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bioRxiv · 10.1101/2025.09.05.674429

Histone methyltransferase DOT1L differentially affects the development of dendritic cell subsets

Bouma, R. G.·de Leeuw, W.-J.·Wang, A. Z.·Malik, M.·Stolwijk, J. G.·Konijn, V. A.·Mensink, A.·Proost, N.·Nijen Twilhaar, M. K.·van Welsem, T.·Seyed Toutounchi, N.·Affandi, A. J.·van Dinter, J. T.·van Leeuwen, F.·den Haan, J. M.
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Abstract

Dendritic cells (DCs) are important orchestrators of immune responses. Their development in the bone marrow is controlled by transcription factors, but epigenetic mechanisms remain poorly understood. DOT1L is emerging as a key epigenetic regulator in immune cells. By mapping DOT1L-mediated histone H3K79 methylation in canonical DC subsets, we observed that DOT1L modified common as well as DC subset-specific genes. In vitro- or in vivo-induced deletion of Dot1l followed by in vitro cell culture resulted in a decrease in myeloid progenitors and plasmacytoid DCs (pDCs) and an increase in cDC2s, while cDC1s remained unchanged. In vitro generated Dot1l-KO DCs were unable to produce IFN upon stimulation. Moreover, transcriptomes of Dot1l-KO DC subsets exhibited enrichment of antigen presentation pathways and MHC class II surface levels were upregulated in pDCs. Mechanistically, inhibition of DOT1L linked the observed effects to its methyltransferase activity. Together, our data indicate that in DCs DOT1L differentially affects the development of canonical subsets and suppresses antigen presentation pathways.

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Bouma, R. G., de Leeuw, W.-J., Wang, A. Z., Malik, M., Stolwijk, J. G., Konijn, V. A., Mensink, A., Proost, N., Nijen Twilhaar, M. K., van Welsem, T., Seyed Toutounchi, N., Affandi, A. J., van Dinter, J. T., van Leeuwen, F., den Haan, J. M.. 2025-09-07. Histone methyltransferase DOT1L differentially affects the development of dendritic cell subsets. https://doi.org/10.1101/2025.09.05.674429

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