Tbx20 Regulates a Genetic Program Essential to Adult Mouse Cardiomyocyte Function

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2011 Nov 15

PMID 22080862

Citations 84

Authors

Tao Shen

Ivy Aneas

Noboru Sakabe

Ralf J Dirschinger

Gang Wang

Scott Smemo

John M Westlund

Hongqiang Cheng

Nancy Dalton

Yusu Gu

Cornelis J Boogerd

Chen-Leng Cai

Kirk Peterson

Ju Chen

Marcelo A Nobrega

Sylvia M Evans

Affiliations

Soon will be listed here.

Abstract

Human mutations in or variants of TBX20 are associated with congenital heart disease, cardiomyopathy, and arrhythmias. To investigate whether cardiac disease in patients with these conditions results from an embryonic or ongoing requirement for Tbx20 in myocardium, we ablated Tbx20 specifically in adult cardiomyocytes in mice. This ablation resulted in the onset of severe cardiomyopathy accompanied by arrhythmias, with death ensuing within 1 to 2 weeks of Tbx20 ablation. Accounting for this dramatic phenotype, we identified molecular signatures that posit Tbx20 as a central integrator of a genetic program that maintains cardiomyocyte function in the adult heart. Expression of a number of genes encoding critical transcription factors, ion channels, and cytoskeletal/myofibrillar proteins was downregulated consequent to loss of Tbx20. Genome-wide ChIP analysis of Tbx20-binding regions in the adult heart revealed that many of these genes were direct downstream targets of Tbx20 and uncovered a previously undescribed DNA-binding site for Tbx20. Bioinformatics and in vivo functional analyses revealed a cohort of transcription factors that, working with Tbx20, integrated multiple environmental signals to maintain ion channel gene expression in the adult heart. Our data provide insight into the mechanisms by which mutations in TBX20 cause adult heart disease in humans.

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References

Sotoodehnia N, Isaacs A, de Bakker P, Dorr M, Newton-Cheh C, Nolte I . Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction. Nat Genet. 2010; 42(12):1068-76. PMC: 3338195. DOI: 10.1038/ng.716. View

Heallen T, Zhang M, Wang J, Bonilla-Claudio M, Klysik E, Johnson R . Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size. Science. 2011; 332(6028):458-61. PMC: 3133743. DOI: 10.1126/science.1199010. View

Rauch R, Hofbeck M, Zweier C, Koch A, Zink S, Trautmann U . Comprehensive genotype-phenotype analysis in 230 patients with tetralogy of Fallot. J Med Genet. 2009; 47(5):321-31. DOI: 10.1136/jmg.2009.070391. View

Liu C, Shen A, Li X, Jiao W, Zhang X, Li Z . T-box transcription factor TBX20 mutations in Chinese patients with congenital heart disease. Eur J Med Genet. 2008; 51(6):580-7. DOI: 10.1016/j.ejmg.2008.09.001. View

Dufour C, Wilson B, Huss J, Kelly D, Alaynick W, Downes M . Genome-wide orchestration of cardiac functions by the orphan nuclear receptors ERRalpha and gamma. Cell Metab. 2007; 5(5):345-56. DOI: 10.1016/j.cmet.2007.03.007. View

Fisher S, Grice E, Vinton R, Bessling S, Urasaki A, Kawakami K . Evaluating the biological relevance of putative enhancers using Tol2 transposon-mediated transgenesis in zebrafish. Nat Protoc. 2007; 1(3):1297-305. DOI: 10.1038/nprot.2006.230. View

Mahony S, Benos P . STAMP: a web tool for exploring DNA-binding motif similarities. Nucleic Acids Res. 2007; 35(Web Server issue):W253-8. PMC: 1933206. DOI: 10.1093/nar/gkm272. View

Zheng M, Cheng H, Li X, Zhang J, Cui L, Ouyang K . Cardiac-specific ablation of Cypher leads to a severe form of dilated cardiomyopathy with premature death. Hum Mol Genet. 2008; 18(4):701-13. PMC: 2722217. DOI: 10.1093/hmg/ddn400. View

Brown D, Martz S, Binder O, Goetz S, Price B, Smith J . Tbx5 and Tbx20 act synergistically to control vertebrate heart morphogenesis. Development. 2005; 132(3):553-63. PMC: 1635804. DOI: 10.1242/dev.01596. View

10.

Vong L, Bi W, OConnor-Halligan K, Li C, Cserjesi P, Schwarz J . MEF2C is required for the normal allocation of cells between the ventricular and sinoatrial precursors of the primary heart field. Dev Dyn. 2006; 235(7):1809-21. DOI: 10.1002/dvdy.20828. View

11.

Benson D, Silberbach G, Kavanaugh-McHugh A, Cottrill C, Zhang Y, Riggs S . Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways. J Clin Invest. 1999; 104(11):1567-73. PMC: 409866. DOI: 10.1172/JCI8154. View

12.

Mori A, Zhu Y, Vahora I, Nieman B, Koshiba-Takeuchi K, Davidson L . Tbx5-dependent rheostatic control of cardiac gene expression and morphogenesis. Dev Biol. 2006; 297(2):566-86. DOI: 10.1016/j.ydbio.2006.05.023. View

13.

Zeisberg E, Ma Q, Juraszek A, Moses K, Schwartz R, Izumo S . Morphogenesis of the right ventricle requires myocardial expression of Gata4. J Clin Invest. 2005; 115(6):1522-31. PMC: 1090473. DOI: 10.1172/JCI23769. View

14.

Reamon-Buettner S, Borlak J . Somatic NKX2-5 mutations as a novel mechanism of disease in complex congenital heart disease. J Med Genet. 2004; 41(9):684-90. PMC: 1735891. DOI: 10.1136/jmg.2003.017483. View

15.

Lakdawala N, Givertz M . Dilated cardiomyopathy with conduction disease and arrhythmia. Circulation. 2010; 122(5):527-34. PMC: 3027355. DOI: 10.1161/CIRCULATIONAHA.109.892240. View

16.

Sawada A, Kiyonari H, Ukita K, Nishioka N, Imuta Y, Sasaki H . Redundant roles of Tead1 and Tead2 in notochord development and the regulation of cell proliferation and survival. Mol Cell Biol. 2008; 28(10):3177-89. PMC: 2423158. DOI: 10.1128/MCB.01759-07. View

17.

Kawakami K, Takeda H, Kawakami N, Kobayashi M, Matsuda N, Mishina M . A transposon-mediated gene trap approach identifies developmentally regulated genes in zebrafish. Dev Cell. 2004; 7(1):133-44. DOI: 10.1016/j.devcel.2004.06.005. View

18.

Pfeufer A, van Noord C, Marciante K, Arking D, Larson M, Smith A . Genome-wide association study of PR interval. Nat Genet. 2010; 42(2):153-9. PMC: 2850197. DOI: 10.1038/ng.517. View

19.

Richards A, Garg V . Genetics of congenital heart disease. Curr Cardiol Rev. 2011; 6(2):91-7. PMC: 2892081. DOI: 10.2174/157340310791162703. View

20.

Rudolph D, Tafuri A, Gass P, Hammerling G, Arnold B, Schutz G . Impaired fetal T cell development and perinatal lethality in mice lacking the cAMP response element binding protein. Proc Natl Acad Sci U S A. 1998; 95(8):4481-6. PMC: 22515. DOI: 10.1073/pnas.95.8.4481. View