Epigenetics and stroke: role of DNA methylation and effect of aging on blood–brain barrier recovery

Abstract

Incomplete recovery of blood–brain barrier (BBB) function contributes to stroke outcomes. How the BBB recovers after stroke remains largely unknown. Emerging evidence suggests that epigenetic factors play a significant role in regulating post-stroke BBB recovery. This study aimed to evaluate the epigenetic and transcriptional profile of cerebral microvessels after thromboembolic (TE) stroke to define potential causes of limited BBB recovery. RNA-sequencing and reduced representation bisulfite sequencing (RRBS) analyses were performed using microvessels isolated from young (6 months) and old (18 months) mice seven days poststroke compared to age-matched sham controls. DNA methylation profiling of poststroke brain microvessels revealed 11,287 differentially methylated regions (DMR) in old and 9818 DMR in young mice, corresponding to annotated genes. These DMR were enriched in genes encoding cell structural proteins (e.g., cell junction, and cell polarity, actin cytoskeleton, extracellular matrix), transporters and channels (e.g., potassium transmembrane transporter, organic anion and inorganic cation transporters, calcium ion transport), and proteins involved in endothelial cell processes (e.g., angiogenesis/vasculogenesis, cell signaling and transcription regulation). Integrated analysis of methylation and RNA sequencing identified changes in cell junctions (occludin), actin remodeling (ezrin) as well as signaling pathways like Rho GTPase (RhoA and Cdc42ep4). Aging as a hub of aberrant methylation affected BBB recovery processes by profound alterations (hypermethylation and repression) in structural protein expression (e.g., claudin-5) as well as activation of a set of genes involved in endothelial to mesenchymal transformation (e.g., Sox9, Snai1), repression of angiogenesis and epigenetic regulation. These findings revealed that DNA methylation plays an important role in regulating BBB repair after stroke, through regulating processes associated with BBB restoration and prevalently with processes enhancing BBB injury.

Targeting the blood–brain barrier to delay aging-accompanied neurological diseases by modulating gut microbiota, circadian rhythms, and their interplays

“…g ., claudin-5) and genes activat-ion ( e . g ., Sox9 , Snai1 ) that is involved in endothelial to mesenchymal transformation, angiogenesis repression and epigenetic regulation, indicating that DNA methylation is critically involved in BBB repair after stroke 31 .…”

“… Ref. Neurological diseases Species BBB changes Possible mechanisms Barisano et al., 2022 34 Alzheimer's disease Human Loss of tight junction (TJ) or adherence junction (AJ) and increased transendothelial translocation Associated with the loss of pericyte coverage Zhang et al., 2020 38 Alzheimer's disease Human Increase of BBB permeability APOE4 can catabolize BBB integrity by activating the MMP9 pathway in pericytes and endothelial cells Lan et al., 2022 39 Parkinson's disease Mouse Reduce of tight junction proteins Elevated levels of VEGFA and iNOS Ruan et al., 2022 38 Parkinson's disease Mouse Loss of endothelial integrity of the brain Microglia-mediated activation of matrix metalloproteinase-2 and 9 Kortekaas et al., 2005 40 Parkinson's disease Human Decrease of P-gp function PD patients carry the 1T allele of the MDR3435 gene Rite et al., 2007 41 Parkinson's disease Mouse Increase of BBB permeability Inflammatory response and activation of astroglia Candelario-Jalil et al., 2022 42 Ischemic stroke Mouse Endothelial dysfunction Increased MMP, oxidative stress burst, microglia activation and peripheral immune cell infiltration Phillips et al., 2023 31 Ischemic stroke Mouse Persistent BBB dysfunction with increased permeability of the paracellular barrier DNA methylation Alvarez et al., 2011 45 Multiple sclerosis Human and mouse Reduced expression of TJ and AJ proteins Immune cell infiltration and upregulation of pro-inflammatory cytokines …”

Genetic disorders and genetic manipulation at the blood-brain barriers

“…Ihezie et al [25] review the role different types of epigenetic mechanisms (DNA methylation, histone modification, non-coding RNAs) in regulating the BBB and potential therapeutic interventions targeting those mechanisms. Phillips et al [26] examined the role of changes in DNA methylation (the methylome) in BBB recovery after ischemic stroke in mice and how this response is altered with aging. Importantly, they correlated changes in the methylome with the transcriptome, and described how methylation status can lead to incomplete BBB recovery which may worsen stroke outcome and enhance the chances of recurrent stroke.…”