Transcriptional Response of Polycomb Group Genes to Status Epilepticus in Mice is Modified by Prior Exposure to Epileptic Preconditioning

Abstract

Exposure of the brain to brief, non-harmful seizures can activate protective mechanisms that temporarily generate a damage-refractory state. This process, termed epileptic tolerance, is associated with large-scale down-regulation of gene expression. Polycomb group (PcG) proteins are master controllers of gene silencing during development that are re-activated by injury to the brain. Here, we explored the transcriptional response of genes associated with polycomb repressive complex (PRC) 1 (Ring1A, Ring1B, and Bmi1) and PRC2 (Ezh1, Ezh2, and Suz12), as well as additional transcriptional regulators Sirt1, Yy1, and Yy2, in a mouse model of status epilepticus (SE). Findings were contrasted to changes after SE in mice previously given brief seizures to evoke tolerance. Real-time quantitative PCR showed SE prompted an early (1 h) increase in expression of several genes in PRC1 and PRC2 in the hippocampus, followed by down-regulation of many of the same genes at later times points (4, 8, and 24 h). Spatio-temporal differences were found among PRC2 genes in epileptic tolerance, including increased expression of Ezh2, Suz12, and Yy2 relative to the normal injury response to SE. In contrast, PRC1 complex genes including Ring 1B and Bmi1 displayed differential down-regulation in epileptic tolerance. The present study characterizes PcG gene expression following SE and shows prior seizure exposure produces select changes to PRC1 and PRC2 composition that may influence differential gene expression in epileptic tolerance.

Amygdalar expression of the microRNA miR‐101a and its target Ezh2 contribute to rodent anxiety‐like behaviour

“…In the cerebellum, Ezh2 restricts dendrite morphogenesis through H3K27me3‐mediated repression of Bdnf (Qi et al ., ). Other work shows that Ezh2 expression is sensitive to external stimuli, such as stress (Hunter et al ., ; Xu et al ., ) and neural activity, which transiently increases Ezh2 and H3K27me levels (Reynolds et al ., ; Palomer et al ., ). Thus, while Ezh2 has traditionally been considered in the context of cell development and differentiation, recent evidence clearly shows numerous important roles in the adult brain, particularly in the ability of neurons to respond to environmental signals.…”

Polycomb repressive complex 2 (PRC2) silences genes responsible for neurodegeneration

“…Exposure to cell extrinsic or intrinsic stressors that can alter neuronal activity and/or metabolism may destabilize the neuronal subtype-specific gene expression patterns by affecting the bivalent state of non-neuronal genes or genes of other neuronal types. As discussed, changes in PRC2 function could be triggered either transiently, by non-persisting events such as seizures 50 , or permanently, by the expression of pathogenic proteins such as mutant huntingtin protein, which can directly interfere with PRC2 recruitment and function 13,14 . In view of our findings, the presence of the large number of self-regulatory transcription factors among PRC2 targets suggest that changes in proteins that control H3K27me3 levels or chromatin distribution globally or locally can trigger self-propagating transcriptional processes that set neurons on a path of neurodegeneration.…”

Epigenetic modulation of gene expression governs the brain's response to injury

“…PcG transcripts were downregulated in injury and tolerance, but to different extents and in a differential manner for genes associated with PRC1 and PRC2. Expression of PRC2-associated genes was higher in tolerance than in injury, while expression of PRC1-associated genes was lower in tolerance [42]. …”