title: DNA methylation functions as a critical regulator of Kir4.1 expression during CNS development.
abstract: 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.
authors.affiliation: Department of Cell, Developmental and Integrative Biology, Center for Glial Biology in Medicine, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Sinifunanya E
authors.initials: SE
authors.lastname: Nwaobi
authors.forename: Erica
authors.initials: E
authors.lastname: Lin
authors.forename: Sasank R
authors.initials: SR
authors.lastname: Peramsetty
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Olsen
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D002490:Central Nervous System / Q000254:growth & development* / Q000378:metabolism*; D018899:CpG Islands / Q000235:genetics; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D064568:S100 Calcium Binding Protein beta Subunit / Q000235:genetics / Q000378:metabolism; D000098854:Kcnj10 Channel
chemical_list: D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D000098854:Kcnj10 Channel; C489787:MAP2 protein, rat; D008869:Microtubule-Associated Proteins; D024661:Potassium Channels, Inwardly Rectifying; D064568:S100 Calcium Binding Protein beta Subunit; C579160:S100B protein, human; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases
keywords: astrocyte; development; epigenetics