GSE124920
Prmt1 safeguards mouse embryonic stem cells against bias toward the extraembryonic endoderm cell fate via arginine methylation of Klf4
Heterogeneous gene expression is a characteristic feature of stem cells and is essential for steering lineage choices. However, the molecular mechanisms of heterogeneity remain largely unknown. Here, we report that depletion of protein arginine methyltransferase 1 (Prmt1) in mouse embryonic stem (ES) cells heterogeneously induces the expression of primitive endoderm (PrE) genes, consequently biasing the cells to fluctuate toward the extraembryonic endoderm stem (XEN) cell fate. Furthermore, the pluripotency factor Klf4 is arginine-methylated by Prmt1 at arginine 396 (R396), which is required for recruitment of the mSin3a/HDAC complex to silence PrE genes. Importantly, when methylation is disrupted by a Prmt1 knockout, a Prmt1 inhibitor, or a blocked methylation site in Klf4, ES cells are predisposed to XEN induction. Our data demonstrate the importance of Prmt1 in the fluctuating heterogeneity of ES cells and reveal a regulatory mechanism for cell fate decisions that is centered on Klf4 methylation mediated by Prmt1. Overall design: Examination the transcriptomes of WT mouse ES cells (as a control) and Prmt1 KO cells, generated by RNA-seq and 10X genomics singel cell RNA seq.