title: L-Proline induces a mesenchymal-like invasive program in embryonic stem cells by remodeling H3K9 and H3K36 methylation.
abstract: 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.
authors: Stem Cell Fate Laboratory, Institute of Genetics and Biophysics "A. Buzzati-Traverso," CNR, 80131 Naples, Italy ; Institute of Genetics and Biophysics "A. Buzzati-Traverso," CNR, 80131 Naples, Italy.
authors: Stefania
authors: S
authors: Comes
authors: Miriam
authors: M
authors: Gagliardi
authors: Nicola
authors: N
authors: Laprano
authors: Annalisa
authors: A
authors: Fico
authors: Amelia
authors: A
authors: Cimmino
authors: Andrea
authors: A
authors: Palamidessi
authors: Dario
authors: D
authors: De Cesare
authors: Sandro
authors: S
authors: De Falco
authors: Claudia
authors: C
authors: Angelini
authors: Giorgio
authors: G
authors: Scita
authors: Eduardo J
authors: EJ
authors: Patriarca
authors: Maria R
authors: MR
authors: Matarazzo
authors: Gabriella
authors: G
authors: Minchiotti
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D002465:Cell Movement; D060833:Cellular Microenvironment; D003599:Cytoskeleton / Q000648:ultrastructure; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects*; D006657:Histones / Q000378:metabolism*; D008648:Mesoderm / Q000166:cytology; D008745:Methylation; D051379:Mice; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D011392:Proline / Q000494:pharmacology*; D015398:Signal Transduction; D059467:Transcriptome
chemical_list: D006657:Histones; D011392:Proline