Role of histone acetylation in the activity-dependent regulation of sulfiredoxin and sestrin 2.
Role of histone acetylation in the activity-dependent regulation of sulfiredoxin and sestrin 2.
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DOI：
10.4161/epi.4.3.8753
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发表时间：
2009-04-01
期刊：
影响因子：
3.7
通讯作者：
Hardingham GE
中科院分区：
文献类型：
--
作者：
Soriano FX;Papadia S;Bell KF;Hardingham GE
过氧化物酶是神经保护性抗氧化酶，可减少氢过氧化物并保护神经元免受氧化应激。然而，它们可以通过其活性部位半胱氨酸的过度氧化而失活，这是一种可以在大脑中响应氧化损伤（如中风和正常衰老）而发生的事件。突触活动促进神经元中过氧化的过氧化物酶的减少，并诱导硫氧还蛋白（Srxn 1）和sestrin 2（Sesn 2）的表达，据报道它们介导了这一过程。我们已经研究了组蛋白乙酰化在这些基因调控中的重要性，以了解更多关于这些基因是如何被突触活动调控的。我们发现，sestrin 2启动子进行活性依赖性组蛋白乙酰化，这有助于其转录激活。相反，启动子近端组蛋白乙酰化不参与硫氧还蛋白的活性依赖性诱导。然而，sestrin 2和sulfiredoxin的表达可以通过用组蛋白去乙酰化酶抑制剂阿司他丁A（TSA）处理神经元来增强组蛋白乙酰化来诱导。此外，保护剂量的TSA抑制暴露于氧化损伤的神经元中过氧化的过氧化物酶的形成。组蛋白去乙酰化酶是与氧化应激相关的神经退行性疾病的新兴治疗靶点。我们的研究结果表明，操纵组蛋白乙酰化酶-去乙酰化酶的神经元的平衡可能会模仿突触活动的影响，防止氧化失活的过氧化物酶。
Peroxiredoxins are neuroprotective antioxidant enzymes that reduce hydroperoxides and protect neurons against oxidative stress. However, they can be inactivated through hyperoxidation of their active site cysteine, an event that can take place in the brain in response to oxidative insults such as stroke and also normal aging. Synaptic activity promotes the reduction of hyperoxidized peroxiredoxins in neurons, and induces the expression of sulfiredoxin (Srxn1) and sestrin 2 (Sesn2) which have been reported to mediate this. We have investigated the importance of histone acetylation in the regulation of these genes, to understand more about how these genes are regulated by synaptic activity. We show that the sestrin 2 promoter undergoes activity-dependent histone acetylation, which contributes to its transcriptional activation. In contrast, promoter-proximal histone acetylation is not involved in the activity-dependent induction of sulfiredoxin. Nevertheless, expression of both sestrin 2 and sulfiredoxin can be induced by enhancing histone acetylation through treatment of neurons with the histone deacetylase inhibitor trichostatin A (TSA). Furthermore, protective doses of TSA inhibit the formation of hyperoxidized peroxiredoxins in neurons exposed to oxidative insults. Histone deacetylases are emerging therapeutic targets in neurodegenerative disorders associated with oxidative stress. Our results indicate that manipulating the histone acetylase-deacetylase balance in neurons may mimic the effects of synaptic activity in preventing the oxidative inactivation of peroxiredoxins.
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DOI：
10.1124/jpet.107.120188
发表时间：
2007-06-01
影响因子：
3.5
作者：
Kim, Hyeon Ju;Rowe, Michael;Chuang, De-Maw
通讯作者：
Chuang, De-Maw
影响因子：
4.7
作者：
Hattori, F;Murayama, N;Oikawa, S
通讯作者：
Oikawa, S
影响因子：
4.7
作者：
Hahnen, E;Eyüpoglu, IY;Blümcke, I
通讯作者：
Blümcke, I
影响因子：
25
作者：
Hardingham, GE;Fukunaga, Y;Bading, H
通讯作者：
Bading, H
影响因子：
5.3
作者：
Langley, Brett;D'Annibale, Melissa A.;Ratan, Rajiv R.
通讯作者：
Ratan, Rajiv R.