Table 1.

Epigenetic Regulatory Mechanisms in Stroke

Epigenetic Mechanisms	Description	Relevance to Stroke
DNA methylation	Refers to the transfer of methyl groups from SAM to cytosine residues in various genomic regions	Levels are increased in the ischemic brain and may be responsible for promoting neural cell death
	Mediated by DNA methyltransferase enzymes	Deficiency of methylenetetrahydrofolate reductase, which is involved in the formation of SAM, causes hyperhomocysteinemia and an increased risk of stroke
	Regulates gene expression as well as diverse cellular processes, including maintenance of genomic stability, XCI, and genomic imprinting	Extent of XCI in female heterozygotes with Fabry disease determines clinical involvement, including risk of stroke
		Imprinted GNAS genomic locus is important for glucose and lipid metabolism and platelet function
		Abnormal DNA methylation is associated with atherosclerosis, obesity, insulin resistance, kidney disease, cancer, and autoimmunity
Histone code modifications, nucleosome remodeling, and higher-order chromatin formation	Refer to highly integrated epigenetic mechanisms that modulate chromatin structure and function at single nucleotides (histone code modification), specific gene loci (nucleosome remodeling), and more extensive genomic regions (higher-order chromatin formation)	Histone acetylation levels are perturbed in the ischemic brain and may be associated with mediating neural cell death and protective responses, including excitotoxicity, oxidative stress, inflammation, cell cycle regulation, DNA repair, and apoptosis
	Mediated by histone-, nucleosome-, and chromatin-modifying enzymes that are often components of large, multifunctional epigenetic macromolecular complexes	Abnormal chromatin is a key feature of necrotic cell death and apoptotic cell death, which are both associated with neural injury in stroke
	Play vital roles in executing genomic programs such as gene activation and silencing	Schimke immunoosseous dysplasia is a disease characterized by increased risk of stroke, which is caused by mutation of a nucleosome remodeling enzyme (ie, SMARCAL1)
		Antichromatin and antihistone antibodies are found in systemic lupus erythematosus, which is associated with an increased risk of stroke due to multiple factors
		Chromatin dynamics are important for modulating cholesterol synthesis, transport, and metabolic pathways

Abbreviations: SAM, S-adenosylmethionine; SMARCAL1, SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A-like 1; XCI, X chromosome inactivation.