mediated chromatin activation and changes into the active compartments in DC progenitors, thereby possibly leading to cDC-specific gene induction. Using an infection model, we found that the chromatin structures of host defense-related gene loci were preestablished in unstimulated cDCs, indicating that the formation of higher-order chromatin structures prior to infection may contribute to the rapid responses to pathogens. Overall, these results suggest that chromatin structure reorganization is closely related to the establishment of cDC-specific gene expression and immune functions. This study advances the fundamental understanding of chromatin reorganization in cDC differentiation and activation.