The Role of Epigenetics in Brain Aneurysm and Subarachnoid Hemorrhage: A Comprehensive Review

Abstract

This comprehensive review explores the emerging field of epigenetics in intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (aSAH). Despite recent advancements, the high mortality of aSAH needs an understanding of its underlying pathophysiology, where epigenetics plays a crucial role. This review synthesizes the current knowledge, focusing on three primary epigenetic mechanisms: DNA methylation, non-coding RNA (ncRNA), and histone modification in IA and aSAH. While DNA methylation studies are relatively limited, they suggest a significant role in the pathogenesis and prognosis of IA and aSAH, highlighting differentially methylated positions in genes presumably involved in these pathologies. However, methodological limitations, including small sample sizes and a lack of diverse population studies, temper these results. The role of ncRNAs, particularly miRNAs, has been more extensively studied, but there are still few studies focused on histone modifications. Despite methodological challenges and inconsistent findings, these studies underscore the involvement of miRNAs in key pathophysiological processes, including vascular smooth muscle regulation and the inflammatory response. This review emphasizes methodological challenges in epigenetic research, advocating for large-scale epigenome-wide association studies integrating genetic and environmental factors, along with longitudinal studies. Such research could unravel the complex mechanisms behind IA and aSAH, guiding the development of targeted therapeutic approaches.

Keywords: DNA methylation; circular RNA; epigenetics; intracranial aneurysm; long non-coding RNA; microRNA; subarachnoid hemorrhage.

Figure 1

Role of the different epigenetic mechanisms in intracranial aneurysm formation and rupture, as well as their impact on complications and prognosis following aSAH. Regarding aneurysm formation and rupture, the most frequently reported pathways involve VSMCs, immune response, and inflammation. Hypermethylated CpGs in the INSR and CDHR5 genes have been associated with delayed cerebral ischemia (DCI), while miRNAs implicated in endothelial cell responses and neurogenesis have been linked to vasospasm and DCI. Differential DNAm in certain genes associated with iron toxicity, miRNAs involved in neuronal apoptosis, and the lncRNA MALAT-1 have been reported to influence the prognosis of aSAH. Keywords: aSAH: aneurysmal subarachnoid hemorrhage; CDHR5: cadherin-related family member 5; circRNA: circular RNA; INSR: insulin receptor; lncRNA: long non-coding RNA; MALAT-1: metastasis-associated lung adenocarcinoma transcript 1; miRNA: microRNA; mRNA: messenger RNA; mTOR: mammalian target of rapamycin; VMSC: vascular muscle smooth cell. Created with Biorender.com.