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J. Biol. Chem., Vol. 280, Issue 19, 19115-19126, May 13, 2005

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Identification of Direct Serum-response Factor Gene Targets during Me₂SO-induced P19 Cardiac Cell Differentiation^*

Shu Xing Zhang, Eduardo Garcia-Gras, Diane R. Wycuff, Suzanne J. Marriot, Nijiati Kadeer, Wei Yu, Eric N. Olson¶, Daniel J. Garry||¶, Michael S. Parmacek**, and Robert J. Schwartz¶

From the Departments of Molecular and Cellular Biology and Medicine, Baylor College of Medicine, Houston, Texas 77030, the Department of Molecular Biology and the ^||Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, and the ^**Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Serum-response factor (SRF) is an obligatory transcription factor, required for the formation of vertebrate mesoderm leading to the origin of the cardiovascular system. Protein A-TEV-tagged chromatin immunoprecipitation technology was used to collect direct SRF-bound gene targets from pluripotent P19 cells, induced by Me₂SO treatment into an enriched cardiac cell population. From 242 sequenced DNA fragments, we identified 188 genomic DNA fragments as potential direct SRF targets that contain CArG boxes and CArG-like boxes. Of the 92 contiguous genes that were identified, a subgroup of 43 SRF targets was then further validated by co-transfection assays with SRF. Expression patterns of representative candidate genes were compared with the LacZ reporter expression activity of the endogenous SRF gene. According to the Unigene data base, 84% of the SRF target candidates were expressed, at least, in the heart. In SRF null embryonic stem cells, 81% of these SRF target candidates were greatly affected by the absence of SRF. Among these SRF-regulated genes, Raf1, Map4k4, and Bicc1 have essential roles in mesoderm formation. The 12 regulated SRF target genes, Mapk10 (JNK3), Txnl2, Azi2, Tera, Sema3a, Lrp4, Actc1, Myl3, Hspg2, Pgm2, Hif3a, and Asb5, have been implicated in cardiovascular formation, and the Ski and Hes6 genes have roles in muscle differentiation. SRF target genes related to cell mitosis and cycle, E2f5, Npm1, Cenpb, Rbbp6, and Scyl1, expressed in the heart tissue were differentially regulated in SRF null ES cells.

Received for publication, December 7, 2004 , and in revised form, January 18, 2005.

^* 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.

^¶ Supported by National Institutes of Health Grant P01 HL49953.

To whom correspondence should be addressed: Institute of Biosciences and Technology, the Texas A & M University System Health Science Center, 2121 W. Holcombe Blvd., Houston, TX 77030. Tel.: 713-677-7710; E-mail: rschwartz{at}ibt.tamhsc.edu.

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