Figure 2. Epigenetic modifications in neuropathic pain.
( A) DNA methylation (Me) occurs mostly at the cytosine of CpG sites 55, 61 (i) but can also happen at the cytosine of CpH sites (H = A, T, or C) 67 (ii). (iii) DNA methyltransferase 3b (DNMT3b) downregulation leads to the demethylation at the CpG sites in the purinergic P2X3 receptor gene promoter 70. ( B) Histone modifications: (i) DNA is wrapped around histone octamers that consist of histones H2A, H2B, H3, and H4. Histone tails, particularly on H3 and H4, can be acetylated (Ac), phosphorylated (Ph), or Me; (ii) Dimethyltransferase G9a mediates dimethylation (me2) of lysine 9 (K9me2) on histone H3 of the promoters of genes encoding K + channels 72 or MOR 73. ( C) Enhancers (orange) are non-coding DNA regions that can be activated by local nucleosome remodeling and binding of transcription factors (TFs), thereby influencing gene expression 21: (i) An inactive enhancer is packed in compact chromatin and cannot be bound by TFs. (ii) Following nerve injury, increased TF binding at spinal microglia enhancers was identified for genes encoding complement system member C4b and chemokines CCL5 and CCL12 [22]. ( D) ncRNAs and their targets in the spinal cord and DRG (listed in the respective dashed boxes) involved in neuropathic pain following SNI or ScNI in mice or rats. ncRNAs include analgesic miRNAs (miR-7a, miR-183, miR-146a-5p) 80– 82 and pain-promoting long non-coding RNA (Kcna2 antisense RNA) 79 or miRNAs (miR-195, miR-221, miR-132-3p) 83– 85. ↓, downregulation; ↑, upregulation; ?, unidentified target; ATG14, gene encoding protein that facilitates autophagy; BDNF, brain-derived neurotrophic factor; CpG, cytosine–phosphate–guanine dinucleotide; DRG, dorsal root ganglion; Kv, voltage-gated potassium channel; miRNA, microRNA; MOR, µ-opioid receptor; Nav, voltage-gated sodium channel; ncRNA, non-coding RNA; ScNI, sciatic nerve injury; SNI, spinal nerve injury; SOCS1, suppressor of cytokine signaling 1, a protein suppressing cytokine signaling; TRAF6, tumor necrosis factor (TNF) receptor associated factor 6, an adapter protein mediating TNF-α signaling.