Schweizer Sophie, Harms Christoph, Lerch Heike, Flynn Jennifer, Hecht Jochen, Yildirim Ferah, Meisel Andreas, Märschenz Stefanie
Department of Experimental Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Center for Stroke Research Berlin, Charité - Universitätsmedizin Berlin, Berlin, Germany.
J Cereb Blood Flow Metab. 2015 Oct;35(10):1640-7. doi: 10.1038/jcbfm.2015.99. Epub 2015 May 13.
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.
脑缺血会引发复杂的转录反应，导致基因表达的整体变化。它主要由转录因子以及表观遗传因子调控。虽然众所周知，抑制具有转录抑制作用的组蛋白脱乙酰酶可带来神经保护作用，但组蛋白甲基转移酶在缺血后转录反应中的作用仍不清楚。我们研究了抑制具有抑制作用的H3K9组蛋白甲基转移酶SUV39H1和G9a对神经元存活、H3K9启动子特征及基因表达的影响。使用特异性阻滞剂毛壳菌素或通过RNA干扰对它们进行抑制，均可促进氧糖剥夺（OGD）模型中神经元的存活。脑源性神经营养因子（BDNF）上调，且BDNF启动子区域显示出活性转录特有的组蛋白标记增加。用K252a阻断BDNF可消除毛壳菌素治疗的保护作用。总之，抑制组蛋白甲基转移酶SUV39H1和G9a在缺氧代谢应激模型中具有神经保护作用，这至少部分是由BDNF介导的。
