Epigenetics: the impact of gene expression on chronic pain

by Matthew Jones
MBS2018, Geisinger Commonwealth School of Medicine
mjones01@som.geisinger.edu
Mentor: Dr. Gregory Shanower, PhD 
Peripheral neuropathic pain refers to pain that is associated with damage or degeneration of peripheral nerves within the human body. These nerves can become damaged in many ways, including infection, metabolic disease, cancer, chemotherapy, and nutritional deficiencies; it can also be induced in mice so that it could be studied [1,2,3]. Damaged neurons can become increasingly sensitive to usually non-painful stimuli and can produce abnormal feelings and sensations in the areas of the body affected by neuropathy, making day-to-day life uncomfortable and sometimes unbearable to people suffering from peripheral neuropathy [3]. Currently, treatment includes the use of anti-depressants, anticonvulsants and topical ointments. However, it is reported that only 40 - 60% of patients receive partial relief, suggesting that these treatments are not effective in alleviating the symptoms associated with peripheral neuropathy [2,3,4]. Despite a lack of success with traditional treatment, there have been promising results in the realm of precision medicine, in which genetic and epigenetic processes have contributed to the relief of pain and abnormal sensations associated with peripheral nerve damage [5]. Epigenetic modification refers to changes that impact gene expression, without altering the genetic code itself. In other words, epigenetics may determine which genes are turned on and which genes are turned off.

A recent study [1] identified that the expression of a receptor gene (mGlu2) in the peripheral nervous system appears to be regulated by the combined activity of several epigenetic enzymes which regulate protein acetylation. Protein acetylation is the addition of a chemical acetyl group to a protein (histone). Histones are proteins that form a structure around which DNA, our genetic material, is wrapped in the cell nucleus. Acetylation on specific sites of the histones is associated with expression of genes. Conversely, histone deacetylase enzymes (HDACs) reduce histone acetylation and inactivate gene expression. When HDACs are active in the peripheral nervous tissue, expression of the mGlu2 gene is reduced through the deacetylation of the histones, and this reduced mGlu2 expression leads to inflammation and pain. Histone acetyl- and deacetyl-transferase enzymes also target a transcription factor protein involved in regulating the expression of the mGlu2 gene. HDAC enzymes target and inactivate this transcription factor by removing an acetylation groups from the protein. 

Mouse models of neuropathic and inflammatory pain response were treated with a histone deacetylase inhibitor (HDACi) with the intention of increasing the expression of mGlu2 receptors in the spinal cords of the mice. Two HDACi compounds were tested, MS-275 and SAHA [1]. It was observed that MS-275 and SAHA were both effective at increasing mGlu2 receptors after a 7-day treatment of 3 mg/kg and 50 mg/kg respectively. In order to test the pain threshold of the mice (and confirm that mGlu2 expression decreased pain), mice were subjected to a painful stimulus and their responses recorded [1]. Results showed that there was indeed an increase in the expression of the mGlu2 receptors in the spinal cord of the mice, and that this lessened the pain, which is known as analgesic effect. The blocked deacetylation of the of the transcription factor mediated the mGlu2 receptor protein expression in mice, and this decreased the inflammatory response from damaged nerves, and lowered the level of pain the mice experienced.

These studies show the far-reaching effects of genetic and epigenetic manipulations, and how they can be used to treat pain and disease more effectively. In addition to being effective in treating neuropathic and inflammatory pain, HDACis have also shown results when applied to the treatment of different types of cancer. [6,7]. Therefore, HDACis are a promising new generation of drugs; however, future studies are needed to improve the use and delivery of these agents.

Here is a link to an animation that explains in detail the information in this post.


References
1. Chiechio S, Zammataro M, Morales ME, Busceti CL, Drago F, Gereau RW, Copani A, Nicoletti F. Epigenetic Modulation of mGlu2 Receptors by Histone Deacetylase Inhibitors in the Treatment of Inflammatory Pain. Molecular Pharmacology 75: 1014–1020, 2009.

2. Danette C. Taylor, DO, MS, FACN. What Is Neuropathic Pain? Treatment, Medication, Definition [Online]. MedicineNet. https://www.medicinenet.com/neuropathic_pain_nerve_pain/article.htm [12 Dec. 2017]

3. Neuropathic pain [Online]. Wikipedia Wikimedia Foundation: 2017. https://en.wikipedia.org/wiki/Neuropathic_pain [11 Dec. 2017].

4. Dworkin RH, O’Connor AB, Backonja M, Farrar JT, Finnerup NB, Jensen TS, Kalso EA, Loeser JD, Miaskowski C, Nurmikko TJ, Portenoy RK, Rice AS, Stacey BR, Treede R-D, Turk DC, Wallace MS. Pharmocologic management of neuropathic pain: evidence-based recommendations. Pain 132: 237-251, 2007.

5. Lin T-B, Hsieh M-C, Lai C-Y, Cheng J-K, Wang H-H, Chau Y-P, Chen G-D, Peng H-Y. Melatonin relieves neuropathic allodynia through spinal MT2-enhanced PP2Ac and downstream HDAC4 shuttling-dependent epigenetic modification ofhmgb1 transcription. Journal of Pineal Research 60: 263–276, 2016.

6. Ropero S, Esterller M. The role of histone deacetylases (HDACs) in human cancer. Molecular Oncology 1: 19-25, 2007.

7. Tate CR, Rhodes LV, Segar HC, Driver JL, Pounder FN, Burow ME, Collins-Burrow BM. Targeting triple-negative breast cancer cells with the histone deacetylase inhibitor panibinostat. Breast Cancer Research 14, 2012.