title: Inhibition of histone methyltransferases SUV39H1 and G9a leads to neuroprotection in an in vitro model of cerebral ischemia.
abstract: Cerebral ischemia induces a complex transcriptional response with global changes in gene expression. It is essentially regulated by transcription factors as well as epigenetic players. While it is well known that the inhibition of transcriptionally repressive histone deacetylases leads to neuroprotection, the role of histone methyltransferases in the postischemic transcriptional response remains elusive. We investigated the effects of inhibition of the repressive H3K9 histone methyltransferases SUV39H1 and G9a on neuronal survival, H3K9 promoter signatures and gene expression. Their inhibition either with the specific blocker chaetocin or by use of RNA interference promoted neuronal survival in oxygen glucose deprivation (OGD). Brain-derived neurotrophic factor (BDNF) was upregulated and BDNF promoter regions showed an increase in histone marks characteristic for active transcription. The BDNF blockade with K252a abrogated the protective effect of chaetocin treatment. In conclusion, inhibition of histone methyltransferases SUV39H1 and G9a confers neuroprotection in a model of hypoxic metabolic stress, which is at least in part mediated by BDNF.
authors.affiliation: Department of Experimental Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Sophie
authors.initials: S
authors.lastname: Schweizer
authors.affiliation: Department of Experimental Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany.|Center for Stroke Research Berlin, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Harms
authors.affiliation: Department of Experimental Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany.|NeuroCure Clinical Research Center, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Lerch
authors.affiliation: Department of Experimental Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Flynn
authors.affiliation: Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Hecht
authors.affiliation: Department of Experimental Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany.|NeuroCure Clinical Research Center, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Ferah
authors.initials: F
authors.lastname: Yildirim
authors.affiliation: Department of Experimental Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany.|Center for Stroke Research Berlin, Charité - Universitätsmedizin Berlin, Berlin, Germany.|NeuroCure Clinical Research Center, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Meisel
authors.affiliation: Department of Experimental Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany.|NeuroCure Clinical Research Center, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Märschenz
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000201:enzymology*; D019208:Brain-Derived Neurotrophic Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002452:Cell Count; D002470:Cell Survival; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000473:pathology; D005260:Female; D005947:Glucose / Q000172:deficiency; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors*; D002534:Hypoxia, Brain / Q000473:pathology; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010879:Piperazines / Q000627:therapeutic use; D011247:Pregnancy; D034622:RNA Interference; D051381:Rats; D017208:Rats, Wistar
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D007527:Isoenzymes; D018696:Neuroprotective Agents; D010879:Piperazines; C002511:chaetocin; D007770:L-Lactate Dehydrogenase; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D005947:Glucose