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Molecular and Cellular Biology, June 2007, p. 4374-4387, Vol. 27, No. 12
0270-7306/07/$08.00+0     doi:10.1128/MCB.02020-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

NF-B Regulation of YY1 Inhibits Skeletal Myogenesis through Transcriptional Silencing of Myofibrillar Genes ^,

Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics,¹ Integrated Biomedical Graduate Program,² Molecular, Cellular, and Developmental Biology Graduate Program,³ The Arthur G. James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210⁴

Received 27 October 2006/ Returned for modification 11 December 2006/ Accepted 20 March 2007

NF-B signaling is implicated as an important regulator of skeletal muscle homeostasis, but the mechanisms by which this transcription factor contributes to muscle maturation and turnover remain unclear. To gain insight into these mechanisms, gene expression profiling was examined in C2C12 myoblasts devoid of NF-B activity. Interestingly, even in proliferating myoblasts, the absence of NF-B caused the pronounced induction of several myofibrillar genes, suggesting that NF-B functions as a negative regulator of late-stage muscle differentiation. Although several myofibrillar promoters contain predicted NF-B binding sites, functional analysis using the troponin-I2 gene as a model revealed that NF-B-mediated repression does not occur through direct DNA binding. In the search for an indirect mediator, the transcriptional repressor YinYang1 (YY1) was identified. While inducers of NF-B stimulated YY1 expression in multiple cell types, genetic ablation of the RelA/p65 subunit of NF-B in both cultured cells and adult skeletal muscle correlated with reduced YY1 transcripts and protein. NF-B regulation of YY1 occurred at the transcriptional level, mediated by direct binding of the p50/p65 heterodimer complex to the YY1 promoter. Furthermore, YY1 was found associated with multiple myofibrillar promoters in C2C12 myoblasts containing NF-B activity. Based on these results, we propose that NF-B regulation of YY1 and transcriptional silencing of myofibrillar genes represent a new mechanism by which NF-B functions in myoblasts to modulate skeletal muscle differentiation.

Published ahead of print on 16 April 2007.

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