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

J Clin Invest. 2007 Mar;117(3):773-83. doi: 10.1172/JCI29850.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldosterone / pharmacology
  • Aldosterone / physiology*
  • Animals
  • Cells, Cultured
  • Down-Regulation
  • Epithelial Sodium Channels / genetics*
  • Epithelial Sodium Channels / metabolism
  • Female
  • Gene Expression Regulation*
  • Histone-Lysine N-Methyltransferase
  • Histones / metabolism
  • Immediate-Early Proteins / genetics
  • Immediate-Early Proteins / physiology*
  • Kidney Tubules, Collecting / metabolism
  • Lysine / genetics
  • Lysine / metabolism
  • Methylation
  • Methyltransferases / metabolism*
  • Mice
  • Mice, Knockout
  • Mutation
  • Nuclear Proteins / metabolism*
  • Phosphorylation
  • Promoter Regions, Genetic
  • Protein Transport
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / physiology*
  • RNA, Messenger / metabolism
  • Serine / genetics
  • Serine / metabolism
  • Sodium Chloride / metabolism
  • Transcription, Genetic / drug effects

Substances

  • Epithelial Sodium Channels
  • Histones
  • Immediate-Early Proteins
  • Mllt3 protein, mouse
  • Nuclear Proteins
  • RNA, Messenger
  • Sodium Chloride
  • Serine
  • Aldosterone
  • Dot1l protein, mouse
  • Methyltransferases
  • Histone-Lysine N-Methyltransferase
  • Protein-Serine-Threonine Kinases
  • serum-glucocorticoid regulated kinase
  • Lysine