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Directed transdifferentiation of mouse mesoderm to heart tissue by defined factors

Abstract

Heart disease is the leading cause of mortality and morbidity in the western world. The heart has little regenerative capacity after damage, leading to much interest in understanding the factors required to produce new cardiac myocytes. Despite a robust understanding of the molecular networks regulating cardiac differentiation1,2, no single transcription factor or combination of factors has been shown to activate the cardiac gene program de novo in mammalian cells or tissues. Here we define the minimal requirements for transdifferentiation of mouse mesoderm to cardiac myocytes. We show that two cardiac transcription factors, Gata4 and Tbx5, and a cardiac-specific subunit of BAF chromatin-remodelling complexes, Baf60c (also called Smarcd3), can direct ectopic differentiation of mouse mesoderm into beating cardiomyocytes, including the normally non-cardiogenic posterior mesoderm and the extraembryonic mesoderm of the amnion. Gata4 with Baf60c initiated ectopic cardiac gene expression. Addition of Tbx5 allowed differentiation into contracting cardiomyocytes and repression of non-cardiac mesodermal genes. Baf60c was essential for the ectopic cardiogenic activity of Gata4 and Tbx5, partly by permitting binding of Gata4 to cardiac genes, indicating a novel instructive role for BAF complexes in tissue-specific regulation. The combined function of these factors establishes a robust mechanism for controlling cellular differentiation, and may allow reprogramming of new cardiomyocytes for regenerative purposes.

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Figure 1: Ectopic induction of cardiac differentiation in mouse embryos.
Figure 2: Induction of cardiac differentiation in embryonic and extraembryonic mesoderm.
Figure 3: Minimal requirements for cardiac gene activation in mouse embryos.
Figure 4: Mechanism for induction of cardiac differentiation.

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Acknowledgements

We thank K. Koshiba-Takeuchi for assistance with immunohistochemistry, H. Ogawa for advice on chromatin immunoprecipitation, B. L. Black and D. Srivastava for discussions and expression constructs, G. R. Crabtree, M. Nemer, E. N. Olson and Y. Saga for expression constructs, and G. Howard and S. Ordway for editorial assistance. This work was supported by Human Frontiers Science Program CDA and short-term fellowships (J.K.T.), MEXT’s program for young independent researchers (J.K.T.), Mitsubishi Foundation (J.K.T.), the Takeda Science Foundation (J.K.T.) and NHLBI (R01HL085860, B.G.B.). This work was also supported by an NIH/NCRR grant (C06 RR018928, J. David Gladstone Institutes) and by William H. Younger, Jr (B.G.B.).

Author Contributions J.K.T. performed all experimental work. J.K.T. and B.G.B. conceived the study. B.G.B. directed the study and wrote the paper.

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Correspondence to Jun K. Takeuchi or Benoit G. Bruneau.

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Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-2 with Legends and Full Legends for Supplementary Movies 1 and 2. (PDF 3508 kb)

Supplementary Movie 1

This movies shows ectopic beating tissue in E8.0 embryos transfected with Tbx5/Gata4/Nkx2-5+Baf60c (see file s1 for full legend). (MOV 3959 kb)

Supplementary Movie 2

This movie shows ectopic beating tissue in E8.0 embryos transfected with Tbx5/Gata4+Baf60c (see file s1 for full legend. (MOV 9552 kb)

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Takeuchi, J., Bruneau, B. Directed transdifferentiation of mouse mesoderm to heart tissue by defined factors. Nature 459, 708–711 (2009). https://doi.org/10.1038/nature08039

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