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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE298064 | GEO | 2026/01/15

REPOSITORIES: GEO

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Metabolic control of innate immune activation in TET2-mutant clonal hematopoiesis [ChIP-seq]

Project description: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.

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