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Am J Physiol Cell Physiol 297: C43-C54, 2009. First published April 29, 2009; doi:10.1152/ajpcell.00468.2008
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GROWTH, DIFFERENTIATION, AND APOPTOSIS

Simultaneous overexpression of Oct4 and Nanog abrogates terminal myogenesis

Kuan Chih Lang,1,* I. Hsuan Lin,1,* Han Fang Teng,1 Yi Cheng Huang,1 Chung Leung Li,2 Kam Tsun Tang,3 and Shen Liang Chen1

1Department of Life Sciences, National Central University, Jhongli, Taiwan; 2Institute of Cellular and Organismic Biology/Genomics Research Center, Academia Sinica, Taipei, Taiwan; and 3Department of Metabolism and Endocrinology, Taipei Veterans General Hospital, Taipei, Taiwan

Submitted 12 September 2008 ; accepted in final form 24 April 2009

Oct4 and Nanog are two embryonic stem (ES) cell-specific transcription factors that play critical roles in the maintenance of ES cell pluripotency. In this study, we investigated the effects of Oct4 and Nanog expression on the differentiation state of myogenic cells, which is sustained by a strong positive feedback loop. Oct4 and Nanog, either independently or simultaneously, were overexpressed in C2C12 myoblasts, and the expression of myogenic lineage-specific genes and terminal differentiation was observed by RT-PCR. Overexpression of Oct4 in C2C12 cultures repressed, while exogenous Nanog did not significantly alter C2C12 terminal differentiation. The expression of Pax7 was reduced in all Oct4-overexpressing myoblasts, and we identified a major Oct4-binding site in the Pax7 promoter. Simultaneous expression of Oct4 and Nanog in myoblasts inhibited the formation of myotubes, concomitant with a reduction in the endogenous levels of hallmark myogenic markers. Furthermore, overexpression of Oct4 and Nanog induced the expression of their endogenous counterparts along with the expression of Sox2. Using mammalian two-hybrid assays, we confirmed that Oct4 functions as a transcriptional repressor whereas Nanog functions as a transcriptional activator during muscle terminal differentiation. Importantly, in nonobese diabetic (NOD) severe combined immunodeficiency (SCID) mice, the pluripotency of C2C12 cells was conferred by overexpression of Oct4 and Nanog. These results suggest that Oct4 in cooperation with Nanog strongly suppresses the myogenic differentiation program and promotes pluripotency in myoblasts.

Pax7; pluripotency; differentiation; stem cell


Address for reprint requests and other correspondence: S. L. Chen, Dept. of Life Sciences, National Central University, 300 Jhongda Rd., Jhongli 32054, Taiwan, ROC (e-mail: slchen{at}cc.ncu.edu.tw)






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