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

Kars, Gizem ; Becker, Peter B. ; Apostolou, Zivkos (2026): Reciprocal targeting of the unfolded protein response regulator Xbp1 and the DOM-A nucleosome remodeler in Drosophila. Nucleic Acids Research, 54 (5): gkag178. ISSN 0305-1048

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.

• Doc-Type: Article (LMU)
• Organisational unit (Faculties): 07 Medicine > Biomedical Center; 07 Medicine > Adolf Butenandt Institute
• DFG subject classification of scientific disciplines: Life sciences
• DFG: Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - 213249687
• DFG: Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - 491502892