Polyamine Metabolism Regulates the T Cell Epigenome Through Hypusination

Puleston, D. J.; Baixauli, F.; Sanin, D. E.; Villa, M.; Kabat, A.; Kaminski, M. M.; Weiss, H.; Grzes, K.; Flachsmann, L. J.; Field, C. S.; Stanckzak, M.; Schimmelpfennig, L.; Hassler, F.; Wang, C.; Yosef, N.; Kuchroo, V. K.; Musa, Y.; Mittler, G.; Buescher, J. M.; Balabanov, S.; Pearce, E. J.; Green, D. R.; Pearce, E. L.

doi:10.1101/2020.01.24.918094

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bioRxiv · 10.1101/2020.01.24.918094

Polyamine Metabolism Regulates the T Cell Epigenome Through Hypusination

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Abstract

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.

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Puleston, D. J., Baixauli, F., Sanin, D. E., Villa, M., Kabat, A., Kaminski, M. M., Weiss, H., Grzes, K., Flachsmann, L. J., Field, C. S., Stanckzak, M., Schimmelpfennig, L., Hassler, F., Wang, C., Yosef, N., Kuchroo, V. K., Musa, Y., Mittler, G., Buescher, J. M., Balabanov, S., Pearce, E. J., Green, D. R., Pearce, E. L.. 2020-01-25. Polyamine Metabolism Regulates the T Cell Epigenome Through Hypusination. https://doi.org/10.1101/2020.01.24.918094

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