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. 2022 Mar 26;14(1):45.
doi: 10.1186/s13148-022-01265-z.

Epigenome-wide DNA methylation profiling of conditioned pain modulation in individuals with non-specific chronic low back pain

Burel R Goodin  1   2 , Demario S Overstreet  1 , Terence M Penn  1 , Rahm Bakshi  1 , Tammie L Quinn  1 , Andrew Sims  3 , Travis Ptacek  4 , Pamela Jackson  5 , D Leann Long  3 , Edwin N Aroke  6
Affiliations

Epigenome-wide DNA methylation profiling of conditioned pain modulation in individuals with non-specific chronic low back pain

Burel R Goodin et al. Clin Epigenetics. .

Abstract

Background: The pathoanatomic cause of chronic low back pain (cLBP) cannot be identified for up to 90% of individuals. However, dysfunctional processing of endogenous nociceptive input, measured as conditioned pain modulation (CPM), has been associated with cLBP and may involve changes in neuronal gene expression. Epigenetic-induced changes such as DNA methylation (DNAm) have been associated with cLBP.

Methods: In the present study, the relationship between CPM and DNAm changes in a sample of community-dwelling adults with nonspecific cLBP (n = 48) and pain-free controls (PFC; n = 50) was examined using reduced representation bisulfite sequencing. Gene ontology (GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were applied to identify key pathways involved in efficient versus deficient CPM.

Results: Based on CPM efficiency, we identified 6006 and 18,305 differentially methylated CpG sites (DMCs) with q values < 0.01 among individuals with cLBP and PFCs, respectively. Most of the DMCs were hypomethylated and annotated to genes of relevance to pain, including OPRM1, ADRB2, CACNA2D3, GNA12, LPL, NAXD, and ASPHD1. In both cLBP and PFC groups, the DMCs annotated genes enriched many GO terms relevant to pain processing, including transcription regulation by RNA polymerase II, nervous system development, generation of neurons, neuron differentiation, and neurogenesis. Both groups also enriched the pathways involved in Rap1-signaling, cancer, and dopaminergic neurogenesis. However, MAPK-Ras signaling pathways were enriched in the cLBP, not the PFC group.

Conclusions: This is the first study to investigate the genome-scale DNA methylation profiles of CPM phenotype in adults with cLBP and PFCs. Based on CPM efficiency, fewer DMC enrichment pathways were unique to the cLBP than the PFCs group. Our results suggest that epigenetically induced modification of neuronal development/differentiation pathways may affect CPM efficiency, suggesting novel potential therapeutic targets for central sensitization. However, CPM efficiency and the experience of nonspecific cLBP may be independent. Further mechanistic studies are required to confirm the relationship between CPM, central sensitization, and nonspecific cLBP.

Keywords: Central sensitization; Conditioned pain modulation; DNA methylation; Epigenetics; Nonspecific chronic low back pain; RRBS; Reduced representation bisulfite sequencing.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Pie charts showing proportional genomic locations of differential methylated CpGs (DMCs) between individuals with efficient and deficient CPM among participants with cLBP (A) and pain-free controls (B). The DMCs were mapped to human genome (hg38)
Fig. 2
Fig. 2
Top 10 GO term enrichment results of DMCs annotated genes between efficient and deficient conditioned pain modulation participants with cLBP. Notes: All depicted GO terms were statistically significant (p < 0.05)
Fig. 3
Fig. 3
Top 10 KEGG and WikiPathways enrichment results of annotated genes with DMCs between efficient and deficient conditioned pain modulation participants with cLBP. Note: * depicts statistically significant pathways (p < 0.05)
Fig. 4
Fig. 4
Top 10 GO term enrichment results of DMCs annotated genes between efficient and deficient conditioned pain modulation in pain free controls. Notes: All depicted GO terms were statistically significant (p < 0.05)
Fig. 5
Fig. 5
Top 10 KEGG and WikiPathways enrichment results of DMCs annotated genes between efficient and deficient conditioned pain modulation in pain free controls. Note: All depicted KEGG pathways were statistically significant and * depicts statistically significant Wikipathways (p < 0.05)
Fig. 6
Fig. 6
Overlap of significantly enriched (p < 0.05) gene ontologies (GO) and functional pathways from annotated differentially methylated genes (DMG) in chronic low back pain (CLBP) and pain-free control (PFC) groups. Venn diagram shows numbers of unique and overlapping biological processes, cellular components, molecular functions, KEGG pathways, and wikipathways enriched by annotated differentially methylated genes between efficient and deficient conditioned pain modulation comparing CLBP to PFC groups. The red circle represents the number of significant GO or pathways within the PFC group; the yellow circle represents the number of significant GO and pathways within the CLBP group
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