Genetic Expression Assessment of N6-Methyladenosine (m6A) in Relation to Migraine Remission After Pregnancy

Abstract

Migraine is a complex neurological disorder with its cause most likely stemming from polygenic and environmental factors (Aczél et al., 2021; Vetvik & MacGregor, 2021). Migraine attacks involve the activation of the trigeminovascular system, resulting in neurogenic vasodilation and inflammation of the meninges (Aczél et al., 2021). N⁶-Methyladenosine (m6A) is a potential factor in migraine etiology because of the transient state of a migraine and the fact that epitranscriptomic marks are dynamic and reversible, responding to conditions such as stress, pollutants, and hormonal imbalances (Wang, H. et al., 2022; Wang, Q. et al., 2022; Zhang et al., 2020). Studies show that the m6A level in the uterus increases as pregnancy progresses (Tarca et al., 2021), which inspired this exploration of m6A regulators in migraine remission. Epitranscriptomic regulation of gene expression related to migraine risk may explain the difficulty in connecting single nucleotide polymorphisms (SNPs) found in genome-wide association studies (GWAS) and the diagnosis and treatment of migraine (Dias et al., 2022). Pregnancy is when epigenetic and epitranscriptomic regulation occurs on a large scale to allow the woman’s body to adapt to support a fetus and birth (Arck & Hecher, 2013; Jenkins et al., 2021; Li et al., 2022; Tarca et al., 2021). Around 20% of women with recurrent menstrual migraine (onset at menarche) are more likely to experience remission during pregnancy while over 70% have improved symptoms (Nappi et al., 2011; Nappi et al., 2022; Vetvik & MacGregor, 2021). This analysis focuses on menstrual migraines to explore whether m6A mRNA and the downstream resulting protein level changes occurring during the third trimester of pregnancy have a role in migraine remission. Since migraine is a threshold disorder, samples from pregnant women and women with menstrual migraines expressed similar genes or at least genes involved in similar processes related to immune response, signaling, and vasculature changes. M6A regulators are linked to immune responses in migraineurs and are also active in the third trimester (Aczél et al., 2021; Brennan & Steitz, 2001; Jenkins et al., 2021; Dixon et al., 2001). The m6A regulators Alpha-ketoglutarate-dependent dioxygenase (FTO), Ras GTPase-activating protein-binding protein 1 (G3BP1), and human antigen R (HuR, also known as ELAVL1) deserve further investigation concerning migraine. If the hypothesis holds, FTO, G3BP1, and HuR will be essential in adapting components of the postpartum milieu to a new normal. We will explore whether the putative pregnancy-migraine genes are regulated to protect women against migraine. Migraine remission due to m6A regulation during pregnancy has not been explored before, underscoring the novelty and impact of this study.