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J. Biol. Chem., Vol. 281, Issue 26, 18059-18068, June 30, 2006

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Dot1a-AF9 Complex Mediates Histone H3 Lys-79 Hypermethylation and Repression of ENaC in an Aldosterone-sensitive Manner^*

Wenzheng Zhang, Xuefeng Xia, Mary Rose Reisenauer, Charles S. Hemenway, and Bruce C. Kone^¶||1

From the Departments of Internal Medicine and ^¶Integrative Biology and Pharmacology, and ^||The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Health Science Center at Houston, Houston, Texas 77030 and the Department of Pediatrics and the Tulane Cancer Center, Tulane University School of Medicine, New Orleans, Louisiana 70112

Aldosterone is a major regulator of epithelial Na⁺ absorption and acts in large part through induction of the epithelial Na⁺ channel (ENaC) gene in the renal collecting duct. We previously identified Dot1a as an aldosterone early repressed gene and a repressor of ENaC transcription through mediating histone H3 Lys-79 methylation associated with the ENaC promoter. Here, we report a novel aldosterone-signaling network involving AF9, Dot1a, and ENaC. AF9 and Dot1a interact in vitro and in vivo as evidenced in multiple assays and colocalize in the nuclei of mIMCD3 renal collecting duct cells. Overexpression of AF9 results in hypermethylation of histone H3 Lys-79 at the endogenous ENaC promoter at most, but not all subregions examined, repression of endogenous ENaC mRNA expression and acts synergistically with Dot1a to inhibit ENaC promoter-luciferase constructs. In contrast, RNA interference-mediated knockdown of AF9 causes the opposite effects. Chromatin immunoprecipitation assays reveal that overexpressed FLAG-AF9, endogenous AF9, and Dot1a are each associated with the ENaC promoter. Aldosterone negatively regulates AF9 expression at both mRNA and protein levels. Thus, Dot1a-AF9 modulates histone H3 Lys-79 methylation at the ENaC promoter and represses ENaC transcription in an aldosterone-sensitive manner. This mechanism appears to be more broadly applicable to other aldosterone-regulated genes because overexpression of AF9 alone or in combination with Dot1a inhibited mRNA levels of three other known aldosterone-inducible genes in mIMCD3 cells.

Received for publication, February 28, 2006 , and in revised form, April 11, 2006.

^* This work was supported by National Institutes of Health Grants K01 DK70834 (to W. Z.), R01 DK075065 (to B. C. K.), and R01 DK47981 (to B. C. K.), and endowment funds from The James T. and Nancy B. Willerson Chair (to B. C. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Internal Medicine, The University of Texas Medical School at Houston, 6431 Fannin, MSB 1.150, Houston, TX 77030. Tel.: 713-500-6501; Fax: 713-500-6497; E-mail: Bruce.C.Kone{at}uth.tmc.edu.

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