Metabolic control of innate immune activation in TET2-mutant clonal hematopoiesis

Somatic mutations in TET2 drive hyper-inflammation in clonal hematopoiesis of indeterminate potential (CHIP), but the molecular link between TET2 inactivation and myeloid immune activation remains unclear. We used in vivo genome-wide genetic perturbations enabled by ultra-diverse barcoding in primary wild-type (WT) or Tet2 knockout (KO) Cas9⁺ hematopoietic stem-progenitor cells (HSPCs) to elucidate the basis of Tet2 KO inflammation. We uncover a metabolic circuit by which Tet2 restrains O-linked N-acetylglucosamine (O-GlcNAc) glycosyltransferase (Ogt), a Tet2 binding partner and metabolic sensor. Tet2 loss disrupts this inhibitory Tet2-Ogt interaction, and dysregulated Ogt facilitates widespread H3K4 trimethylation including lipid-related gene loci and inflammatory lipid droplet formation. We identified that ATP citrate lyase (Acly) is decorated with O-GlcNAc and is a critical node for lipid accumulation and inflammation in Tet2 KO. These findings reveal that Tet2 suppresses inflammation by gating nutrient-responsive chromatin remodeling and nominate metabolic interventions to restrain inflammatory disease in TET2-mutant clonal hematopoiesis.