DNA methylation functions as a critical regulator of Kir4.1 expression during CNS development

• Published in: Glia 2014-03, Vol.62 (3), p.411-427
• Main Authors: Nwaobi, Sinifunanya E., Lin, Erica, Peramsetty, Sasank R., Olsen, Michelle L.
• Format: Article
• Language: English
• Subjects: Age Factors; Alzheimer's disease; Animals; Animals, Newborn; astrocyte; Central Nervous System - growth & development; Central Nervous System - metabolism; CpG Islands - genetics; Deoxyribonucleic acid; development; DNA; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases - metabolism; DNA methylation; DNA Methylation - genetics; Enzyme Inhibitors - pharmacology; Epigenetics; Flow Cytometry; Gene Expression Regulation, Developmental - genetics; Gene Expression Regulation, Developmental - physiology; Genes; Glial Fibrillary Acidic Protein - metabolism; HEK293 Cells; Humans; Male; Microtubule-Associated Proteins - metabolism; Potassium Channels, Inwardly Rectifying - genetics; Potassium Channels, Inwardly Rectifying - metabolism; Rats; Rats, Sprague-Dawley; Rats, Transgenic; S100 Calcium Binding Protein beta Subunit - genetics; S100 Calcium Binding Protein beta Subunit - metabolism
• ISSN: 0894-1491; 1098-1136
• DOI: 10.1002/glia.22613

Kir4.1, a glial‐specific K+ channel, is critical for normal CNS development. Studies using both global and glial‐specific knockout of Kir4.1 reveal abnormal CNS development with the loss of the channel. Specifically, Kir4.1 knockout animals are characterized by ataxia, severe hypomyelination, and early postnatal death. Additionally, Kir4.1 has emerged as a key player in several CNS diseases. Notably, decreased Kir4.1 protein expression occurs in several human CNS pathologies including CNS ischemic injury, spinal cord injury, epilepsy, ALS, and Alzheimer's disease. Despite the emerging significance of Kir4.1 in normal and pathological conditions, its mechanisms of regulation are unknown. Here, we report the first epigenetic regulation of a K+ channel in the CNS. Robust developmental upregulation of Kir4.1 expression in rats is coincident with reductions in DNA methylation of the Kir4.1 gene, KCNJ10. Chromatin immunoprecipitation reveals a dynamic interaction between KCNJ10 and DNA methyltransferase 1 during development. Finally, demethylation of the KCNJ10 promoter is necessary for transcription. These findings indicate DNA methylation is a key regulator of Kir4.1 transcription. Given the essential role of Kir4.1 in normal CNS development, understanding the regulation of this K+ channel is critical to understanding normal glial biology. GLIA 2014;62:411–427 Main Points DNA methylation is a key regulator of Kir4.1 transcription. This is the first report of epigenetic regulation of a CNS ion channel. These findings identify a potential novel therapeutic to target ion channel expression in the CNS.