Abstract
Mammalian BET proteins comprise a family of bromodomain-containing epigenetic regulators with complex functions in chromatin organization and gene regulation. We identified the sole member of the BET protein family in Drosophila, Fs(1)h, as an inhibitor of the stress responsive transcription factor CncC, the fly ortholog of Nrf2. Fs(1)h physically interacts with CncC in a manner that requires the function of its bromodomains and the acetylation of CncC. Treatment of cultured Drosophila cells or adult flies with fs(1)h RNAi or with the BET protein inhibitor JQ1 de-represses CncC transcriptional activity and engages protective gene expression programs. The mechanism by which Fs(1)h inhibits CncC function is distinct from the canonical mechanism that stimulates Nrf2 function by abrogating Keap1-dependent proteasomal degradation. Consistent with the independent modes of CncC regulation by Keap1 and Fs(1)h, combinations of drugs that can specifically target these pathways cause a strong synergistic and specific activation of protective CncC- dependent gene expression and boosts oxidative stress resistance. This synergism might be exploitable for the design of combinatorial therapies to target diseases associated with oxidative stress or inflammation.
Highlights
Nrf2 transcription factors are critically important for the health, homeostasis and longevity of multicellular organisms [1,2,3]
We identified the sole member of the BET protein family in Drosophila, Fs(1)h, as an inhibitor of the stress responsive transcription factor CncC, the fly ortholog of Nrf2
We identified Fs (1)h, a bromodomain-containing BET protein, as a negative regulator of Nrf2 function in Drosophila
Summary
Nrf transcription factors are critically important for the health, homeostasis and longevity of multicellular organisms [1,2,3]. In unstressed cells Keap assembles a Cullin 3-containing ubiquitin ligase complex that targets Nrf for proteolysis by associating with its NH2-terminally located NEH2 domain. This Keap1-mediated degradation of Nrf is relieved upon stress exposure, so that the transcription factor can accumulate in the nucleus and bind to so-called ARE (antioxidant response element) sequences in target gene promoters. Examples include the regulation of energy metabolism [1, 6], stem cell maintenance [7] and aging [8, 9] These functions are probably regulated by signals other than toxic insults and presumably require a different transcriptional response, in terms of kinetics and target gene profile. In order to explore how this expanded range of Nrf functions might be regulated we conducted a large-scale screen for gene products that are involved in Nrf target gene activation
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