Aldosterone-induced Sgk1 relieves Dot1a-Af9–mediated transcriptional repression of epithelial Na+ channel α
Wenzheng Zhang, … , Volker Vallon, Bruce C. Kone
Wenzheng Zhang, … , Volker Vallon, Bruce C. Kone
Published March 1, 2007
Citation Information: J Clin Invest. 2007;117(3):773-783. https://doi.org/10.1172/JCI29850.
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Aldosterone-induced Sgk1 relieves Dot1a-Af9–mediated transcriptional repression of epithelial Na+ channel α

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 ENaCα 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 ENaCα promoter and derepression of ENaCα transcription. Thus, Af9 is a physiologic target of Sgk1, and Sgk1 negatively regulates the Dot1a-Af9 repressor complex that controls transcription of ENaCα and likely other aldosterone-induced genes.

Authors

Wenzheng Zhang, Xuefeng Xia, Mary Rose Reisenauer, Timo Rieg, Florian Lang, Dietmar Kuhl, Volker Vallon, Bruce C. Kone

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Figure 7

Model for aldosterone-sensitive repression of ENaCα expression by targeted histone H3 Lys79 hypermethylation mediated by the Dot1a-Af9-Sgk1 complex.

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Model for aldosterone-sensitive repression of ENaCα expression by target...
Under basal conditions, Dot1a and Af9 form a nuclear complex that directly or indirectly binds specific sites of the ENaCα promoter, leading to hypermethylation of histone H3 Lys79 and repression of ENaCα transcription. Aldosterone stimulates ENaCα transcription by regulating 2 different pathways. In the classical pathway, aldosterone binds and activates the nuclear hormone receptors (NR) that are either glucocorticoid receptor and/or mineralocorticoid receptor homo- or heterodimers to bind the glucocorticoid response element in the ENaCα promoter and transactivate ENaCα. In a parallel pathway, aldosterone releases the repression of ENaCα by (a) downregulating Dot1a (12) and Af9 expression (8), and thus the amount of Dot1a-Af9 complex, presumably via nuclear receptor–dependent or –independent (not shown) mechanisms and/or (b) decreasing the Dot1a-Af9 interaction via Sgk1-mediated phosphorylation of Af9 to limit their availability, leading to histone H3 Lys79 hypomethylation at specific subregions of the ENaCα promoter. Sgk1 might join and downregulate the Dot1a-Af9 complex associated with the ENaCα promoter (not shown for simplicity). In all cases, Af9-free Dot1a binds DNA nonspecifically and catalyzes histone H3 Lys79 methylation throughout the genome under basal conditions (not shown). A hypothetical opposing interaction between the nuclear receptor–aldosterone complex and the Dot1a-Af9 complex (dotted line) may tune the ultimate level of ENaCα transcription. Meth, methylation.