Letter abstract
Nature Cell Biology 10, 567 - 574 (2008)
Published online: 20 April 2008 | doi:10.1038/ncb1719
A crucial role of a high mobility group protein HMGA2 in cardiogenesis
Koshiro Monzen1,9, Yuzuru Ito2,9, Atsuhiko T. Naito3,9, Hiroki Kasai1, Yukio Hiroi1, Doubun Hayashi1,4, Ichiro Shiojima3, Tsutomu Yamazaki5, Kohei Miyazono6, Makoto Asashima2,7,8, Ryozo Nagai1 & Issei Komuro3
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.
- Department of Cardiovascular Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
- ICORP Organ Regeneration Project, Japan Science and Technology Agency (JST), 3-8-1 Komaba, Meguro-ku, Tokyo 153-8902, Japan.
- Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
- Translational Research for Healthcare and Clinical Science, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
- Clinical Bioinformatics, Graduate School of Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
- Molecular Pathology, Graduate School of Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
- 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.
- Organ Development Research Laboratory, National Institute of Advanced Industrial Sciences and Technology (AIST), Tsukuba Central 4, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8562, Japan.
- These authors contributed equally to this work.
Correspondence to: Issei Komuro3 e-mail: komuro-tky@umin.ac.jp
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