BMAL1 coordinates energy metabolism and differentiation of pluripotent stem cells.

In spite of lacking circadian rhythms, several master clock regulators are readily expressed in embryonic stem cells (ESCs). In particular, the role of Brain and Muscle ARNT-Like 1 (Bmal1, also known as Arntl) remains to be addressed. Here, we generated Bmal1 CRISPR/cas9 knock-out ESCs to elucidate the role of BMAL1 in pluripotency maintenance and differentiation. Our findings indicate that although BMAL1 is dispensable for ESC maintenance, it is required for proper differentiation. Moreover, we find that Bmal1 participates in the transcriptional regulation of lineage specification programs during differentiation and gastrulation in vitro. In particular, loss-of-function of Bmal1 changes the metabolic state of ESCs by promoting more oxidation at the expense of glycolysis. Our data points to a circadian clock-independent function of BMAL1 during early developmental stages, and will help in the understanding of the mechanisms that control exit from pluripotency and early cell-fate decisions. RNA profiling of Mouse Embryonic Stem Cells Wild type and KO (CRISPR-Cas9) for Bmal1 (Arntl) gene.