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J. Biol. Chem., Vol. 280, Issue 7, 5909-5916, February 18, 2005

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Alternative Usages of Multiple Promoters of the Acetyl-CoA Carboxylase Gene Are Related to Differential Transcriptional Regulation in Human and Rodent Tissues^*

So-Young Oh, Min-Young Lee, Jong-Min Kim, Sarah Yoon, Soonah Shin, Young Nyun Park, Yong-Ho Ahn, and Kyung-Sup Kim¶

From the Department of Biochemistry and Molecular Biology, Brain Korea 21 Project for Medical Science, Institute of Genetic Science and the Department of Pathology, Yonsei University College of Medicine, 134 Shinchondong Seodaemungu, Seoul 120-752, Korea

Acetyl-CoA carboxylase (ACC) is a critical enzyme in the regulation of fatty acid oxidation and is dominantly expressed in the skeletal muscle, heart, and liver. It has been established that two promoters, P-I and P-II, control the transcription of the ACC gene. However, the precise mechanism involved in controlling tissue-specific gene expression of ACC is largely unknown yet. In this study we revealed that promoter P-I, active in the skeletal muscle and heart but not in the liver, could be activated by myogenic regulatory factors and retinoid X receptors in a synergistic manner. Moreover, P-I was also activated markedly by the cardiac-specific transcription factors, Csx/Nkx2.5 and GATA4. These results suggest that the proper stimulation of P-I by these tissue-specific transcription factors is important for the expression of ACC according to the tissue types. In addition, CpG sites around human exon 1a transcribed by P-I are half-methylated in muscle but completely methylated in the liver, where P-I is absolutely inactive. In humans, the skeletal muscle uses P-II as well as P-I, whereas only P-I is active in rat skeletal muscle. The proximal myogenic regulatory factor-binding sites in human P-II, which are not conserved in rat P-II, might contribute to this difference in P-II usage between human and rat skeletal muscle. Hepatoma-derived cell lines primarily use another novel promoter located about 3 kilobases upstream of P-I, designated as P-O. This study is the first to explain the mechanisms underlying the differential regulation of ACC gene expression between tissues in living organisms.

Received for publication, August 6, 2004 , and in revised form, November 24, 2004.

^* This work was supported by Korea Science and Engineering Foundation Grant R13-2002-054-01002-0. 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.

^¶ To whom correspondence and reprint requests should be addressed: Dept. Biochemistry and Molecular Biology, Yonsei University College of Medicine, 134 Shinchondong Seodaemungu, Seoul 120-752, Korea. Tel.: 82-2-361-5184; Fax: 82-2-312-5041; E-mail: kyungsup59{at}yumc.yonsei.ac.kr.

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