Table 1.
Studies investigating the role of histone modifications in migraine development.
| Study | Title | First Author | Sample | Ethnicity | Genes/Molecules Assessed | Findings |
|---|---|---|---|---|---|---|
| [24] | A high methylation level of a novel −284 bp CpG island in the RAMP1 gene promoter is potentially associated with migraine in women | Carvalho Estefânia | 104 females (54 migraineurs, 50 controls) |
Portuguese | RAMP1 gene promotor methylation | 5 differently methylated CpG dinucleotides (−346, −334, −284, −276, and −234 1) were assessed; −284 CpG unit found to be significantly methylated in migraineurs |
| [25] | Epigenetic regulation of the calcitonin gene-related peptide gene in trigeminal glia | Ki-Youb Park | Rat and human model cell lines; primary cultures of rat TG 11 glia | - | DNA methylation and histone acetylation in the promotor region of the CALCA gene | CT and CGRP mRNAs were assessed; CpG island methylation and histone H3 acetylation at the 18 bp cell-specific enhancer correlated with CALCA gene expression |
| [41] | Methylation of migraine-related genes in different tissues of the rat | Labruijere, S. | Rat tissues (leukocytes, thoracic aorta, dura mater, TG, caudal nuclei); 395 healthy women |
- | Comparison of DNA methylation of migraine-specific genes in different migraine-related tissues: Calca, Ramp1, Crcp, Calcrl, Usf2, Esr1, Gper, Nos3, Mthfr Comparison of DNA methylation of migraine-specific genes between rats and humans |
Methylation of the Crcp, Calcrl, Esr1, and Nos3 genes is tissue-specific; methylation in leukocytes does not correlate with that in other tissues |
| [42] | Using monozygotic twins to dissect common genes in posttraumatic stress disorder and migraine | Charlotte K Bainomugisa | Total: 42 monozygote twins PTSD: 12 participants (10 males, 2 females) Migraineurs: 30 participants (14 males, 16 females) |
Caucasian | Genome-wide DNA methylation levels assessment | Differently methylated genes ADCYAP1, AIM2, CRHR1, DBH, DOCK2, FKBP5, HTR3A, OXTR, RORA, WWC1, and TSNARE1 |
| [43] | Genome-wide DNA methylation profiling in whole blood reveals epigenetic signatures associated with migraine | Gerring Zachary F. | 67 migraineurs and 67 age- and sex = matched controls | Northern Europeans | Epigenome-wide analysis of differently methylated regions | No single methylation probe reached genome-wide significance |
| [44] | Epigenetic DNA methylation changes associated with headache chronification: A retrospective case–control study |
Winsvold, B.S. | 36 female headache patients 35 controls with episodic headache |
Norwegian | Assessment of DNA methylation at 485,000 CpG sites | Possible association of 2 CpG sites in SH2D5 and NPTX2 genes with chronification of episodic headache |
| [45] | Methylation analysis of NPTX2 and SH2D5 genes in chronic migraine: A case–control study |
Sara Perez Pereda | 109 CM patients; 98 EM patients; 98 controls |
N/A | Assessment of methylation of two CpG sites related to NPTX2 7 and SH2D5 8 | No significant differences in methylation levels between CM, EM, and HC 9 in the first exon of the NPTX2 gene or the 50 upstream region of the SH2D5 gene |
| [46] | Epigenetic DNA methylation changes in episodic and chronic migraine | Terlizzi, R. | 18 MOH; 20 EM patients; 11 HC |
N/A | Genome-wide DNA methylation levels association with headache chronification | Hypermethylation of chr10:76993892 island in COMT gene in MOH cases compared to HCs; hypomethylation of GpG site at chr12:110433797-110434205*Island in MOH cases compared to HCs (GIT2 gene), at chr19:44645494-44646069*N_Shore in MOH cases compared to HCs (ZNF234 gene), and at chr16:11348541-11350803*Island in MOH cases compared to HCs (SOCS1 gene) |
| [47] | Analysis of epigenetic age predictors in pain-related conditions | K. M. Kwiatkowska | 22 MOH 10 patients; 18 EM patients; 13 HC |
Italian | Association between epigenetic age and chronic pain, by investigating first- and second-generation epigenetic clocks and DNA methylation surrogates of plasma proteins, blood cell counts, and telomere length in headache conditions |
No significant difference in epigenetic age acceleration, DNA methylation surrogates comprised in GrimAg, and estimates of telomere length and blood cell counts between MOH cases and HCs or between EM cases and HCs. |
| [48] | Neuronal complexity is attenuated in preclinical models of migraine and restored by HDAC6 inhibition | Bertels Z. | Mouse models of migraine | - | HDAC6 inhibition and its effect in mouse models of migraine | HDAC6 inhibition restored neuronal plasticity and decreased the number of cortical spreading depression events |
| [49] | JNK1 regulates histone acetylation in trigeminal neurons following chemical stimulation | Wu, J. | TG neuron culture | - | The role of JNK/c-Jun cascade in the regulation of acetylation of H3 following chemical stimulation in TG neurons | Mustard oil stimulation activated the JNK/c-Jun pathway significantly by enhancing phospho-JNK1, phospho-c-Jun expression, and c-Jun activity, which were correlated with elevated acetylated H3 histone in TG neurons |
| [50] | Analysis of the DNA methylation pattern of the promoter region of calcitonin gene-related peptide 1 gene in patients with EM: An exploratory case–control study | Elisa Rubino | 22 EM patients; 20 controls |
N/A | Evaluation of DNA methylation of CALCA gene in patients with EM | No differences in methylation of the 30 CpG sites at the distal region of CALCA were found in migraineurs compared with controls; no overall difference was found in the methylation level among these six detected CpG sites at the CALCA proximal promoter between migraineurs and controls; however, the DNA methylation profile in two CpG sites at the proximal promoter region of CALCA was lower in migraineurs when compared to HCs |
| [51] | DNA methylation of RAMP1 gene in migraine: An exploratory analysis | Dongjun Wan | 26 migraineurs, 25 matched controls |
Chinese | DNA methylation levels at RAMP1 promoter region | No significant differences in 13 detected CpG sites or units at the RAMP1 promoter region in migraineurs compared with HC |
| [52] | Peripheral changes of endocannabinoid system components in episodic and chronic migraine patients: A pilot study | Rosaria Greco | 25 EM 2 patients (24 females) 26 CM 3-MO 4 (22 females) 24 Controls (18 females) |
N/A 5 | DNA methylation changes in genes involved in ES 6 components | Methylation of CNR1, CNR2, DAGLA, FAAH, MGLL, NAPEPLD, and RPL19P12 was assessed; DNA methylation analysis did not show any significant differences between patients and controls with regard to the detected CpG sites at the promoter region levels of all the evaluated genes |
1 Related to the TSS (transcription start site; 2 episodic migraine; 3 chronic migraine; 4 medication overuse; 5 not available; 6 endocannabinoid system; 7 neuronal pentraxin II protein; 8 SH2 domain-containing 5 protein; 9 healthy controls; 10 medication overuse headache; 11 trigeminal ganglion.