Chromatin structure undergoes global and local reorganization during murine dendritic cell development and activation

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.

A lncRNA identifies Irf8 enhancer element in negative feedback control of dendritic cell differentiation

“…In this study PU.1 was found to regulate chromatin remodeling between the –50 kb enhancer and the Irf8 promoter in myeloid differentiation. In a recent study Kurotaki et al, 2022 determined the higher-order chromatin structure in DC progenitors, cDC1 and cDC2 on a genome-wide scale by Hi-C. In this study, reorganization of chromatin conformation at DC-specific gene loci was observed during cDC differentiation, and IRF8 was found to promote chromatin activation in DC progenitors leading to cDC lineage-specific gene expression.…”

“…During DC differentiation, the Irf8 gene locus shows high epigenetic dynamics, including histone modifications and TF binding identified by ChIP-seq ( Chauvistré and Seré, 2020 ; Durai et al, 2019 ; Grajales-Reyes et al, 2015 ; Lin et al, 2015 ), chromatin accessibility measured by ATAC-seq ( Kurotaki et al, 2019 ; Li et al, 2019 ), and three-dimensional chromatin structure remodeling determined by chromosome conformation capture (3 C) ( Kurotaki et al, 2022 ; Schönheit et al, 2013 ). All this emphasizes the impact of epigenetic regulators on Irf8 gene activity in DC differentiation.…”

Temporally correlated active forces drive segregation and enhanced dynamics in chromosome polymers

“…Cell-type-specific variations in the genome architecture are reflected in the compartment structure [12,[71][72][73]. These observations posit a conundrum: do compartments drive gene expression or vice-versa?…”

Stage-specific dynamic reorganization of genome topology shapes transcriptional neighborhoods in developing human retinal organoids

“… 81 , 82 Furthermore, we observed that most changes in gene expression occur without compartment changes. Similarly, most changes in gene expression occur in stable compartments during differentiation of mouse dendritic cells 83 and during sex differentiation in the Barbados nut tree. 84 Thus, although compartments are globally associated with gene expression, compartment switch and gene expression changes are correlated only at a subset of loci.…”