The SWI/SNF nucleosome remodeler constrains enhancer activity duringDrosophilawing development

Abstract

ABSTRACTChromatin remodeling is central to the dynamic changes in gene expression that drive cell fate determination. During development, the sets of enhancers that are accessible for use change globally as cells transition between stages. While transcription factors and nucleosome remodeling complexes are known to work together to control access to enhancers, it is unclear how the short stretches of DNA that they individually unmask yield the kilobase-sized accessible regions that are characteristic of active enhancers. Here, we performed a genetic screen to investigate the role of ATP-dependent nucleosome remodeling complexes in the control of dynamic enhancer activity. We find that theDrosophilaBAP complex, a member of the SWI/SNF family of nucleosome remodelers, is required for repression of a temporally dynamic enhancer,brdisc. Contrary to expectations, we find that the BAP-specific subunit, Osa, is dispensable for mediating changes in chromatin accessibility between early and late stages of wing development. Instead, we find that Osa is required to constrain the levels ofbrdiscactivity in imaginal wing discs when the enhancer is normally active. Genome-wide profiling reveals that Osa binds directly to thebrdiscenhancer as well as thousands of other developmentally dynamic regulatory sites, including multiple genes encoding components and targets of the Notch signaling pathway. We find that Osa loss of function results in development of ectopic sensory structures that are normally patterned by Notch signaling early in wing development. Moreover, we find that Osa loss of function results in hyperactivation of theDeltagene, which encodes the Notch ligand. Together, these findings indicate that proper constraint of enhancer activity is necessary for regulation of dose-dependent developmental events.