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 Table of Contents  
EDITORIAL
Year : 2017  |  Volume : 31  |  Issue : 1  |  Page : 7-8

Epigenetics, pain, and analgesia


1 Consultant Scientist, Sri Ramakrishna Multi-Speciality Hospital, Coimbatore, Tamil Nadu, India
2 Consultant in Pain Medicine, Sri Ramakrishna Multi-Speciality Hospital, Coimbatore, Tamil Nadu, India

Date of Web Publication5-May-2017

Correspondence Address:
Krishnan Sivaraman
Department of Pain Medicine, Sri Ramakrishna Multi-Speciality Hospital, No: 395, Sarojini Naidu Road, Sidhapudur, Coimbatore - 641 044, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijpn.ijpn_30_17

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How to cite this article:
Sivaraman K, Vijayanand P. Epigenetics, pain, and analgesia. Indian J Pain 2017;31:7-8

How to cite this URL:
Sivaraman K, Vijayanand P. Epigenetics, pain, and analgesia. Indian J Pain [serial online] 2017 [cited 2017 Oct 17];31:7-8. Available from: http://www.indianjpain.org/text.asp?2017/31/1/7/205718




  Introduction Top


To understand the genome function in relation to pathogenesis of a disease is to understand how it gets integrated into the architectural framework of the cell nucleus and how structural elements of the nucleus affect nuclear processes including gene expression. The process of DNA packaging helps in conservation of space within cells, similar to the way in which drawers help to conserve space in an office. Approximately 2 m of DNA is fit into the nucleus of the cell which is just a few micrometers wide aided by DNA packaging. It is intriguing to understand the mechanisms by which the cells access this highly compacted genetic material. DNA present in the cell is never bare; it is accompanied by other proteins to form a complex with various protein partners that help in DNA packaging it into such a tiny space. This DNA-protein complex is called chromatin. The nucleosome is the basic unit of chromatin, in which about 146 bp of double-stranded DNA is wrapped around a histone octamer. The compaction of the genome in the form of chromatin limits accessibility of genes to transcription factors. For proper regulation of gene expression to occur, changes in chromatin structure, called chromatin remodeling, must take place. Altered accessibility of transcription factors to the regulatory DNA is the result of chromatin remodeling contributed by chromatin remodeling complexes such as SWI/SNF and nucleosome remodeling and deacetylase families.[1]


  Epigenetic Mechanisms Top


In addition to chromatin remodeling, DNA and histone modification also regulate chromatin structure and function. Two sets of epigenetic mechanisms are involved in the regulation of gene expression constituting the epigenome in each cell: (i) the changes are brought about primarily by biochemical modifications to histones which include methylation, acetylation, ubiquitination, and phosphorylation of histones and (ii) DNA methylation. These mechanisms exhibit control over different biological processes such as cell differentiation, proliferation, pre-mRNA processing, survival, genomic imprinting, and X chromosome inactivation.[2],[3] A common mechanism of modifying chromatin structure is the covalent addition (or removal) of acetyl, methyl, phosphoryl, or other moieties to the amino-terminal tail domains of the core histones by specific enzymes.[4] Epigenetic regulation is a dynamic process. Epigenetic mechanisms involve various chromatin-modifying enzymes and associated proteins often referred to as “writers,” “readers,” and “erasers.” “Writers” such as histone acetyltransferases (HATs), histone methyltransferases, protein arginine methyltransferases, and kinases catalyze the addition of chemical groups onto either histone tails or the DNA itself. “Erasers” such as histone deacetylases (HDACs), lysine demethylases, and phosphatases catalyze the removal of specific posttranscriptional modifications from histone substrates. “Readers” are dedicated protein factors that contain chromodomains, bromodomains, Tudor domains, and DNA methyl-binding domains. Specific posttranslational marks on histones or a combination of marks and histone variants are recognized by “Readers” that direct a particular transcriptional outcome.[5] Methylation of cytosine residues in genomic DNA is another major epigenetic modification, which plays an important role in genomic imprinting and X-chromosome inactivation. CpG dinucleotides form the consensus target sequences of DNA methylation by various DNA methyltransferases (DNMTs). In mammalian cells, only relatively small CpG dinucleotides get methylated.[6] Cellular plasticity is enabled by the integration of environmental changes by epigenetic mechanisms. For normal functioning of the cells, a strict regulation of the activity of these proteins is necessary. Often, misregulation of writers, readers, and erasers leads to aberrant gene transcription and other diseases.


  Epigenetics and Pain Top


Although pain is a protective phenomenon, persistent experiencing of it leads to considerable deterioration of the quality of life in patients. Chronic pain affects approximately one in five adults and is associated with higher risk of depression and other mental health disorders.[7] PubMed search with the term “pain epigenetics” resulted in 353 articles, of which 132 were reviews. Search with keywords “pain genetics” resulted in 17690, and 3083/17690 articles were reviews showing the dearth of research about the role of epigenetics in pain though a comparatively greater amount of information is available with respect to genetics of pain,

The field of epigenetics provides a new hope for pain research. Understanding the epigenetic mechanisms of various diseases associated with chronic pain at a molecular level is essential for understanding the initiation and progression of the disease. Aberrant expression of chromatin modifying proteins can serve as a direct biomarker in various diseases associated with chronic pain and act as an indicator for proper diagnosis. Identifying the cause of gene misregulation provides opportunities for further development of drugs that can target the cause and eliminate it.

A lot of effort has been made in discovering candidate genes responsible for pain and to figure out the role of specific genes in different aspects of pain signaling. However, instead of considering individual pain-related genes, it would be rather fruitful to consider a more holistic approach that considers epigenetic mechanisms that coordinate and result in different patterns of gene expression related to chronic painful conditions. There are only a few epigenetic therapeutic targets associated with pain. It would be preferable, therefore, to target the underlying epigenetic cause, which could have a greater effect on the outcome as a consequence of the cause being treated in a holistic way.[8] Although the overall role of histone modifications and modifiers of chromatin on pain is understood to some extent, the individual role played by histone modification and chromatin modifiers is poorly understood.

Very few studies are available to demonstrate the potential role of DNA methylation and the activity and expressional levels of DNMTs in pain. Compared with age-matched healthy controls, women with fibromyalgia showed significant differences in DNA methylation patterns. Similarly, hypomethylation was seen in promoter regions of key genes such as CHI3L1, CASP1, STAT3, MAP3K5, MEFV, and WISP3 associated with rheumatoid arthritis.[9]


  Epigenetics and Analgesia Top


The epigenetic phenomenon is reversible, and this provides options to reactivate or silence a gene according to the pathology. A novel concept in the fields of epigenetics and medicine is the epi-drugs, which are natural or synthetic inhibitors of certain histone modifying enzymes, and which are currently considered as potential candidates for pain relief.

Changes in acetylation pattern were seen at the promoters of some pain-related genes such as μ opioid receptor, Kv4.3, Nav1.8, and brain-derived neurotrophic factor. Both HAT inhibitors and HDAC inhibitors show antinociceptive effects in neuropathic pain. MS-275 and SAHA, known HDAC inhibitors, show antinociception by upregulating mGlu2 receptor expression in dorsal root ganglion. Local injection of HDAC inhibitors Trichostatin A (TSA) and SAHA into nucleus raphe magnus demonstrated the analgesic effect on complete Freund's adjuvant-induced inflammatory pain. TSA is also known to reduce visceral pain, but the mechanisms are yet to be deciphered. Spinal nerve ligation-induced neuropathic pain was relieved by anacardic acid, a HAT inhibitor by suppressing the hyperacetylation of histone H3 in the promoter region of macrophage inflammatory protein 2 and its receptor chemokine C-C motif receptor 2. Curcumin, a HAT inhibitor, when administered daily along with morphine for 4 days, reduces the development of morphine-induced mechanical allodynia, thermal hyperalgesia, tolerance, and physical dependence.[9] There is now a need to verify the role of histone acetylation and deacetylation in detail.

The DNA methylation inhibitor 5-azacytidine attenuated chronic constriction injury-induced thermal and mechanical pain hypersensitivities. Intrathecal 5-azacytidine is known to block spinal cord DNA methylation on the whole,[9] the exact mechanism of which needs to be studied.


  The Future Top


The latest development in the field of medicine is epigenome editing. It involves directed alteration of chromatin marks at specific genomic loci using targeted EpiEffectors. EpiEffectors comprising designed DNA recognition domains (zinc finger, TAL effector, or modified CRISPR/Cas9 complex) and catalytic domains from a chromatin-modifying enzyme are the need of the hour to effectively target epigenetic mechanisms.[10] These pieces of evidence stand testament to the importance of histone modifications and DNA methylation in pain. The epi-drugs show varying degrees of specificity and selectivity for the corresponding epigenetic enzymes. The nonepigenetic mechanisms resulting in potential side effects cannot be ruled out as it may inhibit the role of chromatin modifiers or the DNMTs nonspecifically, thereby affecting other genes globally. There is a need, therefore, to understand the role of epigenetics before administration of an apt epi-drug. Epi-drugs along with EpiEffectors carry the promise of going a long way in the alleviation of chronic pain.



 
  References Top

1.
Kouzarides T. Chromatin modifications and their function. Cell 2007;128:693-705.  Back to cited text no. 1
[PUBMED]    
2.
Mazzio EA, Soliman KF. Basic concepts of epigenetics: Impact of environmental signals on gene expression. Epigenetics 2012;7:119-30.  Back to cited text no. 2
[PUBMED]    
3.
Inbar-Feigenberg M, Choufani S, Butcher DT, Roifman M, Weksberg R. Basic concepts of epigenetics. Fertil Steril 2013;99:607-15.  Back to cited text no. 3
[PUBMED]    
4.
Bulger M. Hyperacetylated chromatin domains: Lessons from heterochromatin. J Biol Chem 2005;280:21689-92.  Back to cited text no. 4
[PUBMED]    
5.
Falkenberg KJ, Johnstone RW. Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders. Nat Rev Drug Discov 2014;13:673-91.  Back to cited text no. 5
[PUBMED]    
6.
Jones PA, Takai D. The role of DNA methylation in mammalian epigenetics. Science 2001;293:1068-70.  Back to cited text no. 6
[PUBMED]    
7.
Gureje O, Von Korff M, Simon GE, Gater R. Persistent pain and well-being: A World Health Organization Study in Primary Care. JAMA 1998;280:147-51.  Back to cited text no. 7
[PUBMED]    
8.
McMahon S, Denk F. Pain Research Forum. Pain Epigenetics: Current Research and Future Challenges; 16 April, 2015. Available from: http://www.painresearchforum.org/forums/webinar/52055-webinar-pain-epigenetics-current-research-and-future-challenges. [Last accessed on 2017 Mar 30].  Back to cited text no. 8
    
9.
Liang L, Lutz BM, Bekker A, Tao YX. Epigenetic regulation of chronic pain. Epigenomics 2015;7:235-45.  Back to cited text no. 9
[PUBMED]    
10.
Kungulovski G, Jeltsch A. Epigenome editing: State of the art, concepts, and perspectives. Trends Genet 2016;32:101-13.  Back to cited text no. 10
[PUBMED]    




 

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The Future
Introduction
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Epigenetics and Pain
Epigenetics and ...
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