Epigenetic Regulator Controls Pain

Epigenetic Regulator Controls Development and Maintenance of Chronic Pain | Pain Research Forum | by Matthew Soleiman | Nov 2015

Chronic pain is associated with changes in expression of thousands of genes, making it hard to identify viable genetic targets for pain therapies.

Pain researchers have thus turned to the much smaller number of epigenetic mechanisms, which scale gene expression up or down without editing DNA sequences, as possible targets for better treatments

The authors have undoubtedly shown that G9a is key to the development and maintenance of long-term neuropathic pain states

though she said it remains unclear which genes affected by G9a are responsible for pain relief. “G9a activity regulates the expression of many genes associated with neuropathic pain, and therefore it is currently impossible to attribute the analgesic effect of its inhibition to any specific gene.”

The epigenetics of nerve injury-induced pain

since epigenetic processes, including post-translational modification of histones via acetylation and methylation, affect many genes, researchers have begun to explore how such alterations affect gene expression patterns in the development of chronic neuropathic pain (Denk et al., 2013); histones are the proteins around which DNA wraps.

the authors found that expression of over 2,000 genes was altered in injured DRG, with 42 of these being downregulated potassium channels. “What was really surprising was that the expression level of most (40) of the potassium channel genes was rescued by simply inhibiting G9a activity,” said Pan. In fact, G9a inhibition normalized expression of about 600 genes. Hence, G9a acted on a genomewide scale after nerve injury.

G9a drives pain behavior

Since the earlier experiments indicated that G9a controls expression of hundreds of genes, “potassium channel genes are probably only part of the mechanism of how the G9a inhibitor reduced chronic pain—other signaling pathways are probably also responsible,”

While the authors focused on injured DRG following SNL, Geranton said that G9a may also be important in uninjured DRG. “There is strong evidence to suggest that molecular changes in the uninjured afferents may underlie the development and/or maintenance of neuropathic pain as well,

References: G9a is essential for epigenetic silencing of K(+) channel genes in acute-to-chronic pain transition. Laumet G, Garriga J, Chen S-R, Zhang Y, Li D-P, Smith TM, Dong Y, Jelinek J, Cesaroni M, Issa J-P, Pan H-L Nat Neurosci. 2015 Dec; 18(12):1746-55. Epub 2015 Nov 09.  

 

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