Regulation of position effect variegation at pericentric heterochromatin by Drosophila Keap1‐Nrf2 xenobiotic response factors

Abstract

Summary The Keap1‐Nrf2 signaling pathway plays a central role in the regulation of transcriptional responses to oxidative species and xenobiotic stimuli. The complete range of molecular mechanisms and biological functions of Keap1 and Nrf2 remain to be fully elucidated. To determine the potential roles of Keap1 and Nrf2 in chromatin architecture, we examined the effects of their Drosophila homologs (dKeap1 and CncC) on position effect variegation (PEV), which is a transcriptional reporter for heterochromatin formation and spreading. Loss of function mutations in cncC, dKeap1, and cncC/dKeap1 double mutants all suppressed the variegation of wm4 and SbV PEV alleles, indicating that reduction of CncC or dKeap1 causes a decrease of heterochromatic silencing at pericentric region. Depletion of CncC or dKeap1 in embryos reduced the level of the H3K9me2 heterochromatin marker, but had no effect on the transcription of the genes encoding Su(var)3‐9 and HP1. These results support a potential role of dKeap1 and CncC in the establishment and/or maintenance of pericentric heterochromatin. Our study provides preliminary evidence for a novel epigenetic function of Keap1‐Nrf2 oxidative/xenobiotic response factors in chromatin remodeling.

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

“…Our previous studies found that knockout of dKeap1 reduced the level of heterochromatin marker histone H3K9me2, suggesting that dKeap1 is required for heterochromatin formation and/or maintenance (Carlson et al ., 2019). Given that dKeap1 overexpression relocated Lamin, we tested whether ectopic dKeap1 can alter the organization of heterochromatin in the nucleus.…”

“…In contrast to the well-established model in which Keap1 and Nrf2 factors control antioxidant and detoxifying transcription, the mechanisms whereby Keap1 and Nrf2 regulate developmental genes remains unclear. Keap1 and Nrf2 likely function both in gene activation as transcription activators and in gene silencing by regulating heterochromatin (Carlson et al ., 2022; Carlson et al ., 2019; Deng & Kerppola, 2013, 2014). We hypothesize that Keap1-Nrf2 conducts different roles by forming complexes with different protein partners.…”

“…dKeap1 and CncC activate ecdysone-response genes through binding to the highly-decondensed “puffs” on the polytene chromosome (Deng & Kerppola, 2013). Both dKeap1 and CncC are also required for gene silencing at the pericentromeric heterochromatin (Carlson et al , 2019). Given that the roles of epigenetic mechanisms in the transcriptional regulation of development have been established (Kiefer, 2007), Keap1-Nrf2 family proteins could regulate developmental genes through epigenetic regulation of chromatin structure.…”

Nrf2 and the Nrf2-Interacting Network in Respiratory Inflammation and Diseases

“…Silencing mediator for retinoid and thyroid hormone receptor (SMRT), a transcriptional repressor that mediates histone deacetylation, can interact with Nrf2 Neh4/5 domains and inhibit Nrf2-induced GSTA2 expression [81]. Notably, a recent study in Drosophila showed that depletion of CncC or dKeap1 suppresses pericentric silencing and decreases the level of heterochromatin marker H3K9me2, providing direct evidence in support of the epigenetic role of Keap1/Nrf2 family proteins in chromatin remodeling [82].…”