Taglietti Valentina, Maroli Giovanni, Cermenati Solei, Monteverde Stefania, Ferrante Andrea, Rossi Giuliana, Cossu Giulio, Beltrame Monica, Messina Graziella
Department of Biosciences, University of Milan, Milan 20133, Italy.
Department of Biosciences, University of Milan, Milan 20133, Italy; Division of Cell Matrix Biology and Regenerative Medicine, University of Manchester, Oxford Road, M13 9PL Manchester, UK.
Cell Rep. 2016 Nov 22;17(9):2354-2366. doi: 10.1016/j.celrep.2016.10.082.
Sox6 belongs to the Sox gene family and plays a pivotal role in fiber type differentiation, suppressing transcription of slow-fiber-specific genes during fetal development. Here, we show that Sox6 plays opposite roles in MyHC-I regulation, acting as a positive and negative regulator of MyHC-I expression during embryonic and fetal myogenesis, respectively. During embryonic myogenesis, Sox6 positively regulates MyHC-I via transcriptional activation of Mef2C, whereas during fetal myogenesis, Sox6 requires and cooperates with the transcription factor Nfix in repressing MyHC-I expression. Mechanistically, Nfix is necessary for Sox6 binding to the MyHC-I promoter and thus for Sox6 repressive function, revealing a key role for Nfix in driving Sox6 activity. This feature is evolutionarily conserved, since the orthologs Nfixa and Sox6 contribute to repression of the slow-twitch phenotype in zebrafish embryos. These data demonstrate functional cooperation between Sox6 and Nfix in regulating MyHC-I expression during prenatal muscle development.
Sox6属于Sox基因家族，在纤维类型分化中起关键作用，在胎儿发育过程中抑制慢纤维特异性基因的转录。在此，我们表明Sox6在MyHC-I调节中发挥相反作用，在胚胎和胎儿肌生成过程中分别作为MyHC-I表达的正向和负向调节因子。在胚胎肌生成过程中，Sox6通过Mef2C的转录激活正向调节MyHC-I，而在胎儿肌生成过程中，Sox6需要转录因子Nfix并与其合作来抑制MyHC-I表达。从机制上讲，Nfix是Sox6与MyHC-I启动子结合所必需的，因此也是Sox6抑制功能所必需的，这揭示了Nfix在驱动Sox6活性中的关键作用。这一特征在进化上是保守的，因为直系同源基因Nfixa和Sox6有助于斑马鱼胚胎中慢肌表型的抑制。这些数据证明了Sox6和Nfix在产前肌肉发育过程中调节MyHC-I表达的功能合作。
