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The Journal of Neuroscience, May 1, 2000, 20(9):3175-3181

DNA Methyltransferase Contributes to Delayed Ischemic Brain Injury

Matthias Endres^{1, 2}, Andreas Meisel², Detlev Biniszkiewicz³, Shobu Namura¹, Konstantin Prass², Karsten Ruscher², Andreas Lipski², Rudolf Jaenisch³, Michael A. Moskowitz¹, and Ulrich Dirnagl²

¹ Stroke and Neurovascular Regulation Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, ² Division of Experimental Neurology, Department of Neurology, Charite Hospital, 10098 Berlin, Germany, and ³ Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142

DNA methylation is important for controlling the profile of gene expression and is catalyzed by DNA methyltransferase (MTase), an enzyme that is abundant in brain. Because significant DNA damage and alterations in gene expression develop as a consequence of cerebral ischemia, we measured MTase activity in vitro and DNA methylation in vivo after mild focal brain ischemia. After 30 min middle cerebral artery occlusion (MCAo) and reperfusion, MTase catalytic activity and the 190 kDa band on immunoblot did not change over time. However, [³H]methyl-group incorporation into DNA increased significantly in wild-type mice after reperfusion, but not in mutant mice heterozygous for a DNA methyltransferase gene deletion (Dnmt^S/+). Dnmt^S/+ mice were resistant to mild ischemic damage, suggesting that increased DNA methylation is associated with augmented brain injury after MCA occlusion. Consistent with this formulation, treatment with the MTase inhibitor 5-aza-2'-deoxycytidine and the deacetylation inhibitor trichostatin A conferred stroke protection in wild-type mice. In contrast to mild stroke, however, DNA methylation was not enhanced, and reduced dnmt gene expression was not protective in an ischemia model of excitotoxic/necrotic cell death. In conclusion, our results demonstrate that MTase activity contributes to poor tissue outcome after mild ischemic brain injury.

Key words: cerebral ischemia; delayed cell death; DNA damage; DNA methylation; DNA methyltransferase; gene expression

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Copyright © 2000 Society for Neuroscience  0270-6474/00/2093175-07$05.00/0

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