NF-κB regulation of YY1 inhibits skeletal myogenesis through transcriptional silencing of myofibrillar genes

Huating Wang, Erin Hertlein, Nadine Bakkar, Hao Sun, Swarnali Acharyya, Jingxin Wang, Micheal Carathers, Ramana Davuluri, Denis C. Guttridge*

*Corresponding author for this work

Research output: Contribution to journalArticle

181 Scopus citations

Abstract

NF-κB 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-κB activity. Interestingly, even in proliferating myoblasts, the absence of NF-κB caused the pronounced induction of several myofibrillar genes, suggesting that NF-κB functions as a negative regulator of late-stage muscle differentiation. Although several myofibrillar promoters contain predicted NF-κB binding sites, functional analysis using the troponin-12 gene as a model revealed that NF-κB-mediated repression does not occur through direct DNA binding. In the search for an indirect mediator, the transcriptional repressor YinYang 1 (YY1) was identified. While inducers of NF-κB stimulated YY1 expression in multiple cell types, genetic ablation of the RelA/p65 subunit of NF-κB in both cultured cells and adult skeletal muscle correlated with reduced YY1 transcripts and protein. NF-κB 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-κB activity. Based on these results, we propose that NF-κB regulation of YY1 and transcriptional silencing of myofibrillar genes represent a new mechanism by which NF-κB functions in myoblasts to modulate skeletal muscle differentiation.

Original languageEnglish (US)
Pages (from-to)4374-4387
Number of pages14
JournalMolecular and cellular biology
Volume27
Issue number12
DOIs
StatePublished - Jun 2007

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Wang, H., Hertlein, E., Bakkar, N., Sun, H., Acharyya, S., Wang, J., Carathers, M., Davuluri, R., & Guttridge, D. C. (2007). NF-κB regulation of YY1 inhibits skeletal myogenesis through transcriptional silencing of myofibrillar genes. Molecular and cellular biology, 27(12), 4374-4387. https://doi.org/10.1128/MCB.02020-06