Background-Mutations in sarcomeric and cytoskeletal proteins are a major cause of hereditary cardiomyopathies, but our knowledge remains incomplete as to how the genetic defects execute their effects. Methods and Results-We used cysteine and glycine-rich protein 3, a known cardiomyopathy gene, in a yeast 2-hybrid screen and identified zinc-finger and BTB domain-containing protein 17 (ZBTB17) as a novel interacting partner. ZBTB17 is a transcription factor that contains the peak association signal (rs10927875) at the replicated 1p36 cardiomyopathy locus. ZBTB17 expression protected cardiac myocytes from apoptosis in vitro and in a mouse model with cardiac myocyte-specific deletion of Zbtb17, which develops cardiomyopathy and fibrosis after biomechanical stress. ZBTB17 also regulated cardiac myocyte hypertrophy in vitro and in vivo in a calcineurin-dependent manner. Conclusions-We revealed new functions for ZBTB17 in the heart, a transcription factor that may play a role as a novel cardiomyopathy gene.
Buyandelger, B., Mansfield, C., Kostin, S., Choi, O., Roberts, A. M., Ware, J. S., Mazzarotto, F., Pesce, F., Buchan, R., Isaacson, R. L., Vouffo, J., Gunkel, S., Knoll, G., Mcsweeney, S. J., Wei, H., Perrot, A., Pfeiffer, C., Toliat, M. R., Ilieva, K., Krysztofinska, E., Lopez-Olaneta, M. M., Gomez-Salinero, J. M., Schmidt, A., Ng, K. -., Teucher, N., Chen, J., Teichmann, M., Eilers, M., Haverkamp, W., Regitz-Zagrosek, V., Hasenfuss, G., Braun, T., Pennell, D. J., Gould, I., Barton, P. J. R., Lara-Pezzi, E., Schafer, S., Hubner, N., Felkin, L. E., O'Regan, D. P., Brand, T., Milting, H., Nurnberg, P., Schneider, M. D., Prasad, S., Petretto, E., Knoll, R., ZBTB17 (MIZ1) Is Important for the Cardiac Stress Response and a Novel Candidate Gene for Cardiomyopathy and Heart Failure, <<CIRCULATION, CARDIOVASCULAR GENETICS>>, 2015; 8 (5): 643-652. [doi:10.1161/CIRCGENETICS.113.000690] [https://hdl.handle.net/10807/340370]
ZBTB17 (MIZ1) Is Important for the Cardiac Stress Response and a Novel Candidate Gene for Cardiomyopathy and Heart Failure
Pesce, Francesco;
2015
Abstract
Background-Mutations in sarcomeric and cytoskeletal proteins are a major cause of hereditary cardiomyopathies, but our knowledge remains incomplete as to how the genetic defects execute their effects. Methods and Results-We used cysteine and glycine-rich protein 3, a known cardiomyopathy gene, in a yeast 2-hybrid screen and identified zinc-finger and BTB domain-containing protein 17 (ZBTB17) as a novel interacting partner. ZBTB17 is a transcription factor that contains the peak association signal (rs10927875) at the replicated 1p36 cardiomyopathy locus. ZBTB17 expression protected cardiac myocytes from apoptosis in vitro and in a mouse model with cardiac myocyte-specific deletion of Zbtb17, which develops cardiomyopathy and fibrosis after biomechanical stress. ZBTB17 also regulated cardiac myocyte hypertrophy in vitro and in vivo in a calcineurin-dependent manner. Conclusions-We revealed new functions for ZBTB17 in the heart, a transcription factor that may play a role as a novel cardiomyopathy gene.
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