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DNA methylation: A mechanism for sustained alteration of KIR4.1 expression following central nervous system insult
Author(s) -
Boni Jessica L.,
Kahanovitch Uri,
Nwaobi Sinifunanya E.,
Floyd Candace L.,
Olsen Michelle L.
Publication year - 2020
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.23797
Subject(s) - biology , dna methylation , mecp2 , astrocyte , central nervous system , epigenetics , regulation of gene expression , hippocampal formation , gene expression , neuroscience , gene , microbiology and biotechnology , genetics , phenotype
Kir4.1, a glial‐specific inwardly rectifying potassium channel, is implicated in astrocytic maintenance of K + homeostasis. Underscoring the role of Kir4.1 in central nervous system (CNS) functioning, genetic mutations in KCNJ10 , the gene which encodes Kir4.1, causes seizures, ataxia and developmental disability in humans. Kir4.1 protein and mRNA loss are consistently observed in CNS injury and neurological diseases linked to hyperexcitability and neuronal dysfunction, leading to the notion that Kir4.1 represents an attractive therapeutic target. Despite this, little is understood regarding the mechanisms that underpin this downregulation. Previous work by our lab revealed that DNA hypomethylation of the Kcnj10 gene functions to regulate mRNA levels during astrocyte maturation whereas hypermethylation in vitro led to decreased promoter activity. In the present study, we utilized two vastly different injury models with known acute and chronic loss of Kir4.1 protein and mRNA to evaluate the methylation status of Kcnj10 as a candidate molecular mechanism for reduced transcription and subsequent protein loss. Examining whole hippocampal tissue and isolated astrocytes, in a lithium‐pilocarpine model of epilepsy, we consistently identified hypermethylation of CpG island two, which resides in the large intronic region spanning the Kcnj10 gene. Strikingly similar results were observed using the second injury paradigm, a fifth cervical (C5) vertebral hemi‐contusion model of spinal cord injury. Our previous work indicates the same gene region is significantly hypomethylated when transcription increases during astrocyte maturation. Our results suggest that DNA methylation can bidirectionally modulate Kcnj10 transcription and may represent a targetable molecular mechanism for the restoring astroglial Kir4.1 expression following CNS insult.