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A crucial role of a high mobility group protein HMGA2 in cardiogenesis

Nature Cell Biology volume 10, pages 567–574 (2008)Cite this article

Abstract

The high mobility group (HMG) of nuclear proteins regulates expression of many genes through architectural remodelling of the chromatin structure, and formation of multiprotein complexes on promoter/enhancer regions. This leads to the active transcription of their target genes1,2,3. Here we show that HMGA2, a member of the HMGA sub-family of HMG proteins, has a critical function in cardiogenesis. Overexpression of HMGA2 enhanced, whereas siRNA-mediated knockdown of HMGA2 blocked, cardiomyocyte differentiation of the embryonal carcinoma cell line P19CL6. Moreover, overexpression of a dominant-negative HMGA2 or morpholino-mediated knockdown of HMGA2 expression blocked normal heart formation in Xenopus laevis embryos, suggesting that HMGA2 has an important role in cardiogenesis both in vitro and in vivo. Mechanistically, HMGA2 associated with Smad1/4 and showed synergistic trans-activation of the gene for a cardiac transcription factor Nkx2.5; a conserved HMGA2 binding site was required for the promoter activity of Nkx2.5 gene, both in P19CL6 cells and in transgenic Xenopus embryos. Thus, HMGA2 is a positive regulator of Nkx2.5 gene expression and is essential for normal cardiac development.

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Figure 1: HMGA2 is an essential positive regulator of cardiomyocyte differentiation.
Figure 2: cDNA sequence and expression pattern of XHMGA2.
Figure 3: XHMGA2 is essential for cardiogenesis.
Figure 4: HMGA2 upregulates Nkx2.5 promoter activity in collaboration with Smads.
Figure 5: HMGA2 binding is required for full activation of Nkx2.5 promoter.

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Acknowledgements

We thank G. Manfioletti, P ten Dijke, K. E. Yutzey, M. Whitman and E. Amaya for providing plasmids, and C. Masuo and Y. Itoh for their excellent technical assistance. This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology, and Health and Labor Sciences Research Grants; an Academic Award of the Mochida Memorial Foundation and Uehara Memorial Foundation (to I. K.); and a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to K. M.).

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  1. Koshiro Monzen, Yuzuru Ito and Atsuhiko T. Naito: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiovascular Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Koshiro Monzen, Hiroki Kasai, Yukio Hiroi, Doubun Hayashi & Ryozo Nagai

  2. ICORP Organ Regeneration Project, Japan Science and Technology Agency (JST), 3-8-1 Komaba, Meguro-ku, Tokyo, 153-8902, Japan

    Yuzuru Ito & Makoto Asashima

  3. Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, 260-8670, Chiba, Japan

    Atsuhiko T. Naito, Ichiro Shiojima & Issei Komuro

  4. Translational Research for Healthcare and Clinical Science, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Doubun Hayashi

  5. Clinical Bioinformatics, Graduate School of Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Tsutomu Yamazaki

  6. Molecular Pathology, Graduate School of Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Kohei Miyazono

  7. Department of Life Science (Biology), Graduate School of Arts and Sciences, the University of Tokyo, 3-8-1 Komaba, Meguro-ku, Tokyo, 153-8902, Japan

    Makoto Asashima

  8. Organ Development Research Laboratory, National Institute of Advanced Industrial Sciences and Technology (AIST), Tsukuba Central 4, 1-1-1 Higashi, Tsukuba, 305-8562, Ibaraki, Japan

    Makoto Asashima

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  1. Koshiro Monzen
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Contributions

K. Monzen, Y. I. and A. T. M. contributed equally to this work; I. K. designed and supervised the research; K. Monzen, Y. I., A. T. M., H. K., Y. H. and D. H. performed experiments; I. S., T. Y., K. Miyazono, M. A. and R. N. contributed new reagents/analytical tools; K. Monzen, Y. I. and A. T. M. analysed the data; K. Monzen, Y. I., I. S. and I. K. prepared the manuscript.

Corresponding author

Correspondence to Issei Komuro.

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The authors declare no competing financial interests.

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Supplementary Figures S1, S2, S3, S4, S5, S6, S7, S8 and Supplemental Table S1 (PDF 949 kb)

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Monzen, K., Ito, Y., Naito, A. et al. A crucial role of a high mobility group protein HMGA2 in cardiogenesis. Nat Cell Biol 10, 567–574 (2008). https://doi.org/10.1038/ncb1719

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