1000 Section - DNA Methylation Role in Chronic Pain: Potential Therapeutic Targets

In pain, DNA methylation changes the gene expression mediating the transition from acute to chronic pain.    Alterations in DNA methylation via enzymatic changes serve as a “genomic” memory of pain in the prefrontal cortex.  Changes in gene expression and DNA methylation, occur with an up-regulation of genes involved with synaptic function, Synaptotagmin II (syt2), and associated with long-term changes in DNA methylation. Reversing pathological DNA methylation pathways through epigenetic therapeutics may emerge as promising therapeutics.


Design: We reviewed the latest published data on PubMed, NIH website, and Google Scholar in the last 5 years.

Results:
DNA methylation is important in regulating gene expressions. It is catalyzed by DNA methyltransferases (DNMTs), adding methyl groups from S-adenosyl-l-methionine to carbon-5 position of cytosine bases [5-methylcytosine (5mC)].  DNA methylation is mediated by three separate families of proteins: (Methyl-CpG-Binding Domain) MBD, (Ubiquitin-like, containing PHD and RING finger domains 1) UHRF, and zinc finger proteins.  Injuries upregulate MeCP2 in DRG, and downregulates MOR, related to increase in expression of MeCP2. DNMTs, plays key roles in “reading DNA methylation”, may have roles in neuropathic pain 

Understanding methylation or demethylation of gene promoters caused by DNMT, provide new guidance for therapeutic agents. Administering gene-specific siRNA or lentiviral therapy are prospective targets.

Conclusion: DNA methylation is involved in transition from acute to chronic pain.

The intricate relationship between DNA methylation and gene expression is cornerstone in pain regulation. DNMTs add methyl groups to DNA, interfering with gene transcription, blocking binding of transcription factors to gene promoters. Conversely, Ten-Eleven Translocation (TET) enzymes facilitate gene expression via demethylation. Transcriptional regulators (MBD proteins and MeCP2) are indispensable for modulating gene transcription. TET are crucial epigenetic regulators oxidizing 5mC in DNA to 5-hydroxymethylcytosine (5hmC) and oxidizing forms (5fC, 5caC), initiating DNA demethylation, controlling gene expression, causing cell differentiation. Each step carries therapeutic potential.