A RUNX–CBFβ-driven enhancer directs the Irf8 dose-dependent lineage choice between DCs and monocytes

Murakami, Koichi; Sasaki, Haruka; Nishiyama, Akira; Kurotaki, Daisuke; Kawase, Wataru; Ban, Tomohiro; Nakabayashi, Jun; Kanzaki, Satoko; Sekita, Yoichi; Nakajima, Hitoshi; Ozato, Keiko; Kimura, Tohru; Tamura, Tomohide

doi:10.1038/s41590-021-00871-y

Cited by 37 publications

(59 citation statements)

References 63 publications

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“…The analysis of transcription factor binding motifs enriched in stage- specific peak sets (Fig. 2F) showed that day 4 was enriched in PU.1, IRF8 and combined PU.1:IRF8 motifs, reflecting the requirement for these factors in early DC development (Carotta et al, 2010; Murakami et al, 2021; Sichien et al, 2016). Mature pDCs showed enrichment of motifs for TCF4 and RUNX2, two factors critical for pDC development and function (Cisse et al, 2008; Sawai et al, 2013).…”

Section: Resultsmentioning

confidence: 99%

“…Yadav, N., Lee, J., Kim, J., Shen, J., Hu, M.C., Aldaz, C.M., and Bedford, M.T. ( 2003 cDC signature pDC signature pDC Grajkowska et al, 2017); and enhancers of Irf8 specific for pDCs, cDC1s, monocytes (mono) and DC progenitors (prog) (Bagadia et al, 2019;Murakami et al, 2021).…”

Section: Hybrid Metabolomics Data Processing and Relative Quantificat...mentioning

confidence: 99%

“…Shown are normalized read counts across the indicated genomic loci. Dashed squares indicate the negative distal regulatory region of Id2 (Ghosh et al, 2014); pDC-specific downstream enhancer of Tcf4 (Grajkowska et al, 2017); and enhancers of Irf8 specific for pDCs, cDC1s, monocytes (mono) and DC progenitors (prog) (Bagadia et al, 2019; Murakami et al, 2021).…”

Section: Supplemental Tablementioning

confidence: 99%

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Genome-wide analysis of dendritic cell differentiation

Tiniakou

Hsu

Lopez-Zepeda

et al. 2022

Preprint

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SummaryDendritic cells (DCs) are immune sentinel cells that comprise antigen-presenting conventional DCs (cDCs) and cytokine-producing plasmacytoid DCs (pDCs). Cytokine Flt3 ligand (Flt3L) supports the proliferation of hematopoietic progenitors, and is also necessary and sufficient for DC differentiation. Here we characterized the spontaneous differentiation of a Flt3L-dependent murine progenitor cell line into pDCs and “myeloid” cDCs (cDC2s), and interrogated it using a genome-wide CRISPR/Cas9 dropout screen. The screen revealed multiple regulators of DC differentiation including the glycosylphosphatidylinositol transamidase complex, the Nieman-Pick type C cholesterol transporter and arginine methyltransferase Carm1; the role of Carm1 in pDC and cDC2 differentiation was confirmed by conditional targeting in vivo. We also found that negative regulators of mTOR signaling, including the subunits of TSC and GATOR1 complexes, restricted progenitor growth but enabled DC differentiation. The results provide a comprehensive forward genetic analysis of DC differentiation, and help explain how the opposing processes of proliferation and differentiation could be driven by the same cytokine.

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Section: Resultsmentioning

confidence: 99%

Section: Hybrid Metabolomics Data Processing and Relative Quantificat...mentioning

confidence: 99%

Section: Supplemental Tablementioning

confidence: 99%

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Genome-wide analysis of dendritic cell differentiation

Tiniakou

Hsu

Lopez-Zepeda

et al. 2022

Preprint

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“…Furthermore, variants in IRF8 have been associated with monocyte counts across different populations (43), and a downregulation of IRF8 in monocytes and macrophages of SSc patients that may affect the fibrotic phenotype of the disease was reported (44). A recent study demonstrated that the deletion of an enhancer region corresponding with our SSc GWAS locus in mice model decreased Irf8 expression, resulting in an overproduction of inflammatory Ly6c + monocytes (45). Thus, our results confirm the association of IRF8 with SSc through physical chromatin interactions particularly in CD14 + monocytes.…”

Section: Discussionmentioning

confidence: 99%

Functional genomics in primary T cells and monocytes identifies mechanisms by which genetic susceptibility loci influence systemic sclerosis risk

González‐Serna

Shi

Kerick

et al. 2022

Preprint

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ObjectivesSystemic sclerosis (SSc) is a complex autoimmune disease with a strong genetic component. However, most of the causal genes and variants are still unknown. The challenge in the post-GWAS era is to use functional genomics to translate genetic findings into patients’ benefit, particularly in disease-relevant cell types.MethodsPromoter capture Hi-C (pCHi-C) and RNA sequencing experiments were performed in a total of 30 samples corresponding to CD4+ T cells and CD14+ monocytes (15 samples each) from SSc patients and healthy controls to link SSc-associated variants with their target genes, followed by differential expression and differential interaction analyses between both cell types. We also aimed to identify potential drugs that could be repurposed for its use in SSc.ResultsWe linked SSc-associated loci to 39 new potential target genes, confirming 7 previously assigned genes. We highlight novel causal genes, such as CXCR5 as the most probable candidate gene for the DDX6 locus. Some SSc confirmed genes such as IRF8, STAT4, or CD247 interestingly showed cell type specific interactions. We also identified 15 potential drug targets already in use in other similar immune-mediated diseases that could be repurposed for SSc treatment. Furthermore, we observed that interactions are directly related with the expression of important genes implicated in cell type specific pathways.ConclusionsOur study reveals potential causal genes for SSc-associated loci, some of them acting in a cell type specific manner, suggesting novel biological mechanisms that may mediate SSc pathogenesis.

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“…Initiation and propagation of myeloid programs in multipotent progenitors (MPPs) is governed mainly by the TFs PU.1, CEBPα and ε, Gfi1 and Irf8 ( Rosenbauer and Tenen, 2007 ). Irf8 is a highly important regulator of lineage choices between neutrophils, monocytes and dendritic cells (DCs), and represents an example of a TF driving lineage commitment in a dose-dependent manner; lack of this TF promotes neutrophil generation whereas low and high levels drive differentiation towards inflammatory Ly6C + monocytes and DCs, respectively ( Murakami et al, 2021 ). In line with this, fetal granulocyte-monocyte progenitors (GMPs), which express low levels of Irf8 protein ( Jassinskaja et al, 2021 ), have limited potential to produce fully mature inflammatory monocytes compared to adult GMPs.…”

Section: Intra- and Extracellular Regulation Of Hematopoiesismentioning

confidence: 99%

The Opportunity of Proteomics to Advance the Understanding of Intra- and Extracellular Regulation of Malignant Hematopoiesis

Jassinskaja

Hansson

2022

Front. Cell Dev. Biol.

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Fetal and adult hematopoiesis are regulated by largely distinct sets of cell-intrinsic gene regulatory networks as well as extracellular cues in their respective microenvironment. These ontogeny-specific programs drive hematopoietic stem and progenitor cells (HSPCs) in fetus and adult to divergent susceptibility to initiation and progression of hematological malignancies, such as leukemia. Elucidating how leukemogenic hits disturb the intra- and extracellular programs in HSPCs along ontogeny will provide a better understanding of the causes for age-associated differences in malignant hematopoiesis and facilitate the improvement of strategies for prevention and treatment of pediatric and adult acute leukemia. Here, we review current knowledge of the intrinsic and extrinsic programs regulating normal and malignant hematopoiesis, with a particular focus on the differences between infant and adult acute leukemia. We discuss the recent advances in mass spectrometry-based proteomics and its opportunity for resolving the interplay of cell-intrinsic and niche-associated factors in regulating malignant hematopoiesis.

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A RUNX–CBFβ-driven enhancer directs the Irf8 dose-dependent lineage choice between DCs and monocytes

Cited by 37 publications

References 63 publications

Genome-wide analysis of dendritic cell differentiation

Genome-wide analysis of dendritic cell differentiation

Functional genomics in primary T cells and monocytes identifies mechanisms by which genetic susceptibility loci influence systemic sclerosis risk

The Opportunity of Proteomics to Advance the Understanding of Intra- and Extracellular Regulation of Malignant Hematopoiesis

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