Gene expression profiling in murine monocyte-dendritic cell progenitors (MDPs), common monocyte progenitors (cMoPs) and 32Dcl.3 cells transduced with C/EBPalpha and/or IRF8
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE50052 | GEO | 2014/08/26
SECONDARY ACCESSION(S): PRJNA215873
REPOSITORIES: GEO
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Project description:To understand the mechanism by which IRF8 inhibits neutrophil differentiation Murine bone marrow MDPs and cMoPs were isolated by cell sorting from wild-type or Irf8 deficient mice. 32Dcl.3 cells were transduced with retroviruses carrying murine C/EBPalpha cDNA and/or murine Irf8 cDNA. Two independent experiments were performed.
2014-08-26 | E-GEOD-50052 | biostudies-arrayexpress
Project description:To understand the differentiation program in monocyte/macrophage differentiation, we performed ChIP-seq for IRF8 and H3K4me1 together with gene expression profiling during IRF8-induced monocyte differentiation. Both promoter-proximal and -distal binding of IRF8 associated with induction of the genes especially those related to monocytes/macrophages and immunity. DNA motif analysis for cis-regulatory elements of indirect IRF8 target genes predicted KLF4, essential for Ly6C+ monocyte development, to be a downstream transcription factor regulating the indirect target gene expression. Introduction of KLF4 into an Irf8-/- myeloid progenitor cell line induced a subset of IRF8 target genes and partially induced monocyte/macrophage differentiation. Together, this study revealed the genome-wide behavior of IRF8 and the IRF8-KLF4 axis during monocyte differentiation. Gene expressions in monocyte-like cells differentiated by IRF8 or KLF4 were measured at day 4 after retroviral transductions to myeloid progenitor cell line, Tot2. Two independent experiments were performed.
2013-01-24 | E-GEOD-38810 | biostudies-arrayexpress
Project description:Dendritic cells (DCs) are critical immune regulators involved in autoimmune diseases, but exploiting them clinically requires a detailed picture on the mechanisms orchestrating their development. DNA methylation is attractive in this regard because it is reversible and as such allows therapeutic manipulation. Combining single cell transplantation assays with whole-genome methylation assessment and with mice expressing reduced DNA methyltransferase 1 levels, we show that conventional and plasmacytoid DCs arise from myeloid-restricted hematopoietic stem cells (HSCs), suggesting that both subsets can develop independently of the lymphoid pathway. DC commitment by these HSCs requires an intrinsically high methylation threshold to establish expression of DC genes, particularly the Flt3 cytokine receptor. Reducing methylation depleted DCs and ameliorated systemic lupus erythematosus in mice. These studies shed novel light on the DC origin, show how lineage- and subset-specific methylation dynamics regulate DC fate and provide a potential rationale for targeting DCs in autoimmunity by hypomethylating agents.
2021-11-03 | GSE164124 | GEO
Project description:Dendritic cells (DCs) are essential regulators of immune responses; however, transcriptional mechanisms establishing DC lineage commitment are poorly defined. Here we report that the PU.1 transcription factor induces specific remodeling of the higher-order chromatin structure at the Interferon Regulatory Factor-8 (Irf8) gene to initiate DC fate choice. Generation of an Irf8 reporter mouse enabled us to pinpoint an initial progenitor stage at which DCs separate from other myeloid lineages in the bone marrow. In the absence of Irf8, this progenitor undergoes DC-to-neutrophil reprogramming, indicating that DC commitment requires an active, Irf8-dependent escape from alternative myeloid lineage potential. Mechanistically, myeloid Irf8 expression depends on high PU.1 levels, resulting in local chromosomal looping and activation of a lineage- and developmental stage-specific cis-enhancer. These data delineate PU.1 as a concentration-dependent rheostat of myeloid lineage selection by controlling long-distance contacts between regulatory elements, and suggest that specific higher-order chromatin remodeling at the Irf8 gene determines DC differentiation. Mature macrophages, Granulocytes and DCs were isolated from wildtype mouse spleens for successive RNA extraction and hybridization on Affymetrix microarrays. 3 different pools, each consisting of splenic cells from 5 mice were prepared. Cell populations were isolated by flow cytometry. MDPs were isolated from Wildtype and IRF8 deficient bonemarrow by flowcytometry, again creating 3 biological replicates, each consisting of pooled cells from 5 mice. Differential gene expression between wildtype and IRF8 deficient MDPs was subgrouped into macrophage, granuloctic and DC signatures, derived from expression data of these cell populations.
2013-04-27 | E-GEOD-45467 | biostudies-arrayexpress
Project description:To understand the differentiation program in monocyte/macrophage differentiation, we performed ChIP-seq for IRF8 and H3K4me1 together with gene expression profiling during IRF8-induced monocyte differentiation. Both promoter-proximal and -distal binding of IRF8 associated with induction of the genes especially those related to monocytes/macrophages and immunity. DNA motif analysis for cis-regulatory elements of indirect IRF8 target genes predicted KLF4, essential for Ly6C+ monocyte development, to be a downstream transcription factor regulating the indirect target gene expression. Introduction of KLF4 into an Irf8-/- myeloid progenitor cell line induced a subset of IRF8 target genes and partially induced monocyte/macrophage differentiation. Together, this study revealed the genome-wide behavior of IRF8 and the IRF8-KLF4 axis during monocyte differentiation.
2013-01-24 | GSE38810 | GEO
Project description:Dendritic cells (DCs) are essential regulators of immune responses; however, transcriptional mechanisms establishing DC lineage commitment are poorly defined. Here we report that the PU.1 transcription factor induces specific remodeling of the higher-order chromatin structure at the Interferon Regulatory Factor-8 (Irf8) gene to initiate DC fate choice. Generation of an Irf8 reporter mouse enabled us to pinpoint an initial progenitor stage at which DCs separate from other myeloid lineages in the bone marrow. In the absence of Irf8, this progenitor undergoes DC-to-neutrophil reprogramming, indicating that DC commitment requires an active, Irf8-dependent escape from alternative myeloid lineage potential. Mechanistically, myeloid Irf8 expression depends on high PU.1 levels, resulting in local chromosomal looping and activation of a lineage- and developmental stage-specific cis-enhancer. These data delineate PU.1 as a concentration-dependent rheostat of myeloid lineage selection by controlling long-distance contacts between regulatory elements, and suggest that specific higher-order chromatin remodeling at the Irf8 gene determines DC differentiation.
2013-04-27 | GSE45467 | GEO
Project description:Chromatins were prepared from myeloid progenitor cell line Tot2 cells transduced with retrovirus for control MSCV or MSCV-IRF8. Chromatin immunoprecipitation (ChIP) was carried out by using anti-IRF8 antibody, anti-PU.1 antibody or anti-histone H3K4me1 antibody. ChIP-Seq peaks were identified using the FindPeaks tool in the HOMER package or SICER with input DNA tags as background distribution. Potential IRF8-direct target genes were identified based on ChIP-Seq and the alteration of expression by IRF8-induction. Examination of 2 transcription factor occupancy and 1 histone modifications in myeloid progenitor cells and monocyte-like cells differetiated by IRF8 expression
2013-01-24 | E-GEOD-38824 | biostudies-arrayexpress
Project description:Granulocyte-monocyte progenitors (GMPs) and monocyte-dendritic cell progenitors (MDPs) produce monocytes during homeostasis and in response to increased demand during infection. Both progenitor populations are thought to derive from common myeloid progenitors (CMPs), and a hierarchical relationship (CMP-GMP-MDP-monocyte) is presumed to underlie monocyte differentiation. Here, however, we demonstrate that mouse MDPs arose from CMPs independently of GMPs, and that GMPs and MDPs produced monocytes via similar but distinct monocyte-committed progenitors. GMPs and MDPs yielded classical (Ly6Chi) monocytes with gene expression signatures that were defined by their origins and impacted their function. GMPs produced a subset of "neutrophil-like" monocytes, whereas MDPs gave rise to a subset of monocytes that yielded monocyte-derived dendritic cells. GMPs and MDPs were also independently mobilized to produce specific combinations of myeloid cell types following the injection of microbial components. Thus, the balance of GMP and MDP differentiation shapes the myeloid cell repertoire during homeostasis and following infection.
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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.
2019-06-23 | GSE132240 | GEO
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