DNA METHYLATION: A MECHANISM FOR SUSTAINED ALTERATION OF KIR4.1 EXPRESSION FOLLOWING CENTRAL NERVOUS SYSTEM INSULT

Glia, 2020 · DOI: 10.1002/glia.23797 · Published: July 1, 2020

Simple Explanation

Kir4.1 is a glial-specific potassium channel important for maintaining potassium balance in the brain. Loss of Kir4.1 is linked to neurological diseases. This study investigates how DNA methylation, a process that can alter gene expression, affects Kir4.1 expression after central nervous system (CNS) injury. The researchers used two different injury models – a lithium-pilocarpine model of epilepsy and a spinal cord injury model – to examine the methylation status of the Kcnj10 gene, which encodes Kir4.1. They found that hypermethylation (increased methylation) of a specific region (CpG island two) within the Kcnj10 gene was consistently observed in both injury models. This suggests that DNA methylation can regulate Kcnj10 transcription and that targeting this mechanism might help restore Kir4.1 expression after CNS injury, potentially offering a new therapeutic approach for neurological disorders.

Study Duration

Not specified

Participants

Male Sprague-Dawley rats, aged post-natal day 50–60 (200–300g)

Evidence Level

Not specified

Key Findings

1
Kir4.1 protein and mRNA are downregulated in the hippocampus following status epilepticus (SE) and in the spinal cord following spinal cord injury (SCI).
2
Hypermethylation of CpG island 2 in the Kcnj10 gene is associated with decreased Kir4.1 expression in both the epilepsy and spinal cord injury models.
3
In isolated astrocytes, Kcnj10 mRNA expression is decreased, and hypermethylation of CpG island 2 is observed following SE, suggesting an astrocyte-specific mechanism.

Research Summary

This study investigates the role of DNA methylation in the downregulation of Kir4.1, a potassium channel crucial for CNS function, following CNS injury. Using two different injury models (epilepsy and spinal cord injury), the researchers found that hypermethylation of CpG island 2 in the Kcnj10 gene is consistently associated with decreased Kir4.1 expression. The findings suggest that DNA methylation bidirectionally modulates Kcnj10 transcription and may represent a targetable molecular mechanism for restoring astroglial Kir4.1 expression following CNS insult.

Practical Implications

Therapeutic Target

DNA methylation represents a dynamic therapeutic target in CNS injuries and could potentially be exploited for therapeutic benefit in a wide array of traumatic CNS injuries.

Drug Development

Manipulation of the methylation status of Kcnj10, utilizing DNA methyltransferase inhibitors, may serve as a plausible mechanism to ‘rescue’ Kir4.1 expression post CNS insult.

Personalized Medicine

A more comprehensive understanding of the regulation of Kir4.1 expression may prove to be useful in developing therapies for a diverse clinical subset.

Study Limitations

1
The data presented herein indicates a loss of functional Kir4.1, as indicated by an approximate 50% decrease in Ba2+ sensitive currents in CA1 hippocampal astrocytes post pilocarpine injection, supporting decreased mRNA and protein expression.
2
There are limations to astrocyte electrophysiological studies, most notably, the low input resistance of the astrocyte membrane leads to a poor voltage clamp, a well recognized problem, particularly in the slice prepartation
3
This voltage drop across distance of the astrocyte membrane also predicts significant space clamp issues leading us to underestimate changes in membrane current occuring at sites distal to our recording pipette.

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