Aldosterone-sensitive repression of ENaCα transcription by a histone H3 lysine-79 methyltransferase
Aldosterone-sensitive repression of ENaCα transcription by a histone H3 lysine-79 methyltransferase
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DOI：
10.1152/ajpcell.00431.2005
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发表时间：
2006-03-01
影响因子：
5.5
通讯作者：
Kone, BC
中科院分区：
文献类型：
--
作者：
Zhang, WZ;Xia, XF;Kone, BC
Aldosterone is a major regulator of epithelial Na+ absorption. One of its principal targets is the epithelial Na+ channel alpha-subunit (ENaC alpha), principally expressed in the kidney collecting duct, lung, and colon. Models of aldosterone-mediated trans-activation of the ENaC alpha gene have focused primarily on interactions of liganded nuclear receptors with the ENaC alpha 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 alpha 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 alpha 5'-flanking region, and trans-activation of ENaC alpha. Knockdown of mDot1a by RNA interference increased activity of a stably integrated ENaC alpha promoter-luciferase construct and expression of endogenous ENaC alpha mRNA. Conversely, overexpression of EGFP-tagged mDot1a resulted in hypermethylation of histone H3 K79 at the endogenous ENaC alpha promoter, repression of endogenous ENaC alpha mRNA expression, and decreased activity of the ENaC alpha promoter-luciferase construct. mDot1a-mediated histone H3 K79 hypermethylation and repression of ENaC alpha 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 alpha promoter and hypermethylating histone H3 K79 associated with the ENaC alpha promoter, a negative regulator of ENaC alpha transcription.
