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J. Biol. Chem., Vol. 283, Issue 16, 10318-10329, April 18, 2008

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Myocyte Enhancer Factor 2A Is Transcriptionally Autoregulated^*

Bindu Ramachandran¹, Gengsheng Yu¹², Shiguang Li, Bangmin Zhu³, and Tod Gulick⁴

From the Diabetes Research Laboratory, Department of Medicine, Massachusetts General Hospital, Charlestown, Massachusetts 02129 and the Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115

MEF2 (myocyte enhancer factor 2) proteins are a small family of transcription factors that play pivotal roles in striated muscle differentiation, development, and metabolism, in neuron survival and synaptic formation, and in lymphocyte selection and activation. Products of the four mammalian MEF2 genes, MEF2A, MEF2B, MEF2C, and MEF2D, are expressed with overlapping but distinct temporospatial patterns. Toward analysis of MEF2A functions and the determinants of its regulated expression, we have mapped and begun studies of the transcriptional control regions of this gene. Heterogeneous 5'-untranslated regions of MEF2A mRNAs result from use of alternative promoters and splicing patterns. The two closely approximated TATA-less promoters are 65 kb upstream of the exon containing the sole initiation codon. Ribonuclease protection and primer extension assays show that each promoter is active in various adult tissues. A canonical MEF2 site overlies the major promoter 1 transcription start site. This element specifically binds MEF2 factors, including endogenous nuclear MEF2A according to chromatin immunoprecipitation studies, and is critical to MEF2A transcription in myocytes. The site exerts reciprocal control of the alternative promoters, silencing promoter 1 and activating promoter 2 under some conditions. Erk5 and p38 MAPK signaling stimulate MEF2A expression by activating both promoters from the MEF2 element. MEF2A transcription is therefore subject to positive or negative regulation by its protein products, depending on signaling activities that influence MEF2 factor trans-activity. The sole MEF2 gene of the cephalochordate amphioxus has a similar regulatory region structure, suggesting that this mode of autoregulatory control is conserved among higher metazoan MEF2 genes.

Received for publication, September 11, 2007 , and in revised form, November 15, 2007.

^* This work was supported in part by grants (to T. G.) from the American Heart Association, the Clinical Nutrition Research Center at Harvard Grant P30-DK40561, and National Institutes of Health Grants DK55875, DK02461, and HL72713. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Experimental Procedures and Tables S1 and S2.

¹ Both authors contributed equally to this work.

² Recipient of a Scientist Development Grant from the American Heart Association. Present address: Dept. of Pathology, State University of New York, Buffalo, NY 14203.

³ Present address: Radiation Oncology Dept., Beth Israel Deaconess Medical Center, Boston, MA 02115.

⁴ To whom correspondence should be addressed: Diabetes Research Laboratory, Massachusetts General Hospital, CNY 149 8219, Charlestown, MA 02129. Tel.: 617-724-2356; Fax: 617-726-9452; E-mail: gulick{at}helix.mgh.harvard.edu.

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