Similar Datasets
Project description:Classical type 1 dendritic cells (cDC1s) are required for antiviral and antitumor immunity, which necessitates an understanding of their development. Development of the cDC1 progenitor requires an E-protein-dependent enhancer located 41 kilobases downstream of the transcription start site of the transcription factor Irf8 (+41-kb Irf8 enhancer), but its maturation instead requires the Batf3-dependent +32-kb Irf8 enhancer. To understand this switch, we performed single-cell RNA sequencing of the common dendritic cell progenitor (CDP) and identified a cluster of cells that expressed transcription factors that influence cDC1 development, such as Nfil3, Id2 and Zeb2. Genetic epistasis among these factors revealed that Nfil3 expression is required for the transition from Zeb2hi and Id2lo CDPs to Zeb2lo and Id2hi CDPs, which represent the earliest committed cDC1 progenitors. This genetic circuit blocks E-protein activity to exclude plasmacytoid dendritic cell potential and explains the switch in Irf8 enhancer usage during cDC1 development.
| S-EPMC6707889 | biostudies-literature
Project description:Classical type 1 dendritic cells (cDC1s) are required for anti-viral and anti-tumor immunity, which has motivated a need to understand their development. The development of the cDC1 progentitor requires an E protein–dependent enhancer located 41 kilobases downstream of the transcription start site of the transcription factor IRF8 (+41 kb Irf8 enhancer) but its maturation instead requires the BATF3-dependent +32 kb Irf8 enhancer. To understand this switch, we performed single-cell RNA sequencing of the common dendritic cell progenitor (CDP) and identified a cluster of cells that expressed transcription factors that influence cDC1 development, such as Nfil3, Id2, and Zeb2. Genetic epistasis among these factors revealed that Nfil3 expression is required for the transition from Zeb2hi and Id2lo CDPs to Zeb2lo and Id2hi CDPs, which represent the earliest committed cDC1 progenitors. This genetic circuit blocks E protein activity to exclude plasmacytoid DC potential and explains the switch in Irf8 enhancer usage during cDC1 development.
2019-06-23 | GSE132770 | GEO
Project description:An Nfil3-Zeb2-Id2 pathway imposes Irf8 enhancer switching during cDC1 development
| PRJNA509877 | ENA
Project description:An Nfil3-Zeb2-Id2 pathway imposes Irf8 enhancer switching during cDC1 development (RNA-Seq)
| PRJNA548945 | ENA
Project description:Induction of the transcription factor Irf8 in the common dendritic cell progenitor (CDP) is required for classical type 1 dendritic cell (cDC1) fate specification, but the mechanisms controlling this induction are unclear. In the present study Irf8 enhancers were identified via chromatin profiling of dendritic cells and CRISPR/Cas9 genome editing was used to assess their roles in Irf8 regulation. An enhancer 32 kilobases (kb) downstream of the Irf8 transcriptional start site (+32-kb Irf8) that was active in mature cDC1s was required for the development of this lineage, but not for its specification. Instead, a +41-kb Irf8 enhancer, previously thought to be active only in plasmacytoid dendritic cells, was found to also be transiently accessible in cDC1 progenitors, and deleting this enhancer prevented the induction of Irf8 in CDPs and abolished cDC1 specification. Thus, cryptic activation of the +41-kb Irf8 enhancer in dendritic cell progenitors is responsible for cDC1 fate specification.
| S-EPMC6707878 | biostudies-literature
Project description:We used microarrays to determine whether cDC1s from the two double KO are bona fide cDC1s, and what are the transcriptional changes within these cDC1s.
2019-06-23 | GSE123797 | GEO
Project description:Plasmacytoid dendritic cells (DCs [pDCs]) develop from pre-pDCs, whereas two lineages of conventional DCs (cDCs; cDC1s and cDC2s) develop from lineage-committed pre-cDCs. Several transcription factors (TFs) have been implicated in regulating the development of pDCs (E2-2 and Id2) and cDC1s (Irf8, Id2, and Batf3); however, those required for the early commitment of pre-cDCs toward the cDC2 lineage are unknown. Here, we identify the TF zinc finger E box-binding homeobox 2 (Zeb2) to play a crucial role in regulating DC development. Zeb2 was expressed from the pre-pDC and pre-cDC stage onward and highly expressed in mature pDCs and cDC2s. Mice conditionally lacking Zeb2 in CD11c(+) cells had a cell-intrinsic reduction in pDCs and cDC2s, coupled with an increase in cDC1s. Conversely, mice in which CD11c(+) cells overexpressed Zeb2 displayed a reduction in cDC1s. This was accompanied by altered expression of Id2, which was up-regulated in cDC2s and pDCs from conditional knockout mice. Zeb2 chromatin immunoprecipitation analysis revealed Id2 to be a direct target of Zeb2. Thus, we conclude that Zeb2 regulates commitment to both the cDC2 and pDC lineages through repression of Id2.
| S-EPMC4886362 | biostudies-literature
Project description:Dendritic cells (DCs) are heterogeneous cell populations represented by different subtypes, each varying in terms of gene expression patterns and specific functions. Recent studies identified transcription factors essential for the development of different DC subtypes, yet molecular mechanisms for the developmental program and functions remain poorly understood. In this study, we developed and characterized a mouse DC progenitor-like cell line, designated DC9, from Irf8(-/-) bone marrow cells as a model for DC development and function. Expression of Irf8 in DC9 cells led to plasmacytoid DCs and CD8?(+) DC-like cells, with a concomitant increase in plasmacytoid DC- and CD8?(+) DC-specific gene transcripts and induction of type I IFNs and IL12p40 following TLR ligand stimulation. Irf8 expression in DC9 cells led to an increase in Id2 and Batf3 transcript levels, transcription factors shown to be important for the development of CD8?(+) DCs. We show that, without Irf8, expression of Id2 and Batf3 was not sufficient for directing classical CD8?(+) DC development. When coexpressed with Irf8, Batf3 and Id2 had a synergistic effect on classical CD8?(+) DC development. We demonstrate that Irf8 is upstream of Batf3 and Id2 in the classical CD8?(+) DC developmental program and define the hierarchical relationship of transcription factors important for classical CD8?(+) DC development.
| S-EPMC4805111 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-03-14 | GSE218992 | GEO
Project description:Type 1 conventional dendritic cells (cDC1) are required for effective CD8 T cell responses to many viruses and tumors and for effective checkpoint blockade immunotherapy. Recently, cytokines produced in association with certain tumors were reported to impair anti-tumor immune responses by reducing the abundance of cDC1. However, the reported mechanism of this reduction remains unclear, attributed either to reduced cDC1 development or decreased peripheral cDC1 survival. Here we show that tumor-derived IL-6 blocks cDC1 development from both in murine and human systems. We show that mechanism of this blockade is the IL-6-dependent increase in C/EBPβ expression in the common dendritic cell progenitor (CDP). C/EBPβ and NFIL3 compete for binding to sites in the -165 kb Zeb2 enhancer, and support or repress Zeb2 expression respectively. At homeostastis, pre-cDC1 specification occurs upon Nfil3 induction and consequent Zeb2 suppression. However, IL-6 strongly induces C/EBPβ expression in CDPs, thereby preventing normal NFIL3-dependent pre-cDC1 specification. Importantly, the ability of IL-6 to block cDC1 development is dependent on the presence of C/EBPβ binding sites in the -165 kb Zeb2 enhancer, as this effect is lost in Δ1+2+3 mutnat mice in which these binding sites are mutated. These results explain how tumor-associated IL-6 suppresses cDC1 development and suggest therapeutic approaches preventing abnormal C/EBPβ induction in CDPs may help reestablish cDC1 development to enhance anti-tumor immunity.
2023-06-22 | GSE215751 | GEO