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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE149757 | GEO | 2020/12/20

REPOSITORIES: GEO

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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

Genome wide profiling of chromatin accessibilities in murine mononuclear phagocyte lineage progenitor 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 analyzed chromatin accessibility of bone marrow cells from wild-type and Irf8-/- mice. Combined with the epigenetic profiling by H3K27 acetylation ChIP-seq, the +56 kb enhancer opens at LMPP stage, and gets activated at its highest level in mononuclear phagocyte lineage progenitor cells.

2020-12-20 | GSE149756 | GEO

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)

2023-03-15 | GSE218990 | 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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Histone modification 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 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.

2024-04-24 | GSE239738 | GEO

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

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

IRF8 transcription factor controls survival and function of terminally differentiated conventional and plasmacytoid dendritic cells respectively

Project description:Interferon regulatory factor-8 (IRF8) has been proposed to be essential for development of monocytes, plasmacytoid dendritic cells (pDCs) and type 1 conventional dendritic cells (cDC1s) and remains highly expressed in differentiated DCs. Transcription factors that are required to maintain the identity of terminally differentiated cells are designated “terminal selectors”. Using BM chimeras, conditional Irf8fl/fl mice and various promotors to target Cre recombinase to different stages of monocyte and DC development, we have identified IRF8 as a terminal selector of the cDC1 lineage controlling survival. In monocytes, IRF8 was necessary during early but not late development. Complete or late deletion of IRF8 had no effect on pDC development or survival but altered their phenotype and gene expression profile leading to increased T cell stimulatory function but decreased type 1 interferon production. Thus, IRF8 differentially controls the survival and function of terminally differentiated monocytes, cDC1s and pDCs.

2016-09-20 | GSE85520 | GEO

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