Cross Talk between One-Carbon Metabolism, Eph Signaling, and Histone Methylation Promotes Neural Stem Cell Differentiation

• Published in: Cell reports (Cambridge) Vol. 23; no. 10; pp. 2864 - 2873.e7
• Main Authors: Fawal, Mohamad-Ali, Jungas, Thomas, Kischel, Anthony, Audouard, Christophe, Iacovoni, Jason S., Davy, Alice
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.06.2018
• Subjects: Development Biology; differentiation; ephrin; folate; histone methylation; Life Sciences; neocortex development; neural progenitors; one-carbon metabolism; stem cells; histone methylation; stem cells; folate; differentiation; neural progenitors; neocortex development; one-carbon metabolism; ephrin
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2018.05.005

Metabolic pathways, once seen as a mere consequence of cell states, have emerged as active players in dictating different cellular events such as proliferation, self-renewal, and differentiation. Several studies have reported a role for folate-dependent one-carbon (1C) metabolism in stem cells; however, its exact mode of action and how it interacts with other cues are largely unknown. Here, we report a link between the Eph:ephrin cell-cell communication pathway and 1C metabolism in controlling neural stem cell differentiation. Transcriptional and functional analyses following ephrin stimulation revealed alterations in folate metabolism-related genes and enzymatic activity. In vitro and in vivo data indicate that Eph-B forward signaling alters the methylation state of H3K4 by regulating 1C metabolism and locks neural stem cell in a differentiation-ready state. Our study highlights a functional link between cell-cell communication, metabolism, and epigenomic remodeling in the control of stem cell self-renewal. [Display omitted] •Description of Eph-B transcriptional response in neural stem cells•Eph activation decreases the expression and activity of DHFR•Inhibition of DHFR decreases H3K4 methylation and impairs self-renewal of NSCs•Decreased H3K4 methylation locks NSCs in a pro-differentiation state Fawal et al. present evidence that Eph-B forward signaling inhibits 1C folate metabolism in neural stem cells, leading to differentiation and alteration of H3K4 methylation on progenitor genes. In addition, they show that these epigenomic changes are maintained long term and that NSCs are locked into a differentiation-ready state following Eph-B receptor activation.