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bioRxiv · 10.1101/2025.10.15.682518

Reciprocal targeting of the unfolded protein response regulator Xbp1 and the Dom-A nucleosome remodeler in Drosophila

Kars, G.·Becker, P. B.·Apostolou, Z.
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Abstract

The DOM-A complex regulates cell growth and proliferation in Drosophila. Like the orthologous human P400 complex, DOM-A combines two epigenetic effectors: a SWR1-type histone exchange enzyme, Dom-A, and the Tip60 acetyltransferase. We found Xbp1, a conserved transcription regulator of the unfolded protein response (UPR), as tightly associated with immunopurified DOM-A and explored the functional implications of this interaction. We biochemically determined the Xbp1 DNA recognition motif in chromatin-reconstituted Drosophila genomes. Intersection of the chromatin binding profiles for Xbp1 and Dom-A in proliferating cells and reciprocal protein depletion studies revealed two distinct modes through which Xbp1 binds chromatin. Xbp1 recruits Dom-A to motif-bearing promoters of genes involved in the UPR, such as Xbp1, Hsc70-3 and Gp93, and activates their transcription. Xbp1 also localizes to hundreds of high-confidence Dom-A binding sites that lack Xbp1 recognition motifs. These interactions depend on Dom-A, pointing to a reverse targeting scenario. Upon depletion of Dom-A, Xbp1 protein levels, but not mRNA levels, are reduced. The Xbp1 may thus be stabilized upon binding to DOM-A. The complex interactions of Xbp1 and DOM-A in the genome bear potential to integrate signals from the UPR with the general, DOM-mediated regulation of cell growth and proliferation. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=81 SRC="FIGDIR/small/682518v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@4b60eborg.highwire.dtl.DTLVardef@c7f2d0org.highwire.dtl.DTLVardef@1164265org.highwire.dtl.DTLVardef@612ddd_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Kars, G., Becker, P. B., Apostolou, Z.. 2025-10-15. Reciprocal targeting of the unfolded protein response regulator Xbp1 and the Dom-A nucleosome remodeler in Drosophila. https://doi.org/10.1101/2025.10.15.682518

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