Sirtuin 1 is involved in the generation of induced pluripotent stem cells

Abstract

Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSC) by forced-expression of 4 transcription factors. Recent studies show that the reprogramming efficiency can be improved by inclusion of small molecules that modulate epigenetic enzyme activities. We report here that sirtuin 1 (SIRT1), a member of the sirtuin family of NAD+-dependent protein deacetylases, is involved in iPSC formation. Our data indicated that Sirt1 protein levels in human and mouse embryonic stem cells (ESCs) decreased upon differentiation, while that of mouse fibroblasts increased during reprogramming. By using an efficient mouse fibroblasts reprogramming system using doxycycline (DOX) inducible Yamanaka’s transcription factors delivered by piggyBac (PB) transposition, we further showed that Sirt1 was involved in reprogramming. Suppression of Sirt1 level decreased the efficiency of iPSC formation and increased the level of acetylated p53, a known substrate of Sirt1, during reprogramming. Conversely, resveratrol (RSV), an activator of Sirt1, increased the efficiency of iPSC formation. Consistently, the stimulatory activity of RSV on Sirt1 was associated with a reduction of acetylated p53. Furthermore, RSV and Sirt1 siRNA were applied at different periods during reprogramming. They were most effective in influencing the number of iPSC colonies formation in the initiation phase of reprogramming. The results in this study provide support on the possible use of epigenetic regulatory molecules in improving the efficiency of iPSC production.