Polyamine metabolism regulates the T cell epigenome through hypusination [RNA-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. 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 lymphnode 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.