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. 2022 May 30;23(11):6151. doi: 10.3390/ijms23116151

Table 1.

Epigenetic effects related to CGRP 1 in migraine and migraine-associated syndromes.

Epigenetic Modification Effect Reference
DNA methylation Hypomethylation of two CpG dinucleotides in the promoter of CALCA in sporadic migraine patients [65]
Low DNA methylation trend in the promoter of RAMP1 in migraineurs with higher methylation levels in patients with family history, lower methylation in female migraineurs [68]
Histone modifications Blockade of the CGRP receptor by HDAC6 inhibition, resulting in reversing of NTG-induced chronic allodynia in mice [79]
Co-expression of CGRP-induced abnormal histone modifications, including H3K27me3, with proinflammatory mediators in the spinal dorsal horn and cultured microglial cells [80,81,84]
Altered HDAC2 enrichment in over 1200 genes in microglial cells by CGRP, with most of the genes belonging to immune- and inflammation-related pathways [18]
H3K9ac signal in rat cells expressing CALCA, but lack of such signals in cells non-expressing CALCA; that effect of histone acetylation required DNA methylation to be manifested [14]
CGRP-induced acetylation of H3K9 in astrocytes linked with neuroinflammation in rats with neuropathic pain and H3K9ac enrichment on gene promoters in astroglial cells [87]
Micro RNAs CGRP plasma levels positively correlated with the expression of miR-382-5p, and miR-34a-5p in plasma of migraineurs [93]
Overexpression of miR-30a caused downregulation of CALCA, while knockdown of miR-30 resulted in CALCA upregulation; miR-30a might bind CALCA in its 3′-UTR to degrade it [95]
miR-125a-3p regulated CGRP in inflammatory pain; [99]
increased levels of CGRP induced by NTG were abolished by miR-155-5p antagomir; miR-155-5p agomir aggravated neuroinflammation and central sensitization and increased CGRP expression [100]
Circular RNAs CGRP promoted mmu_circRNA_007893 expression in RAW264.7 macrophages [107]
CGRP regulated migraine-related FOSL2 expression mediated by miR-504-3p sponging by mmu_circRNA_003795 [109,112]
Aberrant expression of mm9_circ_009056 circRNA in CGRP-induced MC3T3 cells [113]
Long non-coding RNAs Gm14461 lncRNA knockdown increased, whereas Gm14461 overexpression decreased CGRP levels in primary mouse trigeminal ganglion neurons [116]
Overexpression of lncRNA-NONRATT021203.2 in rats with induced CIP; lncRNA-NONRATT021203.2 targeted CXCL9, increased in CIP rats; CXCL9 was expressed in the CGRP-positive dorsal root ganglion neurons that colocalized with lncRNA-NONRATT021203.2 [119]

1 Abbreviations: CGRP, calcitonin gene-related peptide; CALCA, calcitonin-related peptide alpha; RAMP1, receptor activity-modifying protein 1; HDAC6, histone deacetylase 6, NTG, nitroglycerin; H3K27me3, trimethylation of histone H3 at lysine 27; H3K9ac, histone H3 acetylated at lysine 9; FOSL2, FOS-like 2 AP-1 transcription factor subunit; CIP, cancer-induced pain; CXCL9, C-X-C motif chemokine ligand 9.