Papers of the Week

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 and expression. Using unbiased steps, we selected the following pro-nociceptive candidate genes that are potentially regulated by DNA methylation: , and . Inhibition of DNMT with 5-Aza-dC in dissociated TG cells produced dose-dependent upregulation of , and . Systemic treatment of animals with 5-Aza-dC significantly increased the expression of , and in TG. Furthermore, the overexpression of DNMT3a, as delivered by a lentiviral vector, significantly downregulated and expression and also reliably decreased and transcripts. MeDIP revealed that this overexpression also significantly enhanced methylation of CGIs associated with and . In addition, bisulfite sequencing data indicated that the CGI associated with 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.