Zac1 is an essential transcription factor for cardiac morphogenesis

Shinsuke Yuasa, Takeshi Onizuka, Kenichiro Shimoji, Yohei Ohno, Toshimi Kageyama, Sung Han Yoon, Toru Egashira, Tomohisa Seki, Hisayuki Hashimoto, Takahiko Nishiyama, Ruri Kaneda, Mitsushige Murata, Fumiyuki Hattori, Shinji Makino, Motoaki Sano, Satoshi Ogawa, Owen W.J. Prall, Richard P. Harvey, Keiichi Fukuda

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

RATIONALE: The transcriptional networks guiding heart development remain poorly understood, despite the identification of several essential cardiac transcription factors. OBJECTIVE: To isolate novel cardiac transcription factors, we performed gene chip analysis and found that Zac1, a zinc finger-type transcription factor, was strongly expressed in the developing heart. This study was designed to investigate the molecular and functional role of Zac1 as a cardiac transcription factor. METHODS AND RESULTS: Zac1 was strongly expressed in the heart from cardiac crescent stages and in the looping heart showed a chamber-restricted pattern. Zac1 stimulated luciferase reporter constructs driven by ANF, BNP, or αMHC promoters. Strong functional synergy was seen between Zac1 and Nkx2-5 on the ANF promoter, which carries adjacent Zac1 and Nkx2-5 DNA-binding sites. Zac1 directly associated with the ANF promoter in vitro and in vivo, and Zac1 and Nkx2-5 physically associated through zinc fingers 5 and 6 in Zac1, and the homeodomain in Nkx2-5. Zac1 is a maternally imprinted gene and is the first such gene found to be involved in heart development. Homozygous and paternally derived heterozygous mice carrying an interruption in the Zac1 locus showed decreased levels of chamber and myofilament genes, increased apoptotic cells, partially penetrant lethality and morphological defects including atrial and ventricular septal defects, and thin ventricular walls. CONCLUSIONS: Zac1 plays an essential role in the cardiac gene regulatory network. Our data provide a potential mechanistic link between Zac1 in cardiogenesis and congenital heart disease manifestations associated with genetic or epigenetic defects in an imprinted gene network.

Original languageEnglish
Pages (from-to)1083-1091
Number of pages9
JournalCirculation research
Volume106
Issue number6
DOIs
Publication statusPublished - 2010 Apr 1

Keywords

  • Heart development
  • Transcription factor
  • Zac1/Plagl1

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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  • Cite this

    Yuasa, S., Onizuka, T., Shimoji, K., Ohno, Y., Kageyama, T., Yoon, S. H., Egashira, T., Seki, T., Hashimoto, H., Nishiyama, T., Kaneda, R., Murata, M., Hattori, F., Makino, S., Sano, M., Ogawa, S., Prall, O. W. J., Harvey, R. P., & Fukuda, K. (2010). Zac1 is an essential transcription factor for cardiac morphogenesis. Circulation research, 106(6), 1083-1091. https://doi.org/10.1161/CIRCRESAHA.109.214130