ZBTB17 (MIZ1) Is Important for the Cardiac Stress Response and a Novel Candidate Gene for Cardiomyopathy and Heart Failure.

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.

• Authors: Byambajav Buyandelger, Catherine Mansfield, Sawa Kostin, Onjee Choi, Angharad M Roberts, James S Ware, Francesco Mazzarotto, Francesco Pesce, Rachel Buchan, Rivka L Isaacson, Josée Vouffo, Sylvia Gunkel, Gudrun Knöll, Sara J McSweeney, Heming Wei, Andreas Perrot, Conny Pfeiffer, Mohammad Reza Toliat, Kristina Ilieva, Ewelina Krysztofinska, Marina M López-Olañeta, Jesús M Gómez-Salinero, Albrecht Schmidt, Keat-Eng Ng, Niels Teucher, Ju Chen, Martin Teichmann, Martin Eilers, Wilhelm Haverkamp, Vera Regitz-Zagrosek, Gerd Hasenfuss, Thomas Braun, Dudley J Pennell, Ian Gould, Paul J R Barton, Enrique Lara-Pezzi, Sebastian Schäfer, Norbert Hübner, Leanne E Felkin, Declan P O'Regan, Thomas Brand, Hendrik Milting, Peter Nürnberg, Michael D Schneider, Sanjay Prasad, Enrico Petretto, Ralph Knöll
• Journal: Circulation. Cardiovascular genetics (Circ Cardiovasc Genet) Vol. 8 Issue 5 Pg. 643-52 (Oct 2015) ISSN: 1942-3268 [Electronic] United States
• PMID: 26175529 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 American Heart Association, Inc.

Chemical References

• DNA-Binding Proteins
• Kruppel-Like Transcription Factors
• LIM Domain Proteins
• Muscle Proteins
• Nuclear Proteins
• Protein Inhibitors of Activated STAT
• ZBTB17 protein, human
• cysteine and glycine-rich protein 3
• Miz1 protein, mouse
• Ubiquitin-Protein Ligases
• Pias2 protein, rat

Topics

• Animals
• Cardiomyopathies (genetics)
• DNA-Binding Proteins
• Heart (physiology)
• Heart Failure (genetics)
• Humans
• Kruppel-Like Transcription Factors (genetics, physiology)
• LIM Domain Proteins (genetics, metabolism)
• Mice
• Muscle Proteins (genetics, metabolism)
• Nuclear Proteins (genetics, physiology)
• Protein Inhibitors of Activated STAT (genetics, physiology)
• Rats
• Stress, Physiological
• Tissue Culture Techniques
• Ubiquitin-Protein Ligases