Program in Developmental Biology, Sloan Kettering Institute, New York, New York, United States of America.
PLoS Genet. 2012;8(3):e1002547. doi: 10.1371/journal.pgen.1002547. Epub 2012 Mar 1.
The activities of developmentally critical transcription factors are regulated via interactions with cofactors. Such interactions influence transcription factor activity either directly through protein-protein interactions or indirectly by altering the local chromatin environment. Using a yeast double-interaction screen, we identified a highly conserved nuclear protein, Akirin, as a novel cofactor of the key Drosophila melanogaster mesoderm and muscle transcription factor Twist. We find that Akirin interacts genetically and physically with Twist to facilitate expression of some, but not all, Twist-regulated genes during embryonic myogenesis. akirin mutant embryos have muscle defects consistent with altered regulation of a subset of Twist-regulated genes. To regulate transcription, Akirin colocalizes and genetically interacts with subunits of the Brahma SWI/SNF-class chromatin remodeling complex. Our results suggest that, mechanistically, Akirin mediates a novel connection between Twist and a chromatin remodeling complex to facilitate changes in the chromatin environment, leading to the optimal expression of some Twist-regulated genes during Drosophila myogenesis. We propose that this Akirin-mediated link between transcription factors and the Brahma complex represents a novel paradigm for providing tissue and target specificity for transcription factor interactions with the chromatin remodeling machinery.
发育关键转录因子的活性通过与辅助因子的相互作用来调节。这种相互作用可以通过蛋白质-蛋白质相互作用直接影响转录因子的活性，也可以通过改变局部染色质环境间接影响。我们使用酵母双杂交筛选，鉴定了一种高度保守的核蛋白Akirin，它是关键的黑腹果蝇中胚层和肌肉转录因子 Twist 的一种新型辅助因子。我们发现，Akirin 在遗传和物理上与 Twist 相互作用，以促进胚胎肌发生过程中一些（但不是全部）Twist 调节基因的表达。akirin 突变体胚胎具有肌肉缺陷，这与一些 Twist 调节基因的调控改变一致。为了调节转录，Akirin 与 Brahma SWI/SNF 类染色质重塑复合物的亚基共定位并相互作用。我们的结果表明，在机制上，Akirin 介导了 Twist 和染色质重塑复合物之间的一种新的联系，以促进染色质环境的改变，从而导致在果蝇肌发生过程中一些 Twist 调节基因的最佳表达。我们提出，这种由 Akirin 介导的转录因子与 Brahma 复合物之间的联系代表了一种新的范例，为转录因子与染色质重塑机制之间的相互作用提供了组织和靶标特异性。
