Akirin Links Twist-Regulated Transcription with the Brahma Chromatin Remodeling Complex during Embryogenesis

Abstract

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.

Author Summary

The proper development of the diverse array of cell types in an organism depends upon the induction and repression of specific genes at particular times and places. This gene regulation requires both the activity of tissue-specific transcriptional regulators and the modulation of the chromatin environment. To date, a complete picture of the interplay between these two processes remains unclear. To address this, we examined the activity of the evolutionarily conserved transcription factor Twist during embryogenesis of Drosophila melanogaster. While Twist has multiple activities and roles during development, a direct link between Twist and chromatin remodeling is unknown. We identified a highly conserved protein, Akirin, as a link between Twist and chromatin remodeling factors. Akirin is required for optimal expression of a Twist-dependent target during muscle development via interactions with the Drosophila SWI/SNF chromatin remodeling complex. Interestingly, Akirin is not required for activation of all Twist-dependent enhancers, suggesting that Akirin refines Twist activity outputs and that different Twist-dependent targets have different requirements for chromatin remodeling during development. Our data further suggests that Akirin similarly links the SWI/SNF chromatin remodeling complex with other transcription factors during development. This work has important ramifications for understanding both normal development and diseases such as cancer.