Circadian-Dependent Intermittent Fasting Influences Ischemic Tolerance and Dendritic Spine Remodeling.

BACKGROUND: Preconditioning by intermittent fasting is linked to improved cognition and motor function, and enhanced recovery after stroke. Although the duration of fasting was shown to elicit different levels of neuroprotection after ischemic stroke, the impact of time of fasting with respect to the circadian cycles remains unexplored. METHODS: Cohorts of mice were subjected to a daily 16-hour fast, either during the dark phase (active-phase intermittent fasting) or the light phase (inactive-phase intermittent fasting) or were fed ad libitum. Following a 6-week dietary regimen, mice were subjected to transient focal cerebral ischemia and underwent behavioral functional assessment. Brain samples were collected for RNA sequencing and histopathologic analyses. RESULTS: Active-phase intermittent fasting cohort exhibited better poststroke motor and cognitive recovery as well as reduced infarction, in contrast to inactive-phase intermittent fasting cohort, when compared with ad libitum cohort. In addition, protection of dendritic spine density/morphology and increased expression of postsynaptic density protein-95 were observed in the active-phase intermittent fasting. CONCLUSIONS: These findings indicate that the time of daily fasting is an important factor in inducing ischemic tolerance by intermittent fasting.

Post-stroke depression: epigenetic and epitranscriptomic modifications and their interplay with gut microbiota.

Epigenetic and epitranscriptomic modifications that regulate physiological processes of an organism at the DNA and RNA levels, respectively, are novel therapeutic candidates for various neurological diseases. Gut microbiota and its metabolites are known to modulate DNA methylation and histone modifications (epigenetics), as well as RNA methylation especially N6-methyladenosine (epitranscriptomics). As gut microbiota as well as these modifications are highly dynamic across the lifespan of an organism, they are implicated in the pathogenesis of stroke and depression. The lack of specific therapeutic interventions for managing post-stroke depression emphasizes the need to identify novel molecular targets. This review highlights the interaction between the gut microbiota and epigenetic/epitranscriptomic pathways and their interplay in modulating candidate genes that are involved in post-stroke depression. This review further focuses on the three candidates, including brain-derived neurotrophic factor, ten-eleven translocation family proteins, and fat mass and obesity-associated protein based on their prevalence and pathoetiologic role in post-stroke depression.

An antioxidant and anti-ER stress combo therapy decreases inflammation, secondary brain damage and promotes neurological recovery following traumatic brain injury in mice.

The complex pathophysiology of post-traumatic brain damage might need a polypharmacological strategy with a combination of drugs that target multiple, synergistic mechanisms. We currently tested a combination of apocynin (curtails formation of reactive oxygen species; ROS), tert-butylhydroquinone (promotes disposal of ROS), and salubrinal (prevents endoplasmic reticulum stress) following a moderate traumatic brain injury (TBI) induced by controlled cortical impact in adult mice. Adult mice of both sexes treated with the above tri-combo showed alleviated motor and cognitive deficits, attenuated secondary lesion volume, and decreased oxidative DNA damage. Concomitantly, tri-combo treatment regulated post-TBI inflammatory response by decreasing the infiltration of T cells and neutrophils and activation of microglia in both sexes. Interestingly, sexual dimorphism was seen in the case of TBI-induced microgliosis and infiltration of macrophages in the tri-combo treated mice. Moreover, the tri-combo treatment prevented TBI-induced white matter volume loss in both sexes. The beneficial effects of tri-combo treatment were long-lasting and were also seen in aged mice. Thus, the present study supports the tri-combo treatment to curtail oxidative stress and endoplasmic reticulum stress concomitantly as a therapeutic strategy to improve TBI outcomes.SIGNIFICANCE STATEMENTOf the several mechanisms that contribute to TBI pathophysiology, oxidative stress, endoplasmic reticulum (ER) stress, and inflammation play a major role. The present study shows the therapeutic potential of a combination of apocynin, tert-butylhydroquinone, and salubrinal to prevent oxidative stress and ER stress and the interrelated inflammatory response in mice subjected to TBI. The beneficial effects of the tri-combo include alleviation of TBI-induced motor and cognitive deficits and lesion volume. The neuroprotective effects of the tri-combo are also linked to its ability to prevent TBI-induced white matter damage. Importantly, neuroprotection by the tri-combo treatment was observed to be not dependent on sex or age. Our data demonstrate that a polypharmacological strategy is efficacious after TBI.

Cerebroprotective Role of N6-Methyladenosine Demethylase FTO (Fat Mass and Obesity-Associated Protein) After Experimental Stroke.

BACKGROUND: FTO (fat mass and obesity-associated protein) demethylates N6-methyladenosine (m6A), which is a critical epitranscriptomic regulator of neuronal function. We previously reported that ischemic stroke induces m6A hypermethylation with a simultaneous decrease in FTO expression in neurons. Currently, we evaluated the functional significance of restoring FTO with an adeno-associated virus 9, and thus reducing m6A methylation in poststroke brain damage. METHODS: Adult male and female C57BL/6J mice were injected with FTO adeno-associated virus 9 (intracerebral) at 21 days prior to inducing transient middle cerebral artery occlusion. Poststroke brain damage (infarction, atrophy, and white matter integrity) and neurobehavioral deficits (motor function, cognition, depression, and anxiety-like behaviors) were evaluated between days 1 and 28 of reperfusion. RESULTS: FTO overexpression significantly decreased the poststroke m6A hypermethylation. More importantly, exogenous FTO substantially decreased poststroke gray and white matter damage and improved motor function recovery, cognition, and depression-like behavior in both sexes. CONCLUSIONS: These results demonstrate that FTO-dependent m6A demethylation minimizes long-term sequelae of stroke independent of sex.

Long Noncoding RNA Fos Downstream Transcript Is Developmentally Dispensable but Vital for Shaping the Poststroke Functional Outcome.

Background and Purpose: Stroke induces the expression of several long noncoding RNAs in the brain. However, their functional significance in poststroke outcome is poorly understood. We recently observed that a brain-specific long noncoding RNA called Fos downstream transcript (FosDT) is induced rapidly in the rodent brain following focal ischemia. Using FosDT knockout rats, we presently evaluated the role of FosDT in poststroke brain damage. Methods: FosDT knockout rats were generated using CRISPR-Cas9 genome editing on a Sprague-Dawley background. Male and female FosDT−/− and FosDT+/+ cohorts were subjected to transient middle cerebral artery occlusion. Postischemic sensorimotor deficits were evaluated between days 1 and 7 and lesion volume on day 7 of reperfusion. The developmental expression profile of FosDT was determined with real-time polymerase chain reaction and mechanistic implications of FosDT in the ischemic brain were conducted with RNA-sequencing analysis and immunostaining of pathological markers. Results: FosDT expression is developmentally regulated, with the adult cerebral cortex showing significantly higher FosDT expression than neonates. FosDT−/− rats did not show any anomalies in growth and development, fertility, brain cytoarchitecture, and cerebral vasculature. However, when subjected to transient focal ischemia, FosDT−/− rats of both sexes showed enhanced sensorimotor recovery and reduced brain damage. RNA-sequencing analysis showed that improved poststroke functional outcome in FosDT−/− rats is partially associated with curtailed induction of inflammatory genes, reduced apoptosis, mitochondrial dysfunction, and oxidative stress. Conclusions: Our study shows that FosDT is developmentally dispensable, mechanistically important, and a functionally promising target to reduce ischemic brain damage and facilitate neurological recovery.

Transient Focal Ischemia Significantly Alters the m6A Epitranscriptomic Tagging of RNAs in the Brain.

Background and Purpose- Adenosine in many types of RNAs can be converted to m6A (N6-methyladenosine) which is a highly dynamic epitranscriptomic modification that regulates RNA metabolism and function. Of all organs, the brain shows the highest abundance of m6A methylation of RNAs. As recent studies showed that m6A modification promotes cell survival after adverse conditions, we currently evaluated the effect of stroke on cerebral m6A methylation in mRNAs and lncRNAs. Methods- Adult C57BL/6J mice were subjected to transient middle cerebral artery occlusion. In the peri-infarct cortex, m6A levels were measured by dot blot analysis, and transcriptome-wide m6A changes were profiled using immunoprecipitated methylated RNAs with microarrays (44 122 mRNAs and 12 496 lncRNAs). Gene ontology analysis was conducted to understand the functional implications of m6A changes after stroke. Expression of m6A writers, readers, and erasers was also estimated in the ischemic brain. Results- Global m6A levels increased significantly at 12 hours and 24 hours of reperfusion compared with sham. While 139 transcripts (122 mRNAs and 17 lncRNAs) were hypermethylated, 8 transcripts (5 mRNAs and 3 lncRNAs) were hypomethylated (>5-fold compared with sham) in the ischemic brain at 12 hours reperfusion. Inflammation, apoptosis, and transcriptional regulation are the major biological processes modulated by the poststroke differentially m6A methylated mRNAs. The m6A writers were unaltered, but the m6A eraser (fat mass and obesity-associated protein) decreased significantly after stroke compared with sham. Conclusions- This is the first study to show that stroke alters the cerebral m6A epitranscriptome, which might have functional implications in poststroke pathophysiology. Visual Overview- An online visual overview is available for this article.

Path Towards Biopsy-Free Diagnosis of Celiac Disease in Pediatric Patients.

BACKGROUND: Laboratory testing for celiac disease in pediatric patients integrates serology, genetic susceptibility and duodenal biopsy examination. The 2023 American College of Gastroenterology guidelines recommend a biopsy-free approach in pediatric patients utilizing tissue transglutaminase antibody titers >10 times upper limit of normal and subsequent endomysial antibody seropositivity as sufficient for diagnosis. The objective of this study is to assess the diagnostic accuracy of biopsy-free approach at our pediatric hospital. METHODS: We conducted a retrospective study involving pediatric patients who underwent biopsy for diagnostic confirmation of celiac disease between May 2019 and May 2023. For these patients, the tissue transglutaminase and endomysial antibody test results were retrieved and performance of biopsy-free approach was assessed using the duodenal histology as the gold standard for celiac disease diagnosis. RESULTS: Tissue transglutaminase antibody titers >10 times upper limit of normal alone demonstrated a positive predictive value of 99% for identifying celiac disease in children. Although endomysial antibody testing is underutilized at our center, its inclusion further improved the predictability to 100 %. CONCLUSION: Positive predictive value of tissue transglutaminase antibody titers >10 times upper limit of normal is sufficiently high for celiac disease diagnosis in children and may allow for deferral of duodenal biopsy at diagnosis.

Loss of Epitranscriptomic Modification N6-Methyladenosine (m6A) Reader YTHDF1 Exacerbates Ischemic Brain Injury in a Sexually Dimorphic Manner.

N6-Methyladenosine (m6A) is a neuronal-enriched, reversible post-transcriptional modification that regulates RNA metabolism. The m6A-modified RNAs recruit various m6A-binding proteins that act as readers. Differential m6A methylation patterns are implicated in ischemic brain damage, yet the precise role of m6A readers in propagating post-stroke m6A signaling remains unclear. We presently evaluated the functional significance of the brain-enriched m6A reader YTHDF1, in post-stroke pathophysiology. Focal cerebral ischemia significantly increased YTHDF1 mRNA and protein expression in adult mice of both sexes. YTHDF1-/- male, but not female, mice subjected to transient middle cerebral artery occlusion (MCAO) showed worsened motor function recovery and increased infarction compared to sex-matched YTHDF1+/+ mice. YTHDF1-/- male, but not female, mice subjected to transient MCAO also showed significantly perturbed expression of genes related to inflammation, and increased infiltration of peripheral immune cells into the peri-infarct cortex, compared with sex-matched YTHDF1+/+ mice. Thus, this study demonstrates a sexual dimorphism of YTHDF1 in regulating post-ischemic inflammation and pathophysiology. Hence, post-stroke epitranscriptomic regulation might be sex-dependent.

Validation of a whole blood machine learning strategy for distinguishing between bacterial and viral infection in a pediatric hospital setting.

Similar symptoms between viral and bacterial diseases often make diagnosis difficult. This study assessed the clinical performance of the newly cleared whole-blood Bacterial versus Viral Score assay in our pediatric cohort to the previously validated serum assay and emergency department physician diagnosis. This assay shows excellent agreement (R = 0.997) with the serum assay and has great diagnostic accuracy when compared to physician diagnosis.

Cystic fibrosis-related diabetes screening at a large pediatric center.

OBJECTIVE: Cystic Fibrosis Foundation guidelines recommend annual diabetes screening by oral glucose tolerance test (OGTT) in pediatric patients with cystic fibrosis (CF) starting at the age of 10 years. Adherence to these guidelines proves to be challenging, and the nationwide screening rates are still considered suboptimal. The aim of this study was to assess and improve the screening rates at our large pediatric center. METHODS: A 4-year retrospective audit of OGTT completion among pediatric patients with CF of age ≥10 years who are not yet diagnosed with diabetes was conducted. A collaborative working group was formed to identify the barriers to screening and formulate a quality improvement plan, which was monitored and evaluated for a 9-month period. RESULTS: Diabetes screening rates determined by OGTT completion at our center showed a gradual decline during the COVID-19 pandemic from 2019 to 2022. Following the implementation of the quality improvement plan during the summer of 2023, there was a marked increase in OGTT ordering compliance by providers as well as test completion by patients. Notably, the fractional OGTT completion rate rose from 45% during the preintervention phase (January-April 2023) to 70% during the postintervention phase (May-September 2023). CONCLUSION: Diabetes screening in pediatric patients with CF can be effectively improved by refining practices related to patient experience, care coordination, and laboratory testing strategies.

SARS-CoV-2 Antibody Titers and Severity of Multisystem Inflammatory Syndrome in Children.

OBJECTIVE: Multisystem inflammatory syndrome in children (MIS-C) is a rare yet serious pathological consequence of SARS-CoV-2 infection which is reported 4-12 weeks after the onset of COVID-19 in children and adolescents. The most common hyper-inflammatory conditions mimicking the clinical presentation of MIS-C include Kawasaki disease and toxic shock syndrome. The surveillance criteria of MIS-C were recently revised by US Center for Disease Control and Prevention to improve diagnostic precision. Although previous studies have shown that SARS-CoV-2 antibody titers correlate with COVID-19 severity, their relation to MIS-C severity remains poorly understood and the aim of the study was to investigate this. METHODS: As all the MIS-C patients get a SARS-CoV-2 antibody test performed on the first day of hospitalization, here we attempted to stratify risk for adverse outcomes due to MIS-C based on the SARS-CoV-2 antibody titers. RESULTS: Our studies demonstrated that SARS-CoV-2 antibody titers, specifically Total (IgG/IgM/partial IgA), Nucleocapsid IgG, and Spike IgM, do not correlate with MIS-C severity assessed based on the ICU admission, inotropic support, and mechanical respiratory support requirements. CONCLUSION: Therefore, it might not be appropriate to predict the clinical course of patients presenting with MISC based on quantitative serology testing.

Immunomodulatory role of glycoRNAs in the brain.

Glycosylation of lipids and proteins significantly increases the molecular diversity in the brain. Membrane-localized glycoconjugates facilitate critical neuro-immune interactions. Therefore, glycodysregulation is increasingly recognized as a novel hallmark of various acute and chronic neurological diseases. Although RNAs are heavily modified, they are never thought to be substrates for glycosylation due to their inaccessibility to the glycosylation machinery in the Golgi apparatus. The astonishing discovery of cell surface glycoRNAs opened new avenues for glycomedicine. This review highlighted the key features of GlycoRNAs and further discussed their potential immunomodulatory role in the brain, particularly focusing on post-stroke neuroinflammation.

Best Practices for Effective Management of Point of Care Testing.

With the recent COVID-19 pandemic, point-of-care testing has gained tremendous attention, particularly in acute care settings. The point-of-care testing landscape is rapidly expanding and being contemplated for any crucial test with a central laboratory turnaround time >25% of the clinical decision time. A typical point-of-care testing program within a large hospital system encompasses a multitude of operators utilizing a wide range of devices across multiple testing sites. Thus, managing a large point-of-care testing network remains a daunting task with challenges related to staffing, standardization, quality management, training and competency assessment, and data management. This review will focus on understanding the general organization as well as the roles and responsibilities of various point-of-care testing stakeholders in addressing these challenges. More importantly, it will discuss the strategies and best practices for effective point-of-care testing management based on consensus recommendations from professional societies as well as our experience at Texas Childrens Hospital.

MicroRNA miR-7 Is Essential for Post-stroke Functional Recovery.

Transient focal ischemia induces a sustained downregulation of miR-7 leading to derepression of its target α-synuclein (α-Syn), which promotes neuronal death. We previously showed that treatment with miR-7 mimic prevents α-Syn induction and protects brain after stroke in rodents irrespective of age and sex. To further decipher the role of miR-7, we currently studied infarction and motor function in miR-7 double knockout mice (lack both miR-7a and miR-7b) subjected to focal ischemia. Adult miR-7-/- mice showed similar motor and cognitive functions to miR-7+/+ mice. However, when subjected to even a mild focal ischemia, the miR-7-/- mice showed exacerbated brain damage and worsened motor function compared with the miR-7+/+ mice. Replenishing miR-7 in miR-7-/- mice (IV injection of miR-7 mimic) restored miR-7 mediated neuroprotection and motor recovery, potentially by preventing α-Syn protein induction. Thus, we show that miR-7 is an essential miRNA in the brain that prevents α-Syn translation and the ensuing brain damage after stroke.

Validation of a multi-analyte immunoassay for distinguishing bacterial vs. viral infections in a pediatric cohort.

BACKGROUND: Clinical presentation of viral and bacterial infections or co-infections overlaps significantly. Pathogen identification is the gold standard for appropriate treatment. Recently, FDA cleared a multivariate index test called MeMed-BV that distinguishes viral and bacterial infections based on the differential expression of 3 host proteins. Here, we sought to validate MeMed-BV immunoassay on MeMed Key analyzer in our pediatric hospital following guidelines from the Clinical and Laboratory Standards Institute. METHODS: The analytical performance of the MeMed-BV test was evaluated with precision (intra- and inter-assay), method comparison and interference studies. The clinical performance (diagnostic sensitivity and specificity) of the MeMed-BV test was assessed by conducting a retrospective cohort study (n = 60) using plasma samples from pediatric patients with acute febrile illness who visited the emergency department of our hospital. RESULTS: MeMed-BV showed acceptable intra- and inter-assay precision with a range of < 3 score units in both the high-score bacterial as well as the low-score viral controls. Diagnostic accuracy studies revealed a sensitivity of 94% and specificity of 88% for identifying bacterial infections or co-infections. Our MeMed-BV results showed an excellent agreement (R = 0.998) with manufacturer's laboratory data and compared well with ELISA studies. Gross hemolysis and icterus did not affect the assay, but gross lipemia showed a considerable bias in samples with moderate likelihood of viral infection. Importantly, the MeMed-BV test performed better than routinely measured infection-related biomarkers like white blood cell counts, procalcitonin and C-reactive protein in classifying bacterial infections. CONCLUSION: MeMed-BV immunoassay demonstrated acceptable analytical performance and is reliable for distinguishing viral and bacterial infections or co-infections in pediatric patients. Future studies are warranted to examine the clinical utility, especially with respect to reducing the need for blood cultures and time to treatment for the patient.

Dysregulation of the Epitranscriptomic Mark m1A in Ischemic Stroke.

Methylation of adenosine at N1 position yields N1-methyladenosine (m1A), which is an epitranscriptomic modification that regulates mRNA metabolism. Recent studies showed that altered m1A methylation promotes acute and chronic neurological diseases. We currently evaluated the effect of focal ischemia on cerebral m1A methylome and its machinery. Adult male C57BL/6J mice were subjected to transient middle cerebral artery occlusion, and the peri-infarct cortex was analyzed at 12 h and 24 h of reperfusion. The bulk abundance of m1A was measured by mass spectrometry and dot blot, and transcriptome-wide m1A alterations were profiled using antibody-independent m1A-quant-seq. Expression of the m1A writers and erasers was estimated by real-time PCR. Ischemia significantly decreased m1A levels and concomitantly upregulated m1A demethylase alkB homolog 3 at 24 h of reperfusion compared to sham. Transcriptome-wide profiling showed differential m1A methylation at 14 sites (8 were hypo- and 6 were hypermethylated). Many of those are located in the 3'-UTRs of unannotated transcripts proximal to the genes involved in regulating protein complex assembly, circadian rhythms, chromatin remodeling, and chromosome organization. Using several different approaches, we show for the first time that m1A epitranscriptomic modification in RNA is highly sensitive to cerebral ischemia.

CDR1as regulates α-synuclein-mediated ischemic brain damage by controlling miR-7 availability.

Transient focal ischemia decreased microRNA-7 (miR-7) levels, leading to derepression of its major target α-synuclein (α-Syn) that promotes secondary brain damage. Circular RNA CDR1as is known to regulate miR-7 abundance and function. Hence, we currently evaluated its functional significance after focal ischemia. Transient middle cerebral artery occlusion (MCAO) in adult mice significantly downregulated both CDR1as and miR-7 levels in the peri-infarct cortex between 3 and 72 h of reperfusion. Interestingly, neither pri-miR-7a nor 7b was altered in the ischemic brain. Intracerebral injection of an AAV9 vector containing a CDR1as gene significantly increased CDR1as levels by 21 days that persisted up to 4 months without inducing any observable toxicity in both sham and MCAO groups. Following transient MCAO, there was a significant increase in miR-7 levels and CDR1as binding to Ago2/miR-7 in the peri-infarct cortex of AAV9-CDR1as cohort compared with AAV9-Control cohort at 1 day of reperfusion. CDR1as overexpression significantly suppressed post-stroke α-Syn protein induction, promoted motor function recovery, decreased infarct size, and curtailed the markers of apoptosis, autophagy mitochondrial fragmentation, and inflammation in the post-stroke brain compared with AAV9-Control-treated cohort. Overall, our findings imply that CDR1as reconstitution is neuroprotective after stroke, probably by protecting miR-7 and preventing α-Syn-mediated neuronal death.

ChatGPT-Exploring Its Role in Clinical Chemistry.

OBJECTIVE: To evaluate the utility of artificial intelligence-powered language models (ChatGPT 3.5 and GPT-4) compared to trainees and clinical chemists in responding to common laboratory questions in the broad area of Clinical Chemistry. METHODS: 35 questions from real-life case scenarios, clinical consultations, and clinical chemistry testing questions were used to evaluate ChatGPT 3.5, and GPT-4 alongside clinical chemistry trainees (residents/fellows) and clinical chemistry faculty. The responses were scored based on category and based on years of experience. RESULTS: The Senior Chemistry Faculty demonstrated superior accuracy with 100% of correct responses compared to 90.5%, 82.9%, and 71.4% of correct responses from the junior chemistry faculty, fellows, and residents respectively. They all outperformed both ChatGPT 3.5 and GPT-4 which generated 60% and 71.4% correct responses respectively. Of the sub-categories examined, ChatGPT 3.5 achieved 100% accuracy in endocrinology while GPT-4 did not achieve 100% accuracy in any subcategory. GPT-4 was overall better than ChatGPT 3.5 by generating similar correct responses as residents (71.4%) but performed poorly to human participants when both partially correct and incorrect indices were considered. CONCLUSION: Despite all the advances in AI-powered language models, ChatGPT 3.5 and GPT-4 cannot replace a trained pathologist in answering clinical chemistry questions. Caution should be observed by people, especially those not trained in clinical chemistry, to interpret test results using chatbots.

Epitranscriptomic Modifications Modulate Normal and Pathological Functions in CNS.

RNA is more than just a combination of four genetically encoded nucleobases as it carries extra information in the form of epitranscriptomic modifications. Diverse chemical groups attach covalently to RNA to enhance the plasticity of cellular transcriptome. The reversible and dynamic nature of epitranscriptomic modifications allows RNAs to achieve rapid and context-specific gene regulation. Dedicated cellular machinery comprising of writers, erasers, and readers drives the epitranscriptomic signaling. Epitranscriptomic modifications control crucial steps of mRNA metabolism such as splicing, export, localization, stability, degradation, and translation. The majority of the epitranscriptomic modifications are highly abundant in the brain and contribute to activity-dependent gene expression. Thus, they regulate the vital physiological processes of the brain, such as synaptic plasticity, neurogenesis, and stress response. Furthermore, epitranscriptomic alterations influence the progression of several neurologic disorders. This review discussed the molecular mechanisms of epitranscriptomic regulation in neurodevelopmental and neuropathological conditions with the goal to identify novel therapeutic targets.

Epigenetic mechanisms and potential therapeutic targets in stroke.

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.