Transdifferentiation Requires iNOS Activation

• DOI: 10.1161/circresaha.116.308263
• Publication Date: 2016-09-14T02:49:28Z
• Authors: Shu Meng; Gang Zhou; Qilin Gu; Palas K. Chanda; Frank Ospino; John P. Cooke
• Keywords: Transdifferentiation

We have previously shown that innate immunity is necessary for transdifferentiation of fibroblasts to endothelial cells. A major signaling molecule involved in inducible nitric oxide synthase (iNOS). Accordingly, we hypothesized iNOS-generated (NO) might enhance transdifferentiation.To elucidate the role NO epigenetic plasticity during transdifferentiation.We exposed BJ formulation included growth factors and immune activator polyinosinic:polycytidylic acid induce Generation transdifferentiated cells was associated with iNOS expression elaboration. In absence acid, or presence antagonists NFκB (nuclear factor kappa B) activity, synthesis cell generation reduced. Furthermore, genetic knockout (in murine embryonic fibroblasts) siRNA knockdown nearly abolished transdifferentiation, an effect could be reversed by overexpression. Notably, induced nuclear localization iNOS, its binding to, nitrosylation of, modifier ring finger protein 1A (RING1A) as assessed immunostaining, Co-IP, mass spectrometry. Nitrosylation RING1A reduced chromatin global levels repressive histone marker H3K27 trimethylation. Overexpression a mutant form (C398A) lacking site almost abrogated transdifferentiation.Overall, our data indicate activation increases S-nitrosylate RING1A, key member polycomb complex. reduces decreases trimethylation level. The release repression critical effective transdifferentiation.