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J. Biol. Chem., Vol. 280, Issue 12, 11816-11828, March 25, 2005

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Serum Response Factor, an Enriched Cardiac Mesoderm Obligatory Factor, Is a Downstream Gene Target for Tbx Genes^*

Matthew R. Barron, Narasimhaswamy S. Belaguli¶, Shu Xiang Zhang||, Mimi Trinh||, Dinaker Iyer, Xanthi Merlo**, John W. Lough**, Michael S. Parmacek, Benoit G. Bruneau, and Robert J. Schwartz||¶¶

From the Departments of ^||Molecular and Cellular Biology, Medicine, and ^¶Surgery, Baylor College of Medicine, Houston, Texas 77030, the ^**Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin 53226-0509, the Division of Cardiovascular Medicine, University of Pennsylvania Health System, Philadelphia, Pennsylvania 19104, and the Cardiovascular Research Division, The Hospital for Sick Children, Toronto, Ontario MG5 1X8, Canada

We tested the idea that T-box factors direct serum response factor (SRF) gene activity early in development. Analysis of SRF-LacZ "knock-in" mice showed highly restricted expression in early embryonic cardiac and skeletal muscle mesoderm and neuroectoderm. Examination of the SRF gene for regulatory regions by linking the promoter and 5'-flanking sequences, up to 5.5 kb, failed to target LacZ transgene activity to the heart and the tail pre-somitic mesenchyme. However, linkage of a minimal SRF promoter with the SRF 3'-untranslated region (UTR), inundated with multimeric T-box binding sites (TBEs), restored robust reporter gene activity to embryonic heart and tail. Finer dissection of the 3'-UTR to a small cluster of TBEs also stimulated transgene activity in the cardiac forming region and the tail, however, when the TBEs contained within these DNA sequences were mutated, preventing Tbx binding, transgene activity was lost. Tbx2, Tbx5, and the cardiac-enriched MYST family histone acetyltransferase TIP60, were observed to be mutual interactive cofactors through the TIP60 zinc finger and the T-box of the Tbx factors. In SRF-null ES cells, TIP60, Tbx2, and Tbx5 were sufficient to stimulate co-transfected SRF reporter activity, however this activity required the presence of the SRF 3'-UTR. SRF gene transactivation was blocked by two distinct TIP60 mutants, in which either the histone acetyltransferase domain was inactivated or the Zn finger-protein binding domain was excised. Our study supports the idea that SRF embryonic cardiac gene expression is dependent upon the SRF 3'-UTR enhancer, Tbx2, Tbx5, and TIP60 histone acetyltransferase activity.

Received for publication, November 2, 2004 , and in revised form, December 6, 2004.

^* This research was supported by National Institutes of Health Grant P01-HL49953 (to R. J. S.). 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.

Both authors contributed equally to this work.

^¶¶ To whom correspondence should be addressed: Inst. of Biosciences and Technology, Texas A&M University Health Sciences Center, 2121 W. Holcombe, Houston, TX 77030. Tel.: 713-677-7710; Fax: 713-677-7725; E-mail: rschwartz{at}ibt.tamhsc.edu.

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