Aldosterone-induced Sgk1 relieves Dot1a-Af9-mediated transcriptional repression of epithelial Na+ channel alpha.

Department of Internal Medicine, University of Texas Medical School at Houston, Houston, Texas 77030, USA.
Aldosterone plays a major role in the regulation of salt balance and the pathophysiology of cardiovascular and renal diseases. Many aldosterone-regulated genes--including that encoding the epithelial Na+ channel (ENaC), a key arbiter of Na+ transport in the kidney and other epithelia--have been identified, but the mechanisms by which the hormone modifies chromatin structure and thus transcription remain unknown. We previously described the basal repression of ENaCalpha by a complex containing the histone H3 Lys79 methyltransferase disruptor of telomeric silencing alternative splice variant a (Dot1a) and the putative transcription factor ALL1-fused gene from chromosome 9 (Af9) as well as the release of this repression by aldosterone treatment. Here we provide evidence from renal collecting duct cells and serum- and glucocorticoid-induced kinase-1 (Sgk1) WT and knockout mice that Sgk1 phosphorylated Af9, thereby impairing the Dot1a-Af9 interaction and leading to targeted histone H3 Lys79 hypomethylation at the ENaCalpha promoter and derepression of ENaCalpha transcription. Thus, Af9 is a physiologic target of Sgk1, and Sgk1 negatively regulates the Dot1a-Af9 repressor complex that controls transcription of ENaCalpha and likely other aldosterone-induced genes.
Mesh Terms:
Aldosterone, Animals, Cells, Cultured, Down-Regulation, Epithelial Sodium Channel, Female, Gene Expression Regulation, Histones, Immediate-Early Proteins, Kidney Tubules, Collecting, Lysine, Methylation, Methyltransferases, Mice, Mice, Knockout, Mutation, Nuclear Proteins, Phosphorylation, Promoter Regions, Genetic, Protein Transport, Protein-Serine-Threonine Kinases, RNA, Messenger, Serine, Sodium Chloride, Transcription, Genetic
J. Clin. Invest. Mar. 01, 2007; 117(3);773-83 [PUBMED:17332896]
Download 2 Interactions For This Publication
Switch View:
  • Interactions (2)