Research Background Significant progress has been made in the last decade in elucidating the molecular mechanisms regulating cardiac morphogenesis, but this process is still only partially understood. To date, only a limited number of genes have been identified that play a role in the transcriptional regulation of heart development (1-5). Mutations in several of these genes have now been shown to cause human congenital heart disease (6-9). We have previously identified a gene critical for normal heart development called FOG-2, a member of the FOG family of transcriptional modulators that also includes FOG-1 and U-shaped (10-13). FOG-2 is a nuclear protein that contains 8 zinc-finger motifs and is expressed early in the developing heart. We demonstrated that FOG-2 physically associates with GATA4, a cardiac-enriched transcription factor that strongly trans-activates a number of cardiac-specific gene promoters. The interaction of FOG-2 with GATA4 blocks GATA4’s ability to activate transcription of these cardiac-specific promoters, thus demonstrating that FOG-2 functions as a transcriptional co-repressor (10). An analysis of the important functional domains of FOG-2 indicated that the repression domain of FOG-2 localizes to the N-terminus of the protein, while multiple zinc fingers of FOG-2 mediate its interaction with GATA4 (Figure 1) (14). Finally, we found that mice with a targeted disruption of the FOG-2 gene die in mid-gestation from cardiac failure secondary to cardiac malformations (15,16). The hearts of these mutant mice have tricuspid atresia, pulmonic stenosis, a large ventricular septal defect, an atrial septal defect, and left ventricular wall hypoplasia. Taken together, these results demonstrate the importance of FOG-2 in cardiogenesis and suggest that transcriptional repression, in addition to activation, plays a critical role in cardiac development. My general research interest is to further our understanding of the transcriptional regulation of cardiac development with the expectation that this will lead to an improved understanding of the molecular basis of congenital heart disease. Further, a more in-depth understanding of transcriptional pathways regulating cardiac development may generate novel paradigms that will be broadly applicable to development of many other organ systems. Finally, elucidation of the transcriptional regulation of heart formation may also suggest potential strategies to repair a heart damaged by a myocardial infarction. For example, fibroblasts or skin cells could potentially be genetically “reprogrammed” to become cardiomyocytes if we understood the transcriptional pathway required to commit cells to the cardiomyocyte lineage and to differentiate them into mature cardiomyocytes. These cells could then be implanted into damaged myocardium to repair the heart following a heart attack, leading to an improvement in cardiac function and patient symptoms. If such a therapy were to be developed, it would have profound effects on the way clinical cardiology is practiced today and dramatically improve long-term outcomes for patients with congestive heart failure. References 1. Fishman, M. C., and Olson, E. N. (1997) Cell 91, 153-156 2. Harvey, R. P. (1998) Seminars in Cell & Developmental Biology 9, 101-108 3. Olson, E. N., and Srivastava, D. (1996) Science 272, 671-676 4. Sucov, H. M. (1998) Annu Rev Physiol 60, 287-308 5. Srivastava, D., and Olson, E. N. (2000) Nature 407, 221-226. 6. Basson, C. T., Bachinsky, D. R., Lin, R. C., Levi, T., Elkins, J. A., Soults, J., Grayzel, D., Kroumpouzou, E., Traill, T. A., Leblanc-Straceski, J., Renault, B., Kucherlapati, R., Seidman, J. G., and Seidman, C. E. (1997) Nat Genet 15, 30-35 7. Li, Q. Y., Newbury-Ecob, R. A., Terrett, J. A., Wilson, D. I., Curtis, A. R., Yi, C. H., Gebuhr, T., Bullen, P. J., Robson, S. C., Strachan, T., Bonnet, D., Lyonnet, S., Young, I. D., Raeburn, J. A., Buckler, A. J., Law, D. J., and Brook, J. D. (1997) Nat Genet 15, 21-29 8. Pehlivan, T., Pober, B. R., Brueckner, M., Garrett, S., Slaugh, R., Van Rheeden, R., Wilson, D. B., Watson, M. S., and Hing, A. V. (1999) Am J Med Genet 83, 201-206 9. Schott, J. J., Benson, D. W., Basson, C. T., Pease, W., Silberbach, G. M., Moak, J. P., Maron, B. J., Seidman, C. E., and Seidman, J. G. (1998) Science 281, 108-111 10. Svensson, E. C., Tufts, R. L., Polk, C. E., and Leiden, J. M. (1999) Proc Natl Acad Sci U S A 96, 956-961 11. Tevosian, S. G., Deconinck, A. E., Cantor, A. B., Rieff, H. I., Fujiwara, Y., Corfas, G., and Orkin, S. H. (1999) Proc Natl Acad Sci U S A 96, 950-955 12. Lu, J. R., McKinsey, T. A., Xu, H., Wang, D. Z., Richardson, J. A., and Olson, E. N. (1999) Mol Cell Biol 19, 4495-4502 13. Holmes, M., Turner, J., Fox, A., Chisholm, O., Crossley, M., and Chong, B. (1999) J Biol Chem 274, 23491-23498 14. Svensson, E. C., Huggins, G. S., Dardik, F. B., Polk, C. E., and Leiden, J. M. (2000) J Biol Chem 275, 20762-20769. 15. Svensson, E. C., Huggins, G. S., Lin, H., Clendenin, C., Jiang, F., Tufts, R., Dardik, F. B., and Leiden, J. M. (2000) Nat Genet 25, 353-356. 16. Tevosian, S. G., Deconinck, A. E., Tanaka, M., Schinke, M., Litovsky, S. H., Izumo, S., Fujiwara, Y., and Orkin, S. H. (2000) Cell 101, 729-739.
Faculty: Morton Arnsdorf, M.D. Harry Fozzard, M.D. Dottie Hanck, Ph.D. Anthony Kim, M.D. Jack Kyle, Ph.D. Victor Mor-Avi, Ph.D. Elizabeth McNally, M.D. Ph.D. Angelo Scanu, M.D. Eric Svensson, M.D. Ph.D. Lab Home Page Research Background Useful Lab Links Lab Personnel Photos Publications Contact Information Research Opportunities