The H3K9 histone methyltransferase G9a modulates renal ischemia reperfusion injury by targeting Sirt1

Ischemia reperfusion (IR) injury dampens renal function and usually confers a great risk of renal failure. Aberrant expression of G9a, a H3K9 methyltransferase of mammalian histone, has been implicated as a driving event in various kidney diseases. However, the role of G9a plays in renal IR injury is required to be clarified. Herein, our results showed that renal IR injury resulted in a rapid elevation of G9a, accompanying the down-regulation of Sirt1, a deacetylase that has been reported to afford renoprotection. Genetic overexpression or therapeutic activation of Sirt1 efficiently ameliorated renal IR injury by elevating anti-oxidative genes expression and reducing the accumulation of reactive oxygen species, including O2 center dot- and center dot OH. In addition, inhibition of G9a activity by BIX01294 (BIX) alleviated IR injury through abolishing O2 center dot- and center dot OH levels in a Sirt1-dependent manner. Mechanistically, we observed that demethylated H3K9 was accumulated on the Sirt1 promoter in renal IR injury. Silencing or suppression of G9a activity erased H3K9me2 from Sirt1 promoter and normalized Sirt1 expression. Further exploration revealed that G9a interacted with chromobox homolog 1 (CBX1) to catalyze H3K9 de-methylation and formed a transcription repressor complex on the Sirt1 promoter, ultimately repressing Sirt1 transcription. In this study, we provided strong evidence that G9a modulated renal IR injury through cooperation with CBX1 to form a transcription repressor complex on the Sirt1 promoter and regulate O2 center dot- and center dot OH generation, indicating that G9a-Sirt1 axis might be a promising therapeutic target in an epigenetic manner.

Automated summary

The study revealed that enhancing the activity of Sirt1 or inhibiting the function of G9a can effectively ameliorate renal ischemia reperfusion (IR) injury. G9a cooperates with CBX1 to form a transcription repressor complex, regulating the expression of Sirt1 by controlling the generation of O2•- and •OH.