GSE183043
Histone methyltransferase DOT1L regulates macrophage lipid biosynthesis and inflammatory responses and affects atherosclerotic plaque stability [ChIP-seq]
Macrophages are critical immune cells in inflammatory diseases and their differentiation and function are tightly regulated by epigenetic alterations. H3K79 methylation is an epigenetic 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 suggests a high relevance of H3K79 methylation in inflammatory disease. Overall design: In total, 7 samples were analyzed (3 biological replicates of SGC0946 treated BMDMs, 3 biological replicates of DMSO (control) treated BMDMs, and 1 BMDM input sample)