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

Wenzheng Zhang; Xuefeng Xia; Diana I. Jalal; Teresa Kuncewicz; William Xu; Gene D. Lesage; Bruce C. Kone

doi:10.1152/ajpcell.00431.2005

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

Journal article

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

Wenzheng Zhang, Xuefeng Xia, Diana I. Jalal, Teresa Kuncewicz, William Xu, Gene D. Lesage and Bruce C. Kone

American Journal of Physiology: Cell Physiology, Vol.290(3), pp.C936-C946

10/19/2005

DOI: 10.1152/ajpcell.00431.2005

PMCID: PMC3009459

PMID: 16236820

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https://www.ncbi.nlm.nih.gov/pmc/articles/3009459View

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Abstract

Aldosterone is a major regulator of epithelial Na + absorption. One of its principal targets is the epithelial Na + channel α-subunit (ENaCα), principally expressed in the kidney collecting duct, lung, and colon. Models of aldosterone-mediated trans -activation of the ENaCα gene have focused primarily on interactions of liganded nuclear receptors with the ENaCα 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 ENaCα 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 ENaCα 5′-flanking region, and trans -activation of ENaCα . Knockdown of mDot1a by RNA interference increased activity of a stably integrated ENaCα promoter-luciferase construct and expression of endogenous ENaCα mRNA. Conversely, overexpression of EGFP-tagged mDot1a resulted in hypermethylation of histone H3 K79 at the endogenous ENaCα promoter, repression of endogenous ENaCα mRNA expression, and decreased activity of the ENaCα promoter-luciferase construct. mDot1a-mediated histone H3 K79 hypermethylation and repression of ENaCα 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 ENaCα promoter and hypermethylating histone H3 K79 associated with the ENaCα promoter, a negative regulator of ENaCα transcription.

chromatin

collecting duct

Dot1

epigenetic

gene regulation

Na+ transport

Details

Title: Subtitle: Aldosterone-sensitive repression of ENaCα transcription by a histone H3 lysine-79 methyltransferase
Creators: Wenzheng Zhang - Brown Foundation
Xuefeng Xia - Brown Foundation
Diana I. Jalal - The University of Texas Health Science Center at Houston
Teresa Kuncewicz - The University of Texas Health Science Center at Houston
William Xu - The University of Texas Health Science Center at Houston
Gene D. Lesage - The University of Texas Health Science Center at Houston
Bruce C. Kone - The University of Texas Health Science Center at Houston
Resource Type: Journal article
Publication Details: American Journal of Physiology: Cell Physiology, Vol.290(3), pp.C936-C946
DOI: 10.1152/ajpcell.00431.2005
PMID: 16236820
PMCID: PMC3009459
NLM abbreviation: Am J Physiol Cell Physiol
ISSN: 0363-6143
eISSN: 1522-1563
Language: English
Date published: 10/19/2005
Academic Unit: Nephrology; Internal Medicine
Record Identifier: 9984359829802771

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