L-proline induces a mesenchymal-like invasive program in embryonic stem cells by remodeling H3K9 and H3K36 methylation

Stefania Comes, Miriam Gagliardi, Nicola Laprano, Annalisa Fico, Amelia Cimmino, Andrea Palamidessi, Dario De Cesare, Sandro De Falco, Claudia Angelini, Giorgio Scita, Eduardo J. Patriarca, Maria R. Matarazzo, Gabriella Minchiotti

Research output: Contribution to journalArticlepeer-review

Abstract

Summary Metabolites are emerging as key mediators of crosstalk between metabolic flux, cellular signaling, and epigenetic regulation of cell fate. We found that the nonessential amino acid L-proline (L-Pro) acts as a signaling molecule that promotes the conversion of embryonic stem cells into mesenchymal-like, spindle-shaped, highly motile, invasive pluripotent stem cells. This embryonic-stem-cell-to-mesenchymal-like transition (esMT) is accompanied by a genome-wide remodeling of the H3K9 and H3K36 methylation status. Consistently, L-Pro-induced esMT is fully reversible either after L-Pro withdrawal or by addition of ascorbic acid (vitamin C), which in turn reduces H3K9 and H3K36 methylation, promoting a mesenchymal-like-to-embryonic-stem-cell transition (MesT). These findings suggest that L-Pro, which is produced by proteolytic remodeling of the extracellular matrix, may act as a microenvironmental cue to control stem cell behavior.

Original languageEnglish
Pages (from-to)307-321
Number of pages15
JournalStem Cell Reports
Volume1
Issue number4
DOIs
Publication statusPublished - Oct 15 2013

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Developmental Biology
  • Genetics

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