Histone Methyltransferase G9a in Primary Sensory Neurons Promotes Inflammatory Pain and Transcription of and via Bivalent Histone Modifications.

Transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) channels are crucial for detecting and transmitting nociceptive stimuli. Inflammatory pain is associated with sustained increases in TRPA1 and TRPV1 expression in primary sensory neurons. However, the epigenetic mechanisms driving this upregulation remain unknown. G9a (encoded by ) catalyzes H3K9me2 and generally represses gene transcription. In this study, we found that intrathecal administration of UNC0638, a specific G9a inhibitor, or G9a-specific siRNA, substantially reduced complete Freund's adjuvant (CFA)-induced pain hypersensitivity. Remarkably, CFA treatment did not induce persistent pain hypersensitivity in male and female mice with conditional knock-out in dorsal root ganglion (DRG) neurons. RNA sequencing and quantitative PCR analyses showed that CFA treatment caused a sustained increase in mRNA levels of and in the DRG. knock-out in DRG neurons elevated baseline and mRNA levels but notably reversed CFA-induced increases in their expression. Chromatin immunoprecipitation revealed that CFA treatment reduced G9a and H3K9me2 levels while increasing H3K9ac and H3K4me3-activating histone marks-at and promoters in the DRG. Strikingly, conditional knock-out in DRG neurons not only diminished H3K9me2 but also reversed CFA-induced increases in H3K9ac and H3K4me3 at and promoters. Our findings suggest that G9a in primary sensory neurons constitutively represses and transcription under normal conditions but paradoxically enhances their transcription during tissue inflammation. This latter action accounts for inflammation-induced TRPA1 and TRPV1 upregulation in the DRG. Thus, G9a could be targeted for alleviating persistent inflammatory pain.