Role of histone acetylation in the activity-dependent regulation of sulfiredoxin and sestrin 2.
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.
Centre for Integrative Physiology, University of Edinburgh, Edinburgh, SCT, UK.
Francesc X
FX
Soriano
Sofia
S
Papadia
Karen F S
KF
Bell
Giles E
GE
Hardingham
D000107:Acetylation; D000818:Animals; D002478:Cells, Cultured; D044127:Epigenesis, Genetic; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism; D050862:Oxidoreductases Acting on Sulfur Group Donors / Q000235:genetics*; D011401:Promoter Regions, Genetic; D051381:Rats; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission / Q000235:genetics*
D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; C012589:trichostatin A; D050862:Oxidoreductases Acting on Sulfur Group Donors; C542495:Srxn1 protein, rat