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An Nfil3-Zeb2-Id2 pathway imposes Irf8 enhancer switching during cDC1 development

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE123800 | GEO | 2019/06/23

REPOSITORIES: GEO

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An Nfil3-Zeb2-Id2 pathway imposes Irf8 enhancer switching during cDC1 development.

Project description: Not available

| S-EPMC6707889 | biostudies-literature

An Nfil3-Zeb2-Id2 pathway imposes Irf8 enhancer switching during cDC1 development (RNA-Seq)

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

An Nfil3-Zeb2-Id2 pathway imposes Irf8 enhancer switching during cDC1 development

Project description:An Nfil3-Zeb2-Id2 pathway imposes Irf8 enhancer switching during cDC1 development

| PRJNA509877 | ENA

An Nfil3-Zeb2-Id2 pathway imposes Irf8 enhancer switching during cDC1 development (RNA-Seq)

Project description:An Nfil3-Zeb2-Id2 pathway imposes Irf8 enhancer switching during cDC1 development (RNA-Seq)

| PRJNA548945 | ENA

Cryptic activation of an Irf8 enhancer governs cDC1 fate specification.

Project description: Not available

| S-EPMC6707878 | biostudies-literature

Expression data from WT cDC1s, Zeb2 KO cDC1s, Nfil3 Zeb2 DKO cDC1s and Zeb2 Id2 DKO cDC1s

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

The transcription factor Zeb2 regulates development of conventional and plasmacytoid DCs by repressing Id2.

Project description: Not available

| S-EPMC4886362 | biostudies-literature

Batf3 and Id2 have a synergistic effect on Irf8-directed classical CD8?+ dendritic cell development.

Project description: Not available

| S-EPMC4805111 | biostudies-literature

Cis-regulation between Irf8 enhancers during cDC1 development

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-03-14 | GSE218992 | GEO

Ablation of cDC1 development by IL-6-induced C/EBPb support in the -165 kb Zeb2 enhancer

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

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