G9a Is Essential for Epigenetic Silencing of K(+) Channel Genes in Acute-to-Chronic Pain Transition

Neuropathic pain is a debilitating clinical problem and difficult to treat. Nerve injury causes a long-lasting reduction in K(+) channel expression in the dorsal root ganglion (DRG), but little is known about the epigenetic mechanisms involved. Here we show that nerve injury increased H3K9me2 occupancy at Kcna4, Kcnd2, Kcnq2 and Kcnma1 promoters but did not affect DNA methylation levels of these genes in DRGs. Nerve injury increased activity of G9a, histone deacetylases and EZH2, but only G9a inhibition consistently restored K(+) channel expression. Selective G9a knockout in DRG neurons completely blocked K(+) channel silencing and chronic pain development after nerve injury. Remarkably, RNA sequencing analysis revealed that G9a inhibition not only reactivated 40 of 42 silenced K(+) channel genes but also normalized 638 genes down- or up-regulated by nerve injury. Thus G9a plays a dominant role in transcriptional repression of K(+) channels and in acute-to-chronic pain transition after nerve injury.