Identification and characterization of the molecular pathways regulating the cell cycle-linked pluripotency exit

Résumé

The self-renewing nature of embryonic stem cells (ESCs) is a consequence of their ability to proliferate while maintaining pluripotency, by means the capacity to differentiate into all adult cell types. Despite the remarkable scientific advances in the knowledge regarding the mechanism(s) controlling pluripotency, little is known about how cell cycle is coordinated with self-renewal and differentiation. Here we have shown a segregation of pluripotency during cell cycle progression, being cells in S-G2/M more primed for cardiac lineage commitment. By characterizing the proteome dynamics during cell cycle, we have identified the DNA demethylation enzyme thymine DNA glycosylase (TDG) as the molecular determinant for cell cycle pluripotent dissociation. Our TDG ChIP-seq data suggests a functional link between TDG and TP53 by which TP53 transcriptional programs would prime S-G2/M cells for cardiomyocyte differentiation. With this study, we have enlightened the mechanisms underlying mouse ESC fate decisions control during cell cycle.