DNA methyltransferase contributes to delayed ischemic brain injury

Area of Science:

• Neuroscience
• Molecular Biology
• Epigenetics

Background:

• DNA methylation, regulated by DNA methyltransferase (MTase), controls gene expression.
• Cerebral ischemia causes DNA damage and altered gene expression.
• MTase is abundant in the brain.

Purpose of the Study:

• To investigate the role of DNA methylation and MTase activity in ischemic brain injury.
• To determine if increased DNA methylation exacerbates or protects against cerebral ischemia.

Main Methods:

• Measuring MTase activity and DNA methylation in vivo and in vitro after middle cerebral artery occlusion (MCAo) in wild-type and Dnmt(S/+) mice.
• Assessing stroke protection with MTase inhibitor (5-aza-2'-deoxycytidine) and deacetylation inhibitor (trichostatin A).
• Evaluating DNA methylation and dnmt gene expression in an excitotoxic cell death model.

Main Results:

• MTase activity and protein levels remained unchanged after mild focal brain ischemia.
• DNA methylation significantly increased in wild-type mice post-reperfusion, but not in Dnmt(S/+) mice.
• Dnmt(S/+) mice showed resistance to mild ischemic damage, suggesting increased DNA methylation is linked to brain injury.
• MTase and deacetylation inhibitors conferred stroke protection in wild-type mice.
• In contrast, DNA methylation was not enhanced, and dnmt gene reduction was not protective in an excitotoxic cell death model.

Conclusions:

• MTase activity contributes to poor tissue outcomes in mild ischemic brain injury.
• Targeting MTase may offer a therapeutic strategy for ischemic stroke.
• The role of DNA methylation in brain injury may differ between mild ischemia and excitotoxic cell death.