The Role of DNA Methylation in Transcriptional Regulation of Pro-Nociceptive Genes in Rat Trigeminal Ganglia

Abstract

Epigenetic modulation by DNA methylation is associated with aberrant gene expression in sensory neurons, which consequently leads to pathological pain responses. In this study, we sought to investigate whether peripheral inflammation alters global DNA methylation in trigeminal ganglia (TG) and results in abnormal expression of pro-nociceptive genes. Our results show that peripheral inflammation remotely reduced the level of global DNA methylation in rat TG with a concurrent reduction in DNMT1 and DNMT3a expression. Using unbiased steps, we selected the following pro-nociceptive candidate genes that are potentially regulated by DNA methylation: TRPV1, TRPA1, P2X3, and PIEZO2. Inhibition of DNMT with 5-Aza-dC in dissociated TG cells produced dose-dependent upregulation of TRPV1, TRPA1, and P2X3. Systemic treatment of animals with 5-Aza-dC significantly increased the expression of TRPV1, TRPA1, and PIEZO2 in TG. Furthermore, the overexpression of DNMT3a, as delivered by a lentiviral vector, significantly downregulated TRPV1 and PIEZO2 expression and also reliably decreased TRPA1 and P2X3 transcripts. MeDIP revealed that this overexpression also significantly enhanced methylation of CGIs associated with TRPV1 and TRPA1. In addition, bisulfite sequencing data indicated that the CGI associated with TRPA1 was methylated in a pattern catalyzed by DNMT3a. Taken together, our results show that all 4 pro-nociceptive genes are subject to epigenetic modulation via DNA methylation, likely via DNMT3a under inflammatory conditions. These findings provide the first evidence for the functional importance of DNA methylation as an epigenetic factor in the transcription of pro-nociceptive genes in TG that are implicated in pathological orofacial pain responses.

Circulating exosomal microRNA profiles in migraine patients receiving acupuncture treatment: A placebo-controlled clinical trial

“…Moreover, assessment of the combination of hsa-miR-369-5p, hsa-miR-145-5p, and hsa-miR-5,010-3p could increase the accuracy. It should be noted that miR-369-5p has been reported to target DNMT3A ( Tao et al, 2018 ), and overexpression of DNMT3A could significantly lower TRPV1 expression ( Bai et al, 2020 ). TRPV1 plays an important role in the pathophysiology of migraine ( Meents et al, 2010 ).…”

Familial occurrence of classical and idiopathic trigeminal neuralgia

“…via deoxyribonucleic acid (DNA) methylation that regulates gene expression. Bai et al [43] found that peripheral inflammation altered DNA methylation in rat trigeminal ganglia, which was accompanied with abnormal expression of pro-nociceptive genes. The observation indicates that trigeminal ganglia pro-nociceptive genes may be subject to epigenetic modulation via DNA methylation.…”

A Review of Recent Evidence on Trigeminal Neuralgia

“…The role of epigenetic factors has also been highlighted by several experimental studies, with one reporting observation of peripheral inflammation-altered DNA methylation in rat trigeminal ganglia and consequent abnormal expression of pro-nociceptive genes [14]. Bai et al [26] suggested that trigeminal ganglia pro-nociceptive genes may be subject to epigenetic modulation via DNA methylation that regulates genes.…”