Chatterjee Nirmalya, Tian Min, Spirohn Kerstin, Boutros Michael, Bohmann Dirk
Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, New York, United States of America.
Division of Signaling and Functional Genomics, German Cancer Research Center (DKFZ) and Department of Cell and Molecular Biology, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
PLoS Genet. 2016 May 27;12(5):e1006072. doi: 10.1371/journal.pgen.1006072. eCollection 2016 May.
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.
哺乳动物的BET蛋白构成了一类含溴结构域的表观遗传调节因子家族,在染色质组织和基因调控中具有复杂功能。我们鉴定出果蝇中BET蛋白家族的唯一成员Fs(1)h,它是应激反应转录因子CncC(Nrf2在果蝇中的同源物)的抑制剂。Fs(1)h以一种需要其溴结构域功能和CncC乙酰化的方式与CncC发生物理相互作用。用fs(1)h RNAi或BET蛋白抑制剂JQ1处理培养的果蝇细胞或成年果蝇,可解除对CncC转录活性的抑制,并启动保护性基因表达程序。Fs(1)h抑制CncC功能的机制不同于通过废除Keap1依赖的蛋白酶体降解来刺激Nrf2功能的经典机制。与Keap1和Fs(1)h对CncC的独立调节模式一致,能够特异性靶向这些途径的药物组合会导致保护性CncC依赖基因表达的强烈协同和特异性激活,并增强氧化应激抗性。这种协同作用可能可用于设计针对与氧化应激或炎症相关疾病的联合疗法。