Epigenetic regulation of inflammation in stroke

Abstract

Despite extensive research, treatments for clinical stroke are still limited only to the administration of tissue plasminogen activator and the recent introduction of mechanical thrombectomy, which can be used in only a limited proportion of patients due to time constraints. A plethora of inflammatory events occur during stroke, arising in part due to the body's immune response to brain injury. Neuroinflammation contributes significantly to neuronal cell death and the development of functional impairment and death in stroke patients. Therefore, elucidating the molecular and cellular mechanisms underlying inflammatory damage following stroke injury will be essential for the development of useful therapies. Research findings increasingly point to the likelihood that epigenetic mechanisms play a role in the pathophysiology of stroke. Epigenetics involves the differential regulation of gene expression, including those involved in brain inflammation and remodelling after stroke. Hence, it is conceivable that epigenetic mechanisms may contribute to differential interindividual vulnerability and injury responses to cerebral ischaemia. In this review, we summarize recent findings on the emerging role of epigenetics in the regulation of neuroinflammation in stroke. We also discuss potential epigenetic targets that may be assessed for the development of stroke therapies.

Keywords: cytokines; epigenetics; inflammasome; ischaemic stroke; neuroinflammation.

Figure 1.

DNA methylation. DNA methylation sites displayed bias at CpG islands or shores. Hypomethylation of CpG islands is normally associated with transcriptional activation. DNA methylation is mediated by a group of enzymes termed DNA methyltransferases (DNMTs), whereas the subsequent removal of methyl group from DNA is mediated by ten–eleven translocation (TET) enzymes. Methyl tags at CpG islands attract methyl-CpG-binding domain (MBD) proteins, which may recruit chromatin-modifying complexes to creates a repressive chromatin, leading to gene silencing.

Figure 2.

Histone acetylation. Histone acetylation occurs at the amino termini of histone tails, and is mediated by a class of enzymes termed histone acetyltransferase (HATs). Subsequent removal of an acetyl group is mediated by another class of enzyme called histone deacetylases (HDACs). Histone acetylation is commonly associated with permissive chromatin accessibility and transcriptional activation.

Figure 3.

Histone methylation. Histone methylation normally shows preference at either lysine or arginine residues of histone tails. Addition of methyl groups to these residues is mediated by either lysine or arginine methyltransferases, respectively. Methyl group addition to arginine residues can either be symmetrical or asymmetrical, and is mediated by several subfamily members of arginine methyltransferases. Unlike histone acetylation, effects of histone methylation on gene transcription are still unclear. Both transcriptional activation and deactivation have been reported to be associated with histone methylation.

Figure 4.

MicroRNAs. miRNA processing follows a complicated cascade. Transcription in the nucleus first produces a long transcript containing numerous miRNA transcripts by RNA polymerase II, termed primary miRNAs (pri-miRNAs). Subsequent processing by Drosha/DGCR8 complexes yields a precursor miRNA (pre-miRNA) to be transported via Exportin-5 towards the cytosol. In the cytosol, pre-miRNAs undergo a second round of processing to become mature miRNAs via interaction with the Dicer/TRBP complex. Eventually, these mature miRNAs will be packaged into an RNA-induced silencing complex (RISC). Together with RISC, mature miRNAs tend to recognize the 3′ untranslated region (3′ UTR) sites of messenger RNA (mRNA) specifically. Targeting by mature miRNAs will either lead to mRNA silencing or degradation.