ハットリ　フミユキ   HATTORI FUMIYUKI   服部　文幸    所属   関西医科大学  iPS・幹細胞再生医学講座    職種   研究教授
論文種別	原著(症例報告除く)
言語種別	英語
査読の有無	その他(不明)
表題	Zac1 is an essential transcription factor for cardiac morphogenesis.
掲載誌名	正式名：Circulation research 略　 称：Circ Res ISSNコード：1524457100097330
巻・号・頁	106(6),pp.1083-91
著者・共著者	Yuasa Shinsuke, Onizuka Takeshi, Shimoji Kenichiro, Ohno Yohei, Kageyama Toshimi, Yoon Sung Han, Egashira Toru, Seki Tomohisa, Hashimoto Hisayuki, Nishiyama Takahiko, Kaneda Ruri, Murata Mitsushige, Hattori Fumiyuki, Makino Shinji, Sano Motoaki, Ogawa Satoshi, Prall Owen W J, Harvey Richard P, Fukuda Keiichi
発行年月	2010/04
概要	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 alphaMHC 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.
DOI	10.1161/CIRCRESAHA.109.214130
PMID	20167925