title: Aldosterone-induced Sgk1 relieves Dot1a-Af9-mediated transcriptional repression of epithelial Na+ channel alpha.
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.
authors.affiliation: Department of Internal Medicine, University of Texas Medical School at Houston, Houston, Texas 77030, USA. Wenzheng.Zhang@uth.tmc.edu
authors.forename: Wenzheng
authors.initials: W
authors.lastname: Zhang
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Xia
authors.forename: Mary Rose
authors.initials: MR
authors.lastname: Reisenauer
authors.forename: Timo
authors.initials: T
authors.lastname: Rieg
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
authors.forename: Dietmar
authors.initials: D
authors.lastname: Kuhl
authors.forename: Volker
authors.initials: V
authors.lastname: Vallon
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Kone
mesh_terms: D000450:Aldosterone / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation; D053503:Epithelial Sodium Channels / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000378:metabolism; D017874:Immediate-Early Proteins / Q000235:genetics / Q000502:physiology*; D007685:Kidney Tubules, Collecting / Q000378:metabolism; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D008745:Methylation; D008780:Methyltransferases / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D021381:Protein Transport; D012333:RNA, Messenger / Q000378:metabolism; D012694:Serine / Q000235:genetics / Q000378:metabolism; D012965:Sodium Chloride / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D000450:Aldosterone; D053503:Epithelial Sodium Channels; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones; D017874:Immediate-Early Proteins; D008239:Lysine; D008780:Methyltransferases; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D012694:Serine; D012965:Sodium Chloride; D000099184:Serum-Glucocorticoid Regulated Kinases; C489902:Mllt3 protein, mouse; C481527:Dot1l protein, mouse