A crucial role of a high mobility group protein HMGA2 in cardiogenesis.
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 genes. 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.
Monzen
Koshiro
K
Department of Cardiovascular Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Ito
Yuzuru
Y
Naito
Atsuhiko T
AT
Kasai
Hiroki
H
Hiroi
Yukio
Y
Hayashi
Doubun
D
Shiojima
Ichiro
I
Yamazaki
Tsutomu
T
Miyazono
Kohei
K
Asashima
Makoto
M
Nagai
Ryozo
R
Komuro
Issei
I
D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D002454:Cell Differentiation; D002460:Cell Line; D018507:Gene Expression Regulation, Developmental; D025743:HMGA2 Protein / Q000235:genetics / Q000378:metabolism*; D006321:Heart / Q000196:embryology / Q000254:growth & development; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis / Q000033:anatomy & histology / Q000196:embryology / Q000502:physiology
D025743:HMGA2 Protein; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C092720:NKX2-5 protein, Xenopus; D034741:RNA, Small Interfering; D014157:Transcription Factors; D029867:Xenopus Proteins