SummaryThe protein level of OCT4, a core pluripotency transcription factor, is vital for embryonic stem cell (ESC) maintenance, differentiation, and somatic cell reprogramming. However, how OCT4 protein levels are controlled during reprogramming remains largely unknown. Here, we identify ubiquitin conjugation sites of OCT4 and report that disruption of WWP2-catalyzed OCT4 ubiquitination or ablation of Wwp2 significantly promotes the efficiency of pluripotency induction from mouse embryonic fibroblasts. Mechanistically, disruption of WWP2-mediated OCT4 ubiquitination elevates OCT4 protein stability and H3K4 methylation level during the reprogramming process. Furthermore, we reveal that OCT4 directly activates expression of Ash2l-b, and that ASH2L-B is a major isoform of ASH2L highly expressed in ESCs and required for somatic cell reprogramming. Together, this study emphasizes the importance of ubiquitination manipulation of the reprogramming factor and its interplay with the epigenetic regulator for successful reprogramming, opening a new avenue to improve the efficiency of pluripotency induction.

Atherosclerosis (AS) is a cardiovascular disease with a relatively high incidence rate. Krüppel-like factor 15 (KLF15) has a role in numerous pathological processes, including nephropathy, abnormal glucose metabolism and myocardial injury. The aim of the present study was to investigate the function of KLF15 in vascular endothelial dysfunction. MTT analyses, nitric oxide (NO) detection and cell adhesion detection kits were used to investigate the viability and adhesion of, and quantity of NO released by Eahy926 cells induced by tumor necrosis factor (TNF)-α, respectively. Reverse transcription-quantitative polymerase chain reaction and western blot analyses were performed to determine the expression levels of KLF15, endothelial nitric oxide synthase, monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), transforming growth factor-β1 (TGF-β1), phosphorylated (p-)transcription factor p65 (p65) and nuclear factor erythroid 2-related factor 2 (Nrf2). The results of the present study demonstrated that TNF-α was able to induce vascular endothelial dysfunction in Eahy926 cells at an optimum concentration of 10 ng/ml. Overexpression of KLF15 markedly enhanced cell viability in addition to the quantity of released NO of TNF-α-induced Eahy926 cells, and increased the expression levels of eNOS and Nrf2. Furthermore, overexpression of KLF15 markedly suppressed the rate of cellular adhesion, and downregulated levels of MCP-1, ICAM-1, TGF-β1 and p-p65 in TNF-α induced Eahy926 cells. In conclusion, the results of the present study suggested that overexpression of KLF15 in Eahy926 cells exhibited a protective effect against TNF-α induced dysfunction via activation of Nrf2 signaling and inhibition of nuclear factor κB signaling.

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