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.
Highlights
Epigenetic processes are structural modifications to chromatin which are indicative of and contribute to the transcriptional state [1]
POLYCOMB REPRESSIVE COMPLEX COMPONENT EXPRESSION IN THE ADULT MOUSE HIPPOCAMPUS Previous studies have reported expression of particular Polycomb group (PcG) members within the adult brain [21, 36, 37], but there has not been a comprehensive characterization of the expression of PcG transcripts and proteins in the hippocampus of the adult C57BL/6 mouse
The transcripts analyzed were; Bmi1, Ring1a, and Ring1b of PRC1; Ezh2, Ezh1, Suz12, and Sirtuin 1 (Sirt1) of PRC2; and Yy1 and Yy2 of the PhoRC; chosen on the basis of their roles in polycomb function, previous implications in neuronal function taken from the literature, and the availability of other resources for further study, including antibodies
Summary
Epigenetic processes are structural modifications to chromatin which are indicative of and contribute to the transcriptional state [1]. These processes include DNA methylation and histone modification and they play an important role in gene expression control. Such modifications are dynamic in the adult brain and may act as important transcriptional determinants in plasticity and memory [2, 3]. Changes in the activity of transcriptional repressor RE1-silencing transcription factor (REST) play a role in events associated with seizures [13], likely through altered histone modification [14]
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