GSK-126 Protects CA1 Neurons from H3K27me3-Mediated Apoptosis in Cerebral Ischemia

Abstract

Epigenetics, including histone modifications, play a significant role in central nervous system diseases, but the underlying mechanism remains to be elucidated. The aim of this study was to evaluate the role of H3K27me3 in regulating transcriptomic and pathogenic mechanisms following global ischemic stroke. Here, we found that in vivo ischemic/reperfusion (I/R) injury induced marked upregulation of H3K27me3 in the hippocampus. The administration of GSK-126 to rat brains decreased the levels of H3K27me3 in the hippocampus and reduced neuronal apoptosis after experimental stroke. Furthermore, ChIP-seq data demonstrated that the primary role of GSK-126 in the ischemic brain is to reduce H3K27me3 enrichment, mediating negative regulation of the execution phase of apoptosis and the MAPK signaling pathway. Further study suggested that the protective role of GSK-126 in ischemic rats was antagonized by U0126, an inhibitor of ERK1/2. Collectively, we demonstrated the potential of H3K27me3 as a novel stroke therapeutic target, and GSK-126 exerted a neuroprotective function in ischemic brain injury, which might be associated with activation of the MAPK/ERK pathway. Graphical Abstract: [Figure not available: see fulltext.]