DOT1L regulates lipid biosynthesis and inflammatory responses in macrophages and promotes atherosclerotic plaque stability.

Cell reports 2022 Nov 22

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Macrophages are critical immune cells in inflammatory diseases, and their differentiation and function are tightly regulated by histone modifications. H3K79 methylation is a histone modification associated with active gene expression, and DOT1L is the only histone methyltransferase for H3K79. Here we determine the role of DOT1L in macrophages by applying a selective DOT1L inhibitor in mouse and human macrophages and using myeloid-specific Dot1l-deficient mice. We found that DOT1L directly regulates macrophage function by controlling lipid biosynthesis gene programs including central lipid regulators like sterol regulatory element-binding proteins SREBP1 and SREBP2. DOT1L inhibition also leads to macrophage hyperactivation, which is associated with disrupted SREBP pathways. In vivo, myeloid Dot1l deficiency reduces atherosclerotic plaque stability and increases the activation of inflammatory plaque macrophages. Our data show that DOT1L is a crucial regulator of macrophage inflammatory responses and lipid regulatory pathways and suggest a high relevance of H3K79 methylation in inflammatory disease. Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

Lisa Willemsen, Koen H M Prange, Annette E Neele, Cindy P A A van Roomen, Marion Gijbels, Guillermo R Griffith, Myrthe den Toom, Linda Beckers, Ricky Siebeler, Nathanael J Spann, Hung-Jen Chen, Laura A Bosmans, Andrej Gorbatenko, Suzanne van Wouw, Noam Zelcer, Heinz Jacobs, Fred van Leeuwen, Menno P J de Winther. DOT1L regulates lipid biosynthesis and inflammatory responses in macrophages and promotes atherosclerotic plaque stability. Cell reports. 2022 Nov 22;41(8):111703