Aldosterone-induced Sgk1 relieves Dot1a-Af9-mediated transcriptional repression of epithelial Na+ channel alpha.
- Citation data:
The Journal of clinical investigation, ISSN: 0021-9738, Vol: 117, Issue: 3, Page: 773-83
- Publication Year:
- Repository URL:
- 10.1172/jci29850; 10.3410/f.1068821.521758
- Medicine; Aldosterone; Animals; Cells; Cultured; Down-Regulation; Epithelial Sodium Channel; Female; Gene Expression Regulation; Histones; Immediate-Early Proteins; Kidney Tubules; Collecting; Lysine; Methylation; Methyltransferases; Mice; Knockout; Mutation; Nuclear Proteins; Phosphorylation; Promoter Regions; Genetic; Protein Transport; Protein-Serine-Threonine Kinases; RNA; Messenger; Serine; Sodium Chloride; Transcription; Medicine and Health Sciences
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.