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In mammals, circadian rhythmicity is sustained via a transcriptional/translational feedback loop referred to as the canonical molecular circadian clock. Circadian rhythm is absent in undifferentiated embryonic stem cells; it begins only after differentiation. We used pluripotent P19 embryonal carcinoma stem cells to check the biological clock before and after differentiation into neurons using retinoic acid. We show that the central clock genes  ARNTL (Bmal), Per2  and  Per3 , and the peripheral clock genes  Rev-erb-α  and  ROR-α , oscillate before and after differentiation, as does the expression of the neuronal differentiation markers  Hes5 , β-3-tubulin (Tubb3) and  Stra13 , but not  Neurod1 . Furthermore, the known clock-modulating compounds ERK, EGFR, Pi3K, p38, DNA methylation and Sirtiun inhibitors, in addition to  Rev-erb-α  ligands, modulate the expression of central and peripheral clock genes. Interestingly Sirtinol, Sirt1 and Sirt2 inhibitors had the greatest significant effect on the expression of clock genes, and increased  Hes5  and  Tubb3  expression during neuronal differentiation. Our findings reveal a new frontier of circadian clock research in stem cells: contrary to what has been published previously, we have shown the clock to be functional and to oscillate, even in undifferentiated stem cells. Modulating the expression of clock genes using small molecules could affect stem cell differentiation.

P19 Cells as a Model for Studying the Circadian Clock in Stem Cells before and after Cell Differentiation