Binding site analysis and identification of reciprocal targeting of Dom-A and Xbp1 in Drosophila melanogaster

The DOM-A complex regulates cell growth and proliferation in Drosophila. Analogous to the mammalian Tip60–p400 complex, DOM-A integrates two epigenetic effectors: a SWR1-type ATPase (Domino-A) that mediates histone exchange and the Tip60/KAT5 acetyltransferase. We identified Xbp1, a conserved transcriptional regulator of the unfolded protein response (UPR), as a tight interactor of the immunopurified DOM-A complex and explored the functional consequences of this association. Integrative analysis of Xbp1 and DOM-A occupancy in proliferating cells, together with reciprocal protein depletion, revealed two distinct modes of Xbp1 chromatin binding. In a sequence-specific mode, Xbp1 recruits DOM-A to motif-bearing promoters of UPR genes. In a second, motif-independent mode, Xbp1 localizes to hundreds of high-confidence DOM-A binding sites that lack Xbp1 recognition motifs; these interactions depend on DOM-A, consistent with a “reverse targeting” mechanism. Consistent with functional coupling, depletion of DOM-A reduces Xbp1 protein abundance without affecting Xbp1 mRNA levels, suggesting post-translational stabilization of Xbp1 upon association with DOM-A. Together, these findings indicate that the genome-wide interplay between Xbp1 and DOM-A may integrate UPR signaling with the broader, DOM-mediated regulation of cell growth and proliferation.