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Molecular and Cellular Biology, December 2004, p. 10151-10160, Vol. 24, No. 23
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.23.10151-10160.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Jumonji Represses Atrial Natriuretic Factor Gene Expression by Inhibiting Transcriptional Activities of Cardiac Transcription Factors

Tae-gyun Kim,1 Junqin Chen,1 Junich Sadoshima,2 and Youngsook Lee1*

Department of Anatomy, University of Wisconsin Medical School, Madison, Wisconsin,1 Cardiovascular Research Institute, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey2

Received 30 March 2004/ Returned for modification 10 June 2004/ Accepted 31 August 2004

Mice with a homozygous knockout of the jumonji (jmj) gene showed abnormal heart development and defective regulation of cardiac-specific genes, including the atrial natriuretic factor (ANF). ANF is one of the earliest markers of cardiac differentiation and a hallmark for cardiac hypertrophy. Here, we show that JMJ represses ANF gene expression by inhibiting transcriptional activities of Nkx2.5 and GATA4. JMJ represses the Nkx2.5- or GATA4-dependent activation of the reporter genes containing the ANF promoter-enhancer or containing the Nkx2.5 or GATA4-binding consensus sequence. JMJ physically associates with Nkx2.5 and GATA4 in vitro and in vivo as determined by glutathione S-transferase pull-down and immunoprecipitation assays. Using mutational analyses, we mapped the protein-protein interaction domains in JMJ, Nkx2.5, and GATA4. We identified two DNA-binding sites of JMJ in the ANF enhancer by gel mobility shift assays. However, these JMJ-binding sites do not seem to mediate ANF repression by JMJ. Mutational analysis of JMJ indicates that the protein-protein interaction domain of JMJ mediates the repression of ANF gene expression. Therefore, JMJ may play important roles in the down-regulation of ANF gene expression and in heart development.

* Corresponding author. Mailing address: Department of Anatomy, University of Wisconsin Medical School, 1300 University Ave., Madison, WI 53706. Phone: (608) 265-6352. Fax: (608) 262-7306. E-mail: youngsooklee{at}facstaff.wisc.edu.

Molecular and Cellular Biology, December 2004, p. 10151-10160, Vol. 24, No. 23
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.23.10151-10160.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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