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Epigenetic repression of cardiac progenitor gene expression by Ezh2 is required for postnatal cardiac homeostasis

Nature Genetics volume 44, pages 343–347 (2012)Cite this article

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Abstract

Adult-onset diseases can be associated with in utero events, but mechanisms for this remain unknown1,2. The Polycomb histone methyltransferase Ezh2 stabilizes transcription by depositing repressive marks during development that persist into adulthood3,4,5,6,7,8,9, but its function in postnatal organ homeostasis is unknown. We show that Ezh2 stabilizes cardiac gene expression and prevents cardiac pathology by repressing the homeodomain transcription factor gene Six1, which functions in cardiac progenitor cells but is stably silenced upon cardiac differentiation10. Deletion of Ezh2 in cardiac progenitors caused postnatal myocardial pathology and destabilized cardiac gene expression with activation of Six1-dependent skeletal muscle genes. Six1 induced cardiomyocyte hypertrophy and skeletal muscle gene expression. Furthermore, genetically reducing Six1 levels rescued the pathology of Ezh2-deficient hearts. Thus, Ezh2-mediated repression of Six1 in differentiating cardiac progenitors is essential for stable gene expression and homeostasis in the postnatal heart. Our results suggest that epigenetic dysregulation in embryonic progenitor cells is a predisposing factor for adult disease and dysregulated stress responses.

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Figure 1: Ezh2 limits cardiac growth and fibrosis.
Figure 2: Ezh2 represses expression of fetal genes, profibrosis factors and Six1.
Figure 3: Six1 is epigenetically repressed by PRC2.
Figure 4: Six1 has differentiated myocardium expression potential.
Figure 5: Six1 induces cardiac hypertrophy and skeletal muscle gene expression in cardiomyocytes.
Figure 6: Ezh2 limits cardiac hypertrophy and fibrosis by repressing Six1.

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Acknowledgements

We thank A. Blais for Six1 antiserum, T. Sukonnik for in situ hybridization, J. Wythe for mT/mG embryos, J. Wylie for technical assistance, D. Miguel-Perez for animal husbandry, A. Holloway and A. Williams (Gladstone Bioinformatics Core) for RNA-seq and microarray data analysis, L. Ta (Gladstone Genomics Core) for microarray experiments, J. Zhang (Gladstone Transgenic Core) for oocyte injection, C. Miller (Gladstone Histology Core) for histology, Bruneau lab members for helpful discussions and G. Howard for editorial assistance. This work was supported by a fellowship from the California Institute for Regenerative Medicine (P.D.-O.), US National Institutes of Health grants U01HL098179 (B.G.B.) and U01HL098166 (C.E.S. and J.G.S.), by the Lawrence J. and Florence A. DeGeorge Charitable Trust/American Heart Association Established Investigator Award (B.G.B.) and by William H. Younger, Jr. (B.G.B.). Animal work was supported by a US National Institutes of Health/National Center for Research Resources grant (C06 RR018928) to the J. David Gladstone Institutes.

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Authors and Affiliations

  1. Gladstone Institute of Cardiovascular Disease, San Francisco, California, USA

    Paul Delgado-Olguín, Yu Huang & Benoit G Bruneau

  2. Urological Diseases Research Center, Children's Hospital Boston, Boston, Massachusetts, USA

    Xue Li

  3. Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA

    Xue Li

  4. Harvard Stem Cell Institute, Cambridge, Massachusetts, USA

    Xue Li

  5. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA

    Danos Christodoulou, Christine E Seidman & J G Seidman

  6. Division of Cardiovascular Medicine, Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, Massachusetts, USA

    Christine E Seidman

  7. Laboratory of Lymphocyte Signaling, The Rockefeller University, New York, New York, USA

    Alexander Tarakhovsky

  8. Department of Pediatrics, University of California, San Francisco, San Francisco, California, USA

    Benoit G Bruneau

  9. Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA

    Benoit G Bruneau

  10. Institute for Regeneration Medicine, University of California, San Francisco, San Francisco, California, USA

    Benoit G Bruneau

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  1. Paul Delgado-Olguín
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Contributions

P.D.-O. designed the study with B.G.B. and performed most of the experiments. Y.H. performed echocardiography. X.L. provided essential information before publication. X.L. and A.T. provided mouse lines. D.C. generated and analyzed RNA-eq data with C.E.S. and J.G.S. P.D.-O. and B.G.B. wrote the paper with input from all the authors.

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Correspondence to Benoit G Bruneau.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1 and 4 and Supplementary Figures 1–14 (PDF 14815 kb)

Supplementary Table 2

RNA-seq data obtained from right ventricular myocardium from Ezh2-deficient hearts (XLSX 1825 kb)

Supplementary Table 3

Signaling pathways in which Six1 target genes missregulated in Ezh2-deficient hearts participate (XLSX 13 kb)

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Delgado-Olguín, P., Huang, Y., Li, X. et al. Epigenetic repression of cardiac progenitor gene expression by Ezh2 is required for postnatal cardiac homeostasis. Nat Genet 44, 343–347 (2012). https://doi.org/10.1038/ng.1068

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