Project description:Dendritic cells (DCs) are important orchestrators of immune responses and can be divided into two conventional DC subsets, cDC1s and cDC2s, and a plasmacytoid DC (pDC) subset, which are involved in the activation of T cells and production of type I interferons (IFNs), respectively. The development of the DC subsets occurs in the bone marrow (BM) under control of different transcription factors and epigenetic modifiers. The histone methyltransferase DOT1L, known as a druggable target in cancer, is emerging as a key epigenetic regulator of differentiation in lymphocytes. DOT1L writes methylation of lysine 79 of histone H3 in gene bodies of actively transcribed genes. Deletion or inhibition of DOT1L affects the differentiation trajectory of innate and adaptive immune cells, leading to altered cell states. Recent studies suggest that DOT1L also plays a role in DC function. Here, we investigated the role of DOT1L in the development of DCs in in vitro BM cultures and in vivo using a tamoxifen-inducible mouse model. H3K79me2 ChIPseq data of sorted DC subsets from the BM revealed distinct H3K79me2 peaks for all three subsets, which suggested differential regulation of the subsets by DOT1L. A comparison of the H3K79me2 ChIPseq data to bulk RNAseq of sorted DC subsets from the BM revealed a stronger correlation between H3K79me2 and global transcription in pDCs and cDC2s compared to cDC1s. In line with this, we observed that Dot1l deletion led to a decrease in pDCs and CpG A-stimulated IFNα production and an increase in cDC2s in in vitro BM cultures, while cDC1s were unchanged. In vivo deletion of Dot1l led to a decrease in common myeloid progenitors (CMPs), monocyte DC progenitors (MDPs), and common DC progenitors (CDPs) in the BM, while common lymphoid progenitor (CLP) and cDC2 numbers were increased. Inhibition of DOT1L resulted in a similar phenotype, which linked the observed effects to the methyltransferase activity of DOT1L. Interestingly, all Dot1l-KO DC subsets exhibited an enrichment of pathways related to antigen presentation and the immune response and MHCII expression was upregulated in Dot1l-KO pDCs and cDC2s in vivo. To conclude, our data indicate that DOT1L function differentially affects the development of DCs with predominant effects in pDCs and cDC2s.

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Mitochondrial metabolism regulates the immunogenic responsiveness of dendritic cells

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