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Histone modification in dendritic cell progenitors and dendritic cells

ABSTRACT: To understand the roles of Irf8 3’ enhancers on Irf8 expression during cDC1 differentiation, we performed Cleavage Under Targets and Tagmentation (CUT&Tag) analysis for H3K27ac of bone marrow cells and splenocytes from wild-type, and the Irf8 enhancer-deficient mice. Phenotypic analysis and integrated analysis of CUT&Tag data with transcriptome data of these mouse mononuclear phagocytic lineage cells revealed that the +56 kb enhancer acts on other 3′ enhancers via an IRF8-dependent TF program and the +32 kb enhancer acts in cis to activate other 3′ enhancers.

ORGANISM(S): Mus musculus

PROVIDER: GSE239738 | GEO | 2024/04/24

REPOSITORIES: GEO

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Gene expression profiling in dendritic cell progenitors and dendritic cells

Project description:To understand the roles of Irf8 3’ enhancers on Irf8 expression during cDC1 differentiation, we performed RNA-seq analysis of bone marrow cells and splenocytes from wild-type, and the Irf8 enhancer-deficient mice. Phenotypic analysis and integrated analysis of transcriptome data with genome-wide CUT&Tag data analysis for H3K27ac revealed that the +56 kb enhancer acts on other 3′ enhancers via an IRF8-dependent TF program and the +32 kb enhancer acts in cis to activate other 3′ enhancers.

2024-04-24 | GSE239739 | GEO

ATAC-seq of dendritic cell progenitors

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. Here we identified Irf8 enhancers and used CRISPR/Cas9 genome editing to assess their roles in Irf8 regulation. An enhancer 32 kilobases 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 DCs (pDCs) was found to also be transiently accessible in cDC1 progenitors. Deletion of this enhancer reduced Irf8 expression in pDCs as expected, but also surprisingly prevented the induction of Irf8 in CDPs and abolished cDC1 specification. Thus, cryptic activation of the +41 kb Irf8 enhancer in DC progenitors is responsible for cDC1 fate specification.

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Histone ChIP-seq of dendritic cell progenitors

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Cis-regulation between Irf8 enhancers during cDC1 development (CUT&RUN)

Project description:Type 1 classical dendritic cells (cDC1s) development requires the transcription factor IRF8, and IRF8 mutations cause severe combined immunodeficiency, including disseminated bacille Calmette-Guérin (BCG) disease. IRF8 regulated enhancers are required for Irf8 expression in early DC progenitors and mature cDC1s. The E-protein-dependent +41 kb enhancer gains accessibility and activates transcription in common DC progenitors (CDPs), and its depletion abrogated pre-cDC1s specification. The Batf3-dependent +32 kb enhancer gains accessibility and activates transcription in pre-cDC1 progenitors, and its depletion impaired cDC1 maturation. The +32 kb Irf8 enhancer locus bears an enhancer transcript, and the production of enhancer RNA (eRNA) Gm39266 is dependent on +41 kb Irf8 enhancer. It was unclear whether the +32 kb and +41 kb enhancers act independently or cooperate to regulate Irf8 expression. We dissected the mechanisms using +32/+41 compound heterozygous mice, and found that while the +41 kb enhancer suffices for pre-cDC1 progenitor specification, the +32 kb and +41 kb enhancers must reside on one allele to support cDC1 maturation. The +41 kb enhancer cis-regulates chromatin accessibility and BATF3 binding at +32 kb enhancer, independent of eRNA Gm39266 transcripts or transcription across +32 kb Irf8 enhancer.

2023-03-15 | GSE218991 | GEO

Cis-regulation between Irf8 enhancers during cDC1 development (ATAC-Seq)

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Optimization of the Irf8 +32 kb enhancer disrupts dendritic cell lineage segregation [scRNA-seq]

Project description:Autoactivation of lineage-determining transcription factors (TFs) mediates bistable expression to generate distinct cell phenotypes essential for complex body plans. Classical dendritic cells type 1 (cDC1) and type 2 (cDC2) provide non-redundant functions required for defense against distinct immune challenges. Interferon Regulatory Factor 8 (IRF8), the cDC1 lineage-determining TF, undergoes autoactivation in cDC1 progenitors to establish cDC1 identity, yet its expression is downregulated during cDC2 differentiation by an unknown mechanism. This study reveals that the Irf8 +32 kb enhancer, responsible for IRF8 autoactivation, has been tuned to possess low-affinity IRF8 binding sites. Incorporation of multiple high-affinity IRF8 binding sites into the Irf8 +32 kb enhancer induces erroneous IRF8 autoactivation in specified cDC2 progenitors, causing their redirection towards cDC1 and a novel hybrid DC subset with mixed lineage phenotypes. These developmental alterations critically impair both cDC1- and cDC2-dependent arms of immunity. Collectively, our findings underscore the significance of enhancer suboptimization in the developmental segregation of classical dendritic cells required for normal immune function.

2024-08-18 | GSE270060 | GEO

Genome wide profiling of active enhancers and IRF8-binding sites in murine mononuclear phagocyte lineage cells

Project description:To understand the mechanism underlying monocyte and dendritic cell development through the regulation of Irf8 expression by the 56 kb downstream (+56 kb) Irf8 enhancer, we performed epigenetic profiling of bone marrow cells and splenocytes from wild-type, the Irf8 +56 kb enhancer-deficient, and IRF8-deficient mice. Taken together with the transcriptome analysis of mononuclear phagocyte lineage cells in these mice, the Irf8 +56 kb enhancer-mediated high Irf8 expression in hematopoietic progenitor cells promote type 1 classical dendritic cell (cDC1) differentiation, while low Irf8 expression in progenitors led to Ly6C+ monocyte development. In addition, IRF8 ChIP-seq of mature cDC1s and monocytes suggested that IRF8 regulates enhancers in cooperation with different transcription factors in each lineage in its expression level.

2020-12-20 | GSE149757 | GEO

Optimization of the Irf8 +32 kb enhancer disrupts dendritic cell lineage segregation [bulk RNA-seq]

Project description:Autoactivation of lineage-determining transcription factors (TFs) mediates bistable expression to generate distinct cell phenotypes essential for complex body plans. Classical dendritic cells type 1 (cDC1) and type 2 (cDC2) provide non-redundant functions required for defense against distinct immune challenges. Interferon Regulatory Factor 8 (IRF8), the cDC1 lineage-determining TF, undergoes autoactivation in cDC1 progenitors to establish cDC1 identity, yet its expression is downregulated during cDC2 differentiation by an unknown mechanism. This study reveals that the Irf8 +32 kb enhancer, responsible for IRF8 autoactivation, has been tuned to possess low-affinity IRF8 binding sites. Increasing these affinities in vivo induces erroneous IRF8 autoactivation in specified cDC2 progenitors, causing their redirection towards cDC1 and a novel hybrid DC subset with mixed lineage phenotypes. These developmental alterations critically impair both cDC1- and cDC2-dependent arms of immunity. Collectively, our findings underscore the significance of enhancer suboptimization in the developmental segregation of classical dendritic cells required for normal immune function.

2024-02-01 | GSE241341 | GEO

Gene expression profiling in murine mononuclear phagocyte lineage cells

Project description:To understand the mechanism underlying monocyte and dendritic cell development through the regulation of Irf8 expression by the 56 kb downstream (+56 kb) Irf8 enhancer, we performed transcriptome analysis of bone marrow cells and splenocytes from wild-type, the Irf8 +56 kb enhancer-deficient, and IRF8-deficient mice. Taken together with the epigenetic profiling of mononuclear phagocyte lineage cells in these mice, the Irf8 +56 kb enhancer-mediated high Irf8 expression in hematopoietic progenitor cells promote type 1 classical dendritic cell (cDC1) differentiation, while low Irf8 expression in progenitors led to Ly6C+ monocyte development.

2020-12-20 | GSE149761 | GEO

Expression data from cDC2 derived from in vitro culture from Batf3 KO pre-cDC1 and IRF8 +32 KO pre-cDC1 compared to cDC1 derived from in vitro culture of WT pre-cDC1 or cDC2 derived from in vitro culture of WT pre-cDC2

Project description:We used gene expression microarrays to determine if Batf3 and the IRF8 +32 kb enhancer are required to sustain IRF8 expression in the pre-cDC1.

2019-06-23 | GSE132768 | GEO

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