Metabolic control of innate immune activation in TET2-mutant clonal hematopoiesis
TET2 mutations drive inflammation in clonal hematopoiesis of indeterminate potential (CHIP), but the mechanism by which TET2 inactivation leads to inflammation is not understood. Here, we used in vivo genome-wide genetic perturbations in primary wildtype (WT) or Tet2 knockout (KO) Cas9+ hematopoietic stem-progenitor cells (HSPCs) in a model of zymosan peritonitis to elucidate the basis of Tet2 KO inflammation. We found that Tet2 restrains O-linked N-acetylglucosamine (O-GlcNAc) glycosyltransferase (Ogt), a Tet2 binding partner and metabolic sensor that integrates nutrient availability. Tet2 loss disrupts this Tet2-Ogt interaction, and dysregulated Ogt facilitates widespread H3K4 trimethylation including lipid-related gene loci and inflammatory lipid droplet formation. We identified ATP citrate lyase (Acly) as a critical node for lipid accumulation, inflammation, and myeloid expansion in Tet2 deficiency. In summary, we reveal that Tet2 serves as a negative regulator of the nutrient sensor Ogt, and that Tet2 inactivation leads to aberrant lipid droplet formation and inflammation. Overall design: RNAseq profiling from various sources including monocytes via single cell RNAseq and bone marrow derived macrophages exposed to various conditions.