Deciphering the DNA code for the function of the Drosophila polydactyl zinc finger protein Suppressor of Hairy-wing

Polydactyl zinc finger (ZF) proteins have prominent roles in gene regulation and often execute multiple regulatory functions. To understand how these proteins perform varied regulation, we studied Drosophila Suppressor of Hairy-wing [Su(Hw)], an exemplar multifunctional polydactyl ZF protein. We identified separation-of-function (SOF) alleles that encode proteins disrupted in a single ZF that retain one of the Su(Hw) regulatory activities. Through extended in vitro analyses of the Su(Hw) ZF domain, we show that clusters of ZFs bind individual modules within a compound DNA consensus sequence. Through in vivo analysis of SOF mutants, we find that Su(Hw) genomic sites separate into sequence subclasses comprised of combinations of modules, with subclasses enriched for different chromatin features. These data suggest a Su(Hw) code, wherein DNA binding dictates its cofactor recruitment and regulatory output. We propose that similar DNA codes might be used to confer multiple regulatory functions of other polydactyl ZF proteins.