Drosophila Keap1 oxidative/xenobiotic response factor interacts with B-type lamin to regulate nuclear lamina and heterochromatin

Abstract

AbstractThe essential function of the Keap1-Nrf2 pathway in mediating transcriptional response to xenobiotic and oxidative stimuli has been well established. However, the mechanisms whereby Keap1 and Nrf2 regulate developmental genes remains unclear. We hypothesized that Drosophila Keap1 (dKeap1) and Nrf2 (CncC) proteins regulate transcription through controlling high-order chromatin structure. Here, we describe evidence supporting that dKeap1 can regulate chromatin through interaction with lamin, the intermediate filament proteins that form nuclear lamina and organize the overall chromatin architecture. dKeap1 and lamin Dm0, the B-type lamin in Drosophila, interact with each other and form complexes in the nucleus. Overexpression of dKeap1 resulted in a redistribution of lamin Dm0 to the intra-nuclear area and consistently, caused a spreading of the heterochromatin marker H3K9me2 from the pericentromeric region to chromosome arms. Overexpression of dKeap1 fusion proteins in the dKeap1 null background significantly disrupted the nuclear lamina morphology, indicating that dKeap1 is required for the maintenance of a normal nuclear lamina. Knock down of dKeap1 partially rescued the lethality caused by lamin Dm0 overexpression, suggesting that dKeap1 and lamin Dm0 function in the same pathway during development. Taken together, these results support a model where dKeap1 regulates chromatin structure and developmental transcription through interaction with lamin proteins, revealing a novel epigenetic function of the Keap1 oxidative/xenobiotic response factor.