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J. Biol. Chem., Vol. 283, Issue 18, 11935-11946, May 2, 2008

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Nuclear Respiratory Factor 1 Controls Myocyte Enhancer Factor 2A Transcription to Provide a Mechanism for Coordinate Expression of Respiratory Chain Subunits^*

Bindu Ramachandran¹, Gengsheng Yu¹², and Tod Gulick³

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

Nuclear respiratory factors NRF1 and NRF2 regulate the expression of nuclear genes encoding heme biosynthetic enzymes, proteins required for mitochondrial genome transcription and protein import, and numerous respiratory chain subunits. NRFs thereby coordinate the expression of nuclear and mitochondrial genes relevant to mitochondrial biogenesis and respiration. Only two of the nuclear-encoded respiratory chain subunits have evolutionarily conserved tissue-specific forms: the cytochrome c oxidase (COX) subunits VIa and VIIa heart/muscle (H) and ubiquitous (L) isoforms. We used genome comparisons to conclude that the promoter regions of COX6A_H and COX7A_H lack NRF sites but have conserved myocyte enhancer factor 2 (MEF2) elements. We show that MEF2A mRNA is induced with forced expression of NRF1 and that the MEF2A 5'-regulatory region contains an evolutionarily conserved canonical element that binds endogenous NRF1 in chromatin immunoprecipitation (ChIP) assays. NRF1 regulates MEF2A promoter-reporters according to overexpression, RNA interference underexpression, and promoter element mutation studies. As there are four mammalian MEF2 isotypes, we used an isoform-specific antibody in ChIP to confirm MEF2A binding to the COX6A_H promoter. These findings support a role for MEF2A as an intermediary in coordinating respiratory chain subunit expression in heart and muscle through a NRF1 MEF2A COX_H transcriptional cascade. MEF2A also bound the MEF2A and PPARGC1A promoters in ChIP, placing it within a feedback loop with PGC1 in controlling NRF1 activity. Interruption of this cascade and loop may account for striated muscle mitochondrial defects in mef2a null mice. Our findings also account for the previously described indirect regulation by NRF1 of other MEF2 targets in muscle such as GLUT4.

Received for publication, September 4, 2007 , and in revised form, January 24, 2008.

^* This work was supported in part by grants from the American Heart Association and the Juvenile Diabetes Foundation; Grant P30-DK40561 from the Clinical Nutrition Research Center at Harvard; and Grants DK55875, DK02461, and HL72713 from the National Institutes of Health (all to T. G.). 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 Figs. S1–S3 and Table S1.

¹ Both authors contributed equally to this work.

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

³ 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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