Polyamine metabolism regulates the T cell epigenome through hypusination [ATAC-seq]

We report here a central role for polyamines in T cell differentiation and function. Deficiency in ornithine decarboxylase (ODC), a critical enzyme for polyamine synthesis, resulted in a profound failure of CD4+ T cells to adopt correct subset specification, underscored by ectopic expression of multiple cytokines and lineage- defining transcription factors across TH1, TH2, TH17, and Treg polarizing conditions, and enhanced colitogenic potential. T cells deficient in deoxyhypusine synthase (DHPS) or deoxyhypusine hydroxylase (DOHH), which sequentially utilize polyamines to generate hypusine, phenocopied Odc-deficient T cells, and mice in which T cells lacked Dhps or Dohh developed colitis. Polyamine-hypusine pathway enzyme deficiency caused widespread chromatin and transcriptional dysregulation accompanied by alterations in histone methylation, histone acetylation, and TCA cycle metabolites. Epigenetic modulation by 2-hydroxyglutarate, or histone acetyltransferase inhibition, restored CD4+ T cell subset specification. Thus, polyamine synthesis via hypusine is critical for maintaining the epigenome to focus TH cell subset fidelity. Overall design: Mice expressing Cre recombinase (CD4Cre) under the control of the CD4 promoter were crossed with Dohh flox/flox and Odc flox/flox mice. CD4 T cells were isolated from the spleen and lymph node of these animals and cultured in T helper subset polarizing conditions. The transcriptome and chromatin accessibility of 3-4 biological replicates per T cell subset in Cre- (WT) or Cre+ (KO) were analysed.