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Review
. 2022 Nov;42(11):2000-2016.
doi: 10.1177/0271678X221116192. Epub 2022 Jul 19.

Epigenetic mechanisms and potential therapeutic targets in stroke

Kahlilia C Morris-Blanco  1 , Anil K Chokkalla  1 , Vijay Arruri  1 , Soomin Jeong  1   2 , Samantha M Probelsky  1 , Raghu Vemuganti  1   2   3
Affiliations
Review

Epigenetic mechanisms and potential therapeutic targets in stroke

Kahlilia C Morris-Blanco et al. J Cereb Blood Flow Metab. 2022 Nov.

Abstract

Accumulating evidence indicates a central role for epigenetic modifications in the progression of stroke pathology. These epigenetic mechanisms are involved in complex and dynamic processes that modulate post-stroke gene expression, cellular injury response, motor function, and cognitive ability. Despite decades of research, stroke continues to be classified as a leading cause of death and disability worldwide with limited clinical interventions. Thus, technological advances in the field of epigenetics may provide innovative targets to develop new stroke therapies. This review presents the evidence on the impact of epigenomic readers, writers, and erasers in both ischemic and hemorrhagic stroke pathophysiology. We specifically explore the role of DNA methylation, DNA hydroxymethylation, histone modifications, and epigenomic regulation by long non-coding RNAs in modulating gene expression and functional outcome after stroke. Furthermore, we highlight promising pharmacological approaches and biomarkers in relation to epigenetics for translational therapeutic applications.

Keywords: Biomarkers; cerebral ischemia; epigenomics; hemorrhagic stroke; neuroprotection.

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Conflict of interest statement

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
Epigenetic control of gene expression. Chemical modifications on the DNA and histones along with noncoding RNAs epigenetically regulate gene expression. (a) DNA methylation is mediated by DNA methyltransferases (DNMTs) that add the methyl group to the cytosine to generate 5-methylcytosine (5mC), which is subsequently converted to 5-hydroxymethylcytosine (5hmC) by ten-eleven translocation (TETs) dioxygenases. 5mC is a suppressive mark, whereas 5hmC is an activation mark for gene expression. (b) Histone acetyltransferases (HATs) mediate the transfer of the acetyl group to the lysine residues, whereas histone deacetylases reverse this mark. Histone acetylation loosens the chromatin and activates gene expression. (c) Histone methyltransferases (HMTs) mediate the transfer of the methyl groups to the lysine or arginine residues, whereas histone demethylases (KDMs) reverse this mark. The location and degree of methylation dictate its role in gene regulation. For example, trimethylation of histone 3, lysine residue 4 (H3K4me3) activates transcription, whereas H3K27me3 suppresses transcription. (d) Noncoding RNAs bind to the regulatory proteins in the nucleus, such as chromatin modifying proteins and transcription factors, and can act as scaffolds, decoys, or guides to control gene expression.
Figure 2.
Figure 2.
Epigenetic signatures controlling key post-stroke pathological processes. Multiple pathological processes synergistically potentiate the post-stroke outcome. Epigenetic modifications including 5mC, 5hmC, H3ac, H4ac, H3K9me2, H3K9me3, H3K27me3 and H3K4me3 are implicated in the cell damaging processes such as apoptosis, inflammation, autophagy and mitochondrial dysfunction as well as in recovery related processes such as neuroplasticity, angiogenesis and neurogenesis after stroke.
Figure 3.
Figure 3.
Epigenomic regulation by stroke-sensitive lncRNAs. LncRNAs interact with epigenetic regulators of DNA and histone modifications to fine tune the post-stroke transcriptome. Predominant stroke-sensitive lncRNAs that are involved in the epigenetic regulation include FosDT, HOTAIR, H19, GAS5, MEG3 and XIST.
Figure 4.
Figure 4.
Epigenetic therapies for stroke. Epigenetic imbalance is a well-understood pathological hallmark of stroke. Specifically, DNA methylation (5mC) and hydroxymethylation (5hmC) are elevated, whereas histone methylation (H3K9me2) and acetylation (H3-Ac and H4-Ac) are suppressed in the ischemic brain. Drugs/Molecules targeting the epigenetic enzymes (DNMTs, TETs, KDMs and HDACs) and noncoding RNAs showed promising therapeutic benefits in experimental stroke models, underscoring the dire need for clinical trials.
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References

    1. Isles AR. Epigenetics, chromatin and brain development and function. Brain Neurosci Adv 2018; 2: 2398212818812011. - PMC - PubMed
    1. Bertogliat MJ, Morris-Blanco KC, Vemuganti R. Epigenetic mechanisms of neurodegenerative diseases and acute brain injury. Neurochem Int 2020; 133: 104642. - PMC - PubMed
    1. Smith WS. Pathophysiology of focal cerebral ischemia: a therapeutic perspective. J Vasc Interv Radiol 2004; 15: S3–12. - PubMed
    1. Macdonald RL. Delayed neurological deterioration after subarachnoid haemorrhage. Nat Rev Neurol 2014; 10: 44–58. - PubMed
    1. Aronowski J, Zhao X. Molecular pathophysiology of cerebral hemorrhage: secondary brain injury. Stroke 2011; 42: 1781–1786. - PMC - PubMed

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