EZH2 Methyltransferase Regulates Neuroinflammation and Neuropathic Pain

Abstract

Recent studies by us and others have shown that enhancer of zeste homolog-2 (EZH2), a histone methyltransferase, in glial cells regulates the genesis of neuropathic pain by modulating the production of proinflammatory cytokines and chemokines. In this review, we summarize recent advances in this research area. EZH2 is a subunit of polycomb repressive complex 2 (PRC2), which primarily serves as a histone methyltransferase to catalyze methylation of histone 3 on lysine 27 (H3K27), ultimately resulting in transcriptional repression. Animals with neuropathic pain exhibit increased EZH2 activity and neuroinflammation of the injured nerve, spinal cord, and anterior cingulate cortex. Inhibition of EZH2 with DZNep or GSK-126 ameliorates neuroinflammation and neuropathic pain. EZH2 protein expression increases upon activation of Toll-like receptor 4 and calcitonin gene-related peptide receptors, downregulation of miR-124-3p and miR-378 microRNAs, or upregulation of Lncenc1 and MALAT1 long noncoding RNAs. Genes suppressed by EZH2 include suppressor of cytokine signaling 3 (SOCS3), nuclear factor (erythroid-derived 2)-like-2 factor (NrF2), miR-29b-3p, miR-146a-5p, and brain-specific angiogenesis inhibitor 1 (BAI1). Pro-inflammatory mediators facilitate neuronal activation along pain-signaling pathways by sensitizing nociceptors in the periphery, as well as enhancing excitatory synaptic activities and suppressing inhibitory synaptic activities in the CNS. These studies collectively reveal that EZH2 is implicated in signaling pathways known to be key players in the process of neuroinflammation and genesis of neuropathic pain. Therefore, targeting the EZH2 signaling pathway may open a new avenue to mitigate neuroinflammation and neuropathic pain.

Keywords: Schwann cells; analgesics; epigenetic; ncRNA; nociception.

Figure 1

Assembly of PRC2 core and non-core subunits. EZH2 contains the SET domain, which exerts methyltransferase activity on the PRC2 complex. EED: embryonic ectoderm development; EZH2: enhancer of zeste homolog 2; RBBP4: retinoblastoma binding protein 4, SUZ12: suppressor of zeste 12 homolog; SET: Su(var)3-9, enhancer-of-zeste, and trithorax domain; AEBP2: adipocyte enhancer-binding protein 2; PCL: polycomb-like proteins; JARID2: jimonji, AT-rich interactive domain 2.

Figure 2

Model of H3K27 methylation by PRC2. PRC2 catalyzes the nucleophilic attack of the SAM cofactor, resulting in the transfer of the methyl group (in red) from SAM to the lysine residue of H3K27. This transfer repeats two more times to produce a tri-methylated lysine-27 residue of histone 3 (H3K27me3), which ultimately results in a more tightly packed heterochromatin complex that represses gene transcription. SAH is further metabolized into adenosine and homocysteine via SAH hydrolase. The catalytic subunit (EZH2) of PRC2 and SAH hydrolase can be inhibited by SAM-competitive inhibitors and SAH hydrolase inhibitors, respectively. SAM: S-adenosyl-L-methionine; SAH: S-adenosyl-L-homocysteine.

Figure 3

The EZH2 signaling pathway in the regulation of neuroinflammation and neuropathic pain. Upstream signaling molecules regulating EZH2 protein expression and function and downstream signaling molecules used by EZH2 in microglia (left) are shown. The EZH2 signaling pathways in Schwann cells (right) remain unknown (shown in dash line). Genes with expression or activity that is enhanced are indicated in green, while genes with expression or activity that is suppressed are in red.