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The histone demethylase KDM5C regulates IRF transcriptional programming impacting dendritic cell population heterogeneity and function (CUT&RUN)

ABSTRACT: Functional and phenotypic heterogeneity of dendritic cells (DCs) plays a crucial role in facilitating the development of diverse immune responses essential for host protection. We found that KDM5C, a histone lysine demethylase, regulates conventional DC (cDC) and plasmacytoid DC (pDC) population heterogeneity and function. Mice deficient in KDM5C in DCs, have increased proportions of cDC2Bs and cDC1s, which was partly dependent on type I interferon and pDCs. Loss of KDM5C resulted in an increase in Ly6C- pDCs, which, compared to Ly6C+ pDCs, have limited ability to produce type I interferon and can more efficiently stimulate antigen-specific CD8 T cells. KDM5C-deficient DCs have increased expression of inflammatory genes, altered expression of lineage-specific genes, and reduced function. In response to Listeria infection, KDM5C-deficient mice mounted reduced CD8 responses due to decreased antigen presentation by cDC1s. Thus, KDM5C is a key regulator of DC heterogeneity and a critical driver functional properties of DCs.

ORGANISM(S): Mus musculus

PROVIDER: GSE263076 | GEO | 2024/09/25

REPOSITORIES: GEO

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The histone demethylase KDM5C regulates IRF transcriptional programming impacting dendritic cell population heterogeneity and function (RNA-seq)

Project description:Functional and phenotypic heterogeneity of dendritic cells (DCs) plays a crucial role in facilitating the development of diverse immune responses essential for host protection. We found that KDM5C, a histone lysine demethylase, regulates conventional DC (cDC) and plasmacytoid DC (pDC) population heterogeneity and function. Mice deficient in KDM5C in DCs, have increased proportions of cDC2Bs and cDC1s, which was partly dependent on type I interferon and pDCs. Loss of KDM5C resulted in an increase in Ly6C- pDCs, which, compared to Ly6C+ pDCs, have limited ability to produce type I interferon and can more efficiently stimulate antigen-specific CD8 T cells. KDM5C-deficient DCs have increased expression of inflammatory genes, altered expression of lineage-specific genes, and reduced function. In response to Listeria infection, KDM5C-deficient mice mounted reduced CD8 responses due to decreased antigen presentation by cDC1s. Thus, KDM5C is a key regulator of DC heterogeneity and a critical driver functional properties of DCs.

2024-09-25 | GSE262866 | GEO

Clonal lineage tracing reveals shared origin of conventional and plasmacytoid dendritic cells

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DC-SCRIPT (Zpf366) binding in cDC1 and cDC2 cells from wildtype and DC-SCRIPT knockout mice

Project description:The functional diversification of dendritic cells (DCs) is a key step in establishing protective immune responses. Despite the importance of this lineage diversity, its genetic basis is not fully understood. DC-SCRIPT (Zfp366) is a poorly known transcription factor expressed in conventional DCs (cDCs) and their committed bone marrow progenitors but not in plasmacytoid DCs (pDCs). We show that mice lacking DC-SCRIPT displayed substantially impaired development of IRF8-dependent conventional DC1 (cDC1), while cDC2 differentiated normally. The residual DC-SCRIPT-deficient cDC1s had impaired CD8+ T-cell cross-priming, which could be in part explained by the direct control of DC-SCRIPT on IL-12p40 production. Genome-wide mapping of DC-SCRIPT binding and gene expression analyses revealed a key role for DC-SCRIPT in maintaining cDC1 identity via the direct regulation of cDC1 signature genes, including Irf8. Our study reveals DC-SCRIPT to be a critical component of the gene regulatory program shaping the functional attributes of cDC1s.

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RNA-seq analysis of mouse cDC1 and cDC2 populations upon DC-SCRIPT depletion

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RNA-seq and CUT&Tag analysis of mouse cDC1 and cDC2 populations upon DC-SCRIPT depletion

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RNA-seq profiling of wild type and Trim33-/- splenic dendritic cells

Project description:The homeostatic control mechanism of dendritic cells (DCs), including pDCs, cDC1s and cDC2s, is not fully elucidated. Transcriptome profiling of wildtype and TRIM33 conditional knockout mice revealed a key role of TRIM33 in maintaining the homeostasis of all DC subsets.

2024-06-01 | GSE193183 | 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.

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

Project description:Plasmacytoid dendritic cells (pDCs) develop from pre-pDCs, while two lineages of conventional DCs (cDC1s and cDC2s) develop from lineage-committed pre-cDCs. A number of transcription factors (TFs) have been implicated in regulating the development of pDCs (E2-2, Id2) and cDC1s (IRF8, Id2 and Batf3) however, those required for the early commitment of pre-cDCs towards the cDC2 lineage are unknown. Here we identified the TF Zinc finger E box binding homeobox 2 (Zeb2), to play a crucial role in regulating DC development. Zeb2 was expressed from the pre-pDC and pre-cDC stage onwards, and highly expressed in mature pDCs and cDC2s. Mice conditionally lacking Zeb2 in CD11c+ cells had a cell intrinsic reduction in pDCs and cDC2s, coupled with an increase in cDC1s. Conversely, mice in which CD11c+ cells overexpressed Zeb2 displayed a reduction in cDC1s. This was accompanied by altered expression of Id2, which was upregulated in cDC2s and pDCs from conditional knock-out mice. Zeb2 ChIP analysis revealed Id2 to be a direct target of Zeb2. Thus, we conclude that Zeb2 regulates commitment to both the cDC2 and pDC lineages through repression of Id2.

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Genome-wide screening identifies Trim33 as an essential regulator of dendritic cell differentiation [Hoxb8-FL ATAC-Seq]

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