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This Article Full Text Full Text (PDF) All Versions of this Article: 290/3/C936    most recent 00431.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (9) Citing Articles via Google Scholar Google Scholar Articles by Zhang, W. Articles by Kone, B. C. Search for Related Content PubMed PubMed Citation Articles by Zhang, W. Articles by Kone, B. C.

MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Aldosterone-sensitive repression of ENaC transcription by a histone H3 lysine-79 methyltransferase

Departments of ¹Internal Medicine and ²Integrative Biology, The University of Texas Health Sciences Center, Houston; and ³The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, Houston, Texas

Submitted 23 August 2005 ; accepted in final form 12 October 2005

Aldosterone is a major regulator of epithelial Na⁺ absorption. One of its principal targets is the epithelial Na⁺ channel -subunit (ENaC), principally expressed in the kidney collecting duct, lung, and colon. Models of aldosterone-mediated trans-activation of the ENaC gene have focused primarily on interactions of liganded nuclear receptors with the ENaC gene promoter. Herein, we demonstrate that the murine histone H3 lysine-79 methyltransferase, murine disruptor of telomeric silencing alternative splice variant "a" (mDot1a), is a novel component in the aldosterone signaling network controlling transcription of the ENaC gene. Aldosterone downregulated mDot1a mRNA levels in murine inner medullary collecting ducts cells, which was associated with histone H3 K79 hypomethylation in bulk histones and at specific sites in the ENaC 5'-flanking region, and trans-activation of ENaC. Knockdown of mDot1a by RNA interference increased activity of a stably integrated ENaC promoter-luciferase construct and expression of endogenous ENaC mRNA. Conversely, overexpression of EGFP-tagged mDot1a resulted in hypermethylation of histone H3 K79 at the endogenous ENaC promoter, repression of endogenous ENaC mRNA expression, and decreased activity of the ENaC promoter-luciferase construct. mDot1a-mediated histone H3 K79 hypermethylation and repression of ENaC promoter activity was abolished by mDot1a mutations that eliminate its methyltransferase activity. Collectively, our data identify mDot1a as a novel aldosterone-regulated histone modification enzyme, and, through binding the ENaC promoter and hypermethylating histone H3 K79 associated with the ENaC promoter, a negative regulator of ENaC transcription.

gene regulation; collecting duct; Na⁺ transport; chromatin; epigenetic; Dot1

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