RT Journal Article
SR Electronic
T1 Polyamine metabolism regulates the T cell epigenome through hypusination
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.01.24.918094
DO 10.1101/2020.01.24.918094
A1 Daniel J. Puleston
A1 Francesc Baixauli
A1 David E. Sanin
A1 Matteo Villa
A1 Agnieszka Kabat
A1 Marcin M. Kamiński
A1 Hauke Weiss
A1 Katarzyna Grzes
A1 Lea Flachsmann
A1 Cameron S. Field
A1 Michal Stanckzak
A1 Lena Schimmelpfennig
A1 Fabian Hassler
A1 Chao Wang
A1 Nir Yosef
A1 Vijay K. Kuchroo
A1 Yaarub Musa
A1 Gerhard Mittler
A1 Joerg M. Buescher
A1 Stefan Balabanov
A1 Edward J. Pearce
A1 Douglas R. Green
A1 Erika L. Pearce
YR 2020
UL http://biorxiv.org/content/early/2020/01/25/2020.01.24.918094.abstract
AB 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.