Epigenetic Landscapes of Pain: DNA Methylation Dynamics in Chronic Pain

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2024 Aug 10

PMID 39125894

Authors

Huan-Yu Xiong

Arne Wyns

Jente Van Campenhout

Jolien Hendrix

Elke de Bruyne

Lode Godderis

Siobhan Schabrun

Jo Nijs

Andrea Polli

Affiliations

Soon will be listed here.

Abstract

Chronic pain is a prevalent condition with a multifaceted pathogenesis, where epigenetic modifications, particularly DNA methylation, might play an important role. This review delves into the intricate mechanisms by which DNA methylation and demethylation regulate genes associated with nociception and pain perception in nociceptive pathways. We explore the dynamic nature of these epigenetic processes, mediated by DNA methyltransferases (DNMTs) and ten-eleven translocation (TET) enzymes, which modulate the expression of pro- and anti-nociceptive genes. Aberrant DNA methylation profiles have been observed in patients with various chronic pain syndromes, correlating with hypersensitivity to painful stimuli, neuronal hyperexcitability, and inflammatory responses. Genome-wide analyses shed light on differentially methylated regions and genes that could serve as potential biomarkers for chronic pain in the epigenetic landscape. The transition from acute to chronic pain is marked by rapid DNA methylation reprogramming, suggesting its potential role in pain chronicity. This review highlights the importance of understanding the temporal dynamics of DNA methylation during this transition to develop targeted therapeutic interventions. Reversing pathological DNA methylation patterns through epigenetic therapies emerges as a promising strategy for pain management.

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References

Jackson T, Thomas S, Stabile V, Han X, Shotwell M, McQueen K . Prevalence of chronic pain in low-income and middle-income countries: a systematic review and meta-analysis. Lancet. 2015; 385 Suppl 2:S10. DOI: 10.1016/S0140-6736(15)60805-4. View

Wu Y, Zhang H, Lu X, Du H, Li Y, Zhang P . Targeting GATA1 and p2x7r Locus Binding in Spinal Astrocytes Suppresses Chronic Visceral Pain by Promoting DNA Demethylation. Neurosci Bull. 2021; 38(4):359-372. PMC: 9068853. DOI: 10.1007/s12264-021-00799-1. View

Kaas G, Zhong C, Eason D, Ross D, Vachhani R, Ming G . TET1 controls CNS 5-methylcytosine hydroxylation, active DNA demethylation, gene transcription, and memory formation. Neuron. 2013; 79(6):1086-93. PMC: 3816951. DOI: 10.1016/j.neuron.2013.08.032. View

Shiers S, Price T . Molecular, circuit, and anatomical changes in the prefrontal cortex in chronic pain. Pain. 2020; 161(8):1726-1729. PMC: 7575617. DOI: 10.1097/j.pain.0000000000001897. View

Topper M, Vaz M, Marrone K, Brahmer J, Baylin S . The emerging role of epigenetic therapeutics in immuno-oncology. Nat Rev Clin Oncol. 2019; 17(2):75-90. PMC: 7254932. DOI: 10.1038/s41571-019-0266-5. View

Moller Johansen L, Gerra M, Arendt-Nielsen L . Time course of DNA methylation in pain conditions: From experimental models to humans. Eur J Pain. 2020; 25(2):296-312. DOI: 10.1002/ejp.1674. View

Gombert S, Rhein M, Winterpacht A, Munster T, Hillemacher T, Leffler A . Transient receptor potential ankyrin 1 promoter methylation and peripheral pain sensitivity in Crohn's disease. Clin Epigenetics. 2020; 12(1):1. PMC: 6938615. DOI: 10.1186/s13148-019-0796-9. View

Bautista D, Jordt S, Nikai T, Tsuruda P, Read A, Poblete J . TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell. 2006; 124(6):1269-82. DOI: 10.1016/j.cell.2006.02.023. View

Wang W, Li C, Cai Y, Pan Z . Pain vulnerability and DNA methyltransferase 3a involved in the affective dimension of chronic pain. Mol Pain. 2017; 13:1744806917726713. PMC: 5580851. DOI: 10.1177/1744806917726713. View

10.

Chen W, Wang X, Sun Q, Zhang Y, Liu J, Hu T . The upregulation of NLRP3 inflammasome in dorsal root ganglion by ten-eleven translocation methylcytosine dioxygenase 2 (TET2) contributed to diabetic neuropathic pain in mice. J Neuroinflammation. 2022; 19(1):302. PMC: 9756585. DOI: 10.1186/s12974-022-02669-7. View

11.

Choi L, Huang J . A pilot study of S-adenosylmethionine in treatment of functional abdominal pain in children. Altern Ther Health Med. 2013; 19(5):61-4. View

12.

Zhang W, Spector T, Deloukas P, Bell J, Engelhardt B . Predicting genome-wide DNA methylation using methylation marks, genomic position, and DNA regulatory elements. Genome Biol. 2015; 16:14. PMC: 4389802. DOI: 10.1186/s13059-015-0581-9. View

13.

Sukenaga N, Ikeda-Miyagawa Y, Tanada D, Tunetoh T, Nakano S, Inui T . Correlation Between DNA Methylation of TRPA1 and Chronic Pain States in Human Whole Blood Cells. Pain Med. 2016; 17(10):1906-1910. DOI: 10.1093/pm/pnv088. View

14.

Zanette S, Dussan-Sarria J, Souza A, Deitos A, Torres I, Caumo W . Higher serum S100B and BDNF levels are correlated with a lower pressure-pain threshold in fibromyalgia. Mol Pain. 2014; 10:46. PMC: 4094546. DOI: 10.1186/1744-8069-10-46. View

15.

Zhao J, Liang L, Gu X, Li Z, Wu S, Sun L . DNA methyltransferase DNMT3a contributes to neuropathic pain by repressing Kcna2 in primary afferent neurons. Nat Commun. 2017; 8:14712. PMC: 5344974. DOI: 10.1038/ncomms14712. View

16.

Haas L, Portela L, Bohmer A, Oses J, Lara D . Increased plasma levels of brain derived neurotrophic factor (BDNF) in patients with fibromyalgia. Neurochem Res. 2010; 35(5):830-4. DOI: 10.1007/s11064-010-0129-z. View

17.

Chahrour M, Jung S, Shaw C, Zhou X, Wong S, Qin J . MeCP2, a key contributor to neurological disease, activates and represses transcription. Science. 2008; 320(5880):1224-9. PMC: 2443785. DOI: 10.1126/science.1153252. View

18.

Descalzi G, Ikegami D, Ushijima T, Nestler E, Zachariou V, Narita M . Epigenetic mechanisms of chronic pain. Trends Neurosci. 2015; 38(4):237-46. PMC: 4459752. DOI: 10.1016/j.tins.2015.02.001. View

19.

Gershman A, Sauria M, Guitart X, Vollger M, Hook P, Hoyt S . Epigenetic patterns in a complete human genome. Science. 2022; 376(6588):eabj5089. PMC: 9170183. DOI: 10.1126/science.abj5089. View

20.

Kriaucionis S, Heintz N . The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science. 2009; 324(5929):929-30. PMC: 3263819. DOI: 10.1126/science.1169786. View