L-Proline Induces a Mesenchymal-like Invasive Program in Embryonic Stem Cells by Remodeling H3K9 and H3K36 Methylation

SummaryMetabolites 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

Metabolic alterations in a murine model of Barth syndrome

Barth syndrome (BTHS) is a rare monogenic disease characterized by cardiomyopathy, skeletal myopathy and neutropenia, caused by mutations in the Xq28 locus. Mutations in the locus result in the loss of function of the Tafazzin protein (Taz), a transacylase responsible for the final step in the production of mature cardiolipin (CL). CL is a fundamental component of the inner mitochondrial membrane, where it cooperates in the maintenance of membrane stability and in various cellular processes such as mitochondrial respiration, autophagy and reactive oxygen species sensing. Using a novel murine model of BTHS, we investigated the mitochondrial phenotype, the metabolic signature and the gene expression profile in the heart of Taz knockout (KO) mice. We identified extensive heart-specific changes in the structure and composition of the mitochondria accompanied by alterations of the metabolome and gene expression. The alterations are specific to the adult, so probably derive from a developmental process happening after birth. The alteration of the gene expression seems to indicate activation of the unfolded protein response, suggesting an effect of stress response pathways in the cellular processes which underlie Barth syndrome