One-carbon metabolites control cellular identity [scRNA-seq]

Metabolomic analyses reveal the specific array of metabolites present in a cell type or tissue at any given time. Multiple lines of evidence indicate that metabolites provide a readout of ongoing cellular functions, and changes in the metabolome correlate with specific biological processes1–4 as seen, for instance, during cellular differentiation. These changes are potentially associated with the regulation of signaling pathways and gene expression networks that are critical to alter cellular identity5–7. However, it is less clear whether specific metabolites or metabolic pathways can drive changes in cellular identity. To identify metabolites engaged with cell state transitions, we performed metabolomic analyses at the earliest stages of cellular differentiation and uncovered metabolites transiently upregulated just as the first transcriptional changes emerged. Specifically, we observed a wave of one-carbon metabolism conserved between three different multipotent stem cell types. Treatment of fully differentiated cells with these metabolites caused the loss of mature identity and transition toward progenitor-like states, thus demonstrating that the metabolome plays a causative role in initiating and modulating cell fate. Our studies reveal a metabolic intervention that can reprogram cellular phenotypes and could potentially be applied in regenerative medicine applications Single cell RNA sequencing of three primary cell lines including neural stem cells(NSCs),astrocytes and MIM-treated astrocytes.