| dc.description.abstract | Reprograming of somatic cells into induced pluripotent stem cells (iPSC) by expressing Oct4, Sox2, Klf4, and c-Myc has paved the way for producing patient-specific pluripotent cells to treat inherited diseases, such as Duchenne muscular dystrophy. However, current reprogramming approach has some risks, such as viral transduction caused random integration of multiple pro-viral copies and low efficiency. Recently, it was shown that a small compound called valporic acid (VPA), a histone deacetylase (HDAC) inhibitor, could improve reprogramming efficiency. Our previous study had shown that VPA can enhance Oct4 promoter activity by targeting its proximal hormone response element (HRE), but the underlying mechanism is not clearly defined. In this study, we found that inhibition of HDACs might play a minor role in the VPA mediated activation of Oct4 promoter. We discovered that VPA activated Oct4 promoter through inducing the PI3K/Akt/mTOR signaling pathway. The proximal HRE of Oct4 promoter was targeted by several nuclear receptors and we found that VPA reversed the repressive effect of some NRs, such as TR2 (nuclear receptor subfamily 2, group C, member 1) and COUP-TFII (nuclear receptor subfamily 2, group F, member 2), but enhanced the inducing effect of other NRs, including PPARδ (peroxisome proliferator activator receptor delta). We concluded that VPA triggered PI3K/Akt/mTOR signaling plays critical role in activating Oct4 promoter activity during somatic reprogramming. | en_US |