DNA methylation: A mechanism for sustained alteration of KIR4.1 expression following central nervous system insult

Boni, Jessica L.; Kahanovitch, Uri; Nwaobi, Sinifunanya E.; Floyd, Candace L.; Olsen, Michelle L.

doi:10.1002/glia.23797

Cited by 11 publications

(5 citation statements)

References 95 publications

(152 reference statements)

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“…In a recent study, Boni et al (2020) showed that DNA methylation can bidirectionally modulate transcription of the gene KCNJ10 representing "a targetable molecular mechanism for the restoring astroglial Kir4.1 expression after central nervous system (CNS) insult. " Therefore, DNA hypo-or hypermethylation of candidate genes in astrocytes might be a promising genetic targets for therapeutic intervention of epileptogenesis (Williams-Karnesky et al, 2013).…”

Section: Dna Methylationmentioning

confidence: 99%

“…In animal models of structural epilepsy (i.e., induced by injections of pentilentetrazol, PTZ or electrical stimulation of hippocampus) astrocyte swelling was observed through specific targeting of AQP4 or Kir4.1 (see Murphy et al, 2017 ). Genetic mutations in the gene KCNJ10, which encodes Kir4.1, is known to cause seizures in humans (see Boni et al, 2020 ).…”

Section: The Role Of Astrocytes In Structural/metabolic/infectious/im...mentioning

confidence: 99%

“…In a recent study, Boni et al (2020) showed that DNA methylation can bidirectionally modulate transcription of the gene KCNJ10 representing “a targetable molecular mechanism for the restoring astroglial Kir4.1 expression after central nervous system (CNS) insult.” Therefore, DNA hypo- or hypermethylation of candidate genes in astrocytes might be a promising genetic targets for therapeutic intervention of epileptogenesis (Williams-Karnesky et al, 2013). DNA methylation could potentially alter astrocyte reactivity and inflammatory status through controlling the signaling transducer and activator of transcription 3 (STAT3) pathway, along with other signaling pathways ( O'Callaghan et al, 2014 ; Neal and Richardson, 2018 ).…”

Section: The Role Of Astrocytes In Structural/metabolic/infectious/im...mentioning

confidence: 99%

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Astrocytes as a target for therapeutic strategies in epilepsy: current insights

Çarçak,

Onat,

Sitnikova

2023

Front. Mol. Neurosci.

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Astrocytes are specialized non-neuronal glial cells of the central nervous system, contributing to neuronal excitability and synaptic transmission (gliotransmission). Astrocytes play a key roles in epileptogenesis and seizure generation. Epilepsy, as a chronic disorder characterized by neuronal hyperexcitation and hypersynchronization, is accompanied by substantial disturbances of glial cells and impairment of astrocytic functions and neuronal signaling. Anti-seizure drugs that provide symptomatic control of seizures primarily target neural activity. In epileptic patients with inadequate control of seizures with available anti-seizure drugs, novel therapeutic candidates are needed. These candidates should treat epilepsy with anti-epileptogenic and disease-modifying effects. Evidence from human and animal studies shows that astrocytes have value for developing new anti-seizure and anti-epileptogenic drugs. In this review, we present the key functions of astrocytes contributing to neuronal hyperexcitability and synaptic activity following an etiology-based approach. We analyze the role of astrocytes in both development (epileptogenesis) and generation of seizures (ictogenesis). Several promising new strategies that attempted to modify astroglial functions for treating epilepsy are being developed: (1) selective targeting of glia-related molecular mechanisms of glutamate transport; (2) modulation of tonic GABA release from astrocytes; (3) gliotransmission; (4) targeting the astrocytic Kir4.1-BDNF system; (5) astrocytic Na+/K+/ATPase activity; (6) targeting DNA hypo- or hypermethylation of candidate genes in astrocytes; (7) targeting astrocytic gap junction regulators; (8) targeting astrocytic adenosine kinase (the major adenosine-metabolizing enzyme); and (9) targeting microglia-astrocyte communication and inflammatory pathways. Novel disease-modifying therapeutic strategies have now been developed, such as astroglia-targeted gene therapy with a broad spectrum of genetic constructs to target astroglial cells.

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Section: Dna Methylationmentioning

confidence: 99%

Section: The Role Of Astrocytes In Structural/metabolic/infectious/im...mentioning

confidence: 99%

Section: The Role Of Astrocytes In Structural/metabolic/infectious/im...mentioning

confidence: 99%

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Astrocytes as a target for therapeutic strategies in epilepsy: current insights

Çarçak,

Onat,

Sitnikova

2023

Front. Mol. Neurosci.

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“…Another study reported the upregulation of astroglia’s potassium channel gene ( Kir4.1 or KCNJ10 ) and reduced GLT-1 ( SLC1A2 ) activity (which removes ~90% of extracellular/synapse glutamate) and increased neuronal bursting activity of the lateral habenula as key factors in the induction of depression-like behaviors [ 68 , 69 ]. A recent study revealed that DNA methylation regulates KCNJ10 expression in astrocytes [ 74 ]. Aberrant DNA methylation of NMDAR (more specifically, the hypermethylation of the GRIN2A subunit) was also reported in the hippocampus and prefrontal cortex of MDD patients [ 76 ].…”

Section: Astroglia Pathology and Dysfunction In Depressionmentioning

confidence: 99%

Epigenetic Alterations of Brain Non-Neuronal Cells in Major Mental Diseases

Abdolmaleky

Martin

Zhou

et al. 2023

Genes

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The tissue-specific expression and epigenetic dysregulation of many genes in cells derived from the postmortem brains of patients have been reported to provide a fundamental biological framework for major mental diseases such as autism, schizophrenia, bipolar disorder, and major depression. However, until recently, the impact of non-neuronal brain cells, which arises due to cell-type-specific alterations, has not been adequately scrutinized; this is because of the absence of techniques that directly evaluate their functionality. With the emergence of single-cell technologies, such as RNA sequencing (RNA-seq) and other novel techniques, various studies have now started to uncover the cell-type-specific expression and DNA methylation regulation of many genes (e.g., TREM2, MECP2, SLC1A2, TGFB2, NTRK2, S100B, KCNJ10, and HMGB1, and several complement genes such as C1q, C3, C3R, and C4) in the non-neuronal brain cells involved in the pathogenesis of mental diseases. Additionally, several lines of experimental evidence indicate that inflammation and inflammation-induced oxidative stress, as well as many insidious/latent infectious elements including the gut microbiome, alter the expression status and the epigenetic landscapes of brain non-neuronal cells. Here, we present supporting evidence highlighting the importance of the contribution of the brain’s non-neuronal cells (in particular, microglia and different types of astrocytes) in the pathogenesis of mental diseases. Furthermore, we also address the potential impacts of the gut microbiome in the dysfunction of enteric and brain glia, as well as astrocytes, which, in turn, may affect neuronal functions in mental disorders. Finally, we present evidence that supports that microbiota transplantations from the affected individuals or mice provoke the corresponding disease-like behavior in the recipient mice, while specific bacterial species may have beneficial effects.

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“…Lithium can improve the microenvironment in the spinal cord and promote the regeneration and survival of motor neurons [ 90 ]. Lithium chloride can boost the secretion of brain-derived neurotrophic factor (BDNF) in the axons of motor neurons following spinal cord injury [ 91 , 92 ]. Lithium chloride can also help restore the function of the blood–spinal cord barrier after a spinal cord injury [ 93 ].…”

Section: Lithium and Cellular Biology Of Scimentioning

confidence: 99%

Main Cations and Cellular Biology of Traumatic Spinal Cord Injury

Munteanu

Rotariu

Turnea

et al. 2022

Cells

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Traumatic spinal cord injury is a life-changing condition with a significant socio-economic impact on patients, their relatives, their caregivers, and even the community. Despite considerable medical advances, there is still a lack of options for the effective treatment of these patients. The major complexity and significant disabling potential of the pathophysiology that spinal cord trauma triggers are the main factors that have led to incremental scientific research on this topic, including trying to describe the molecular and cellular mechanisms that regulate spinal cord repair and regeneration. Scientists have identified various practical approaches to promote cell growth and survival, remyelination, and neuroplasticity in this part of the central nervous system. This review focuses on specific detailed aspects of the involvement of cations in the cell biology of such pathology and on the possibility of repairing damaged spinal cord tissue. In this context, the cellular biology of sodium, potassium, lithium, calcium, and magnesium is essential for understanding the related pathophysiology and also the possibilities to counteract the harmful effects of traumatic events. Lithium, sodium, potassium—monovalent cations—and calcium and magnesium—bivalent cations—can influence many protein–protein interactions, gene transcription, ion channel functions, cellular energy processes—phosphorylation, oxidation—inflammation, etc. For data systematization and synthesis, we used the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) methodology, trying to make, as far as possible, some order in seeing the “big forest” instead of “trees”. Although we would have expected a large number of articles to address the topic, we were still surprised to find only 51 unique articles after removing duplicates from the 207 articles initially identified. Our article integrates data on many biochemical processes influenced by cations at the molecular level to understand the real possibilities of therapeutic intervention—which must maintain a very narrow balance in cell ion concentrations. Multimolecular, multi-cellular: neuronal cells, glial cells, non-neuronal cells, but also multi-ionic interactions play an important role in the balance between neuro-degenerative pathophysiological processes and the development of effective neuroprotective strategies. This article emphasizes the need for studying cation dynamics as an important future direction.

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DNA methylation: A mechanism for sustained alteration of KIR4.1 expression following central nervous system insult

Cited by 11 publications

References 95 publications

Astrocytes as a target for therapeutic strategies in epilepsy: current insights

Astrocytes as a target for therapeutic strategies in epilepsy: current insights

Epigenetic Alterations of Brain Non-Neuronal Cells in Major Mental Diseases

Main Cations and Cellular Biology of Traumatic Spinal Cord Injury

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