biostudies-literatureKim PGNCI NIH HHS183-197.e9https://www.ebi.ac.uk/biostudies/studies/S-EPMC12933725biostudies-literatureUnknown33(2)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 dropletCell chemical biologyMetabolic control of innate immune activation in TET2-mutant clonal hematopoiesis.PMC12933725P01 CA066996R35 CA253125Roy Burman SSVander Heiden MGMiller APEbert BLBullock KPark PBoileau MYue HDeik ATrinh MNArmstrong SAYoon HClish CHergott CBPierce KARutter JCChoy AHRyback BAMcConkey MLoke JShin WKim PGFischer ESfalseMetabolic 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 droplet2026-01-01T00:00:00Z2026 Feb2026-07-16T20:47:46.518Z2026-07-10T03:12:56.63ZS-EPMC129337254167206610.1016/j.chembiol.2026.01.006