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

Fingerprint

Morphogenesis
Transcription Factors
Gene Regulatory Networks
Atrial Natriuretic Factor
Zinc Fingers
Genes
Atrial Heart Septal Defects
Myofibrils
Ventricular Heart Septal Defects
Oligonucleotide Array Sequence Analysis
Luciferases
Epigenomics
Heart Diseases
Binding Sites
DNA

Keywords

  • Heart development
  • Transcription factor
  • Zac1/Plagl1

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Zac1 is an essential transcription factor for cardiac morphogenesis. / 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.

In: Circulation Research, Vol. 106, No. 6, 04.2010, p. 1083-1091.

Research output: Contribution to journalArticle

Yuasa, S, Onizuka, T, Shimoji, K, Ohno, Y, Kageyama, T, Yoon, SH, Egashira, T, Seki, T, Hashimoto, H, Nishiyama, T, Kaneda, R, Murata, M, Hattori, F, Makino, S, Sano, M, Ogawa, S, Prall, OWJ, Harvey, RP & Fukuda, K 2010, 'Zac1 is an essential transcription factor for cardiac morphogenesis', Circulation Research, vol. 106, no. 6, pp. 1083-1091. https://doi.org/10.1161/CIRCRESAHA.109.214130
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. / Zac1 is an essential transcription factor for cardiac morphogenesis. In: Circulation Research. 2010 ; Vol. 106, No. 6. pp. 1083-1091.
@article{e0db92215d71435fbac791a787cf7daa,
title = "Zac1 is an essential transcription factor for cardiac morphogenesis",
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.",
keywords = "Heart development, Transcription factor, Zac1/Plagl1",
author = "Shinsuke Yuasa and Takeshi Onizuka and Kenichiro Shimoji and Yohei Ohno and Toshimi Kageyama and Yoon, {Sung Han} and Toru Egashira and Tomohisa Seki and Hisayuki Hashimoto and Takahiko Nishiyama and Ruri Kaneda and Mitsushige Murata and Fumiyuki Hattori and Shinji Makino and Motoaki Sano and Satoshi Ogawa and Prall, {Owen W J} and Harvey, {Richard P.} and Keiichi Fukuda",
year = "2010",
month = "4",
doi = "10.1161/CIRCRESAHA.109.214130",
language = "English",
volume = "106",
pages = "1083--1091",
journal = "Circulation Research",
issn = "0009-7330",
publisher = "Lippincott Williams and Wilkins",
number = "6",

}

TY - JOUR

T1 - Zac1 is an essential transcription factor for cardiac morphogenesis

AU - Yuasa, Shinsuke

AU - Onizuka, Takeshi

AU - Shimoji, Kenichiro

AU - Ohno, Yohei

AU - Kageyama, Toshimi

AU - Yoon, Sung Han

AU - Egashira, Toru

AU - Seki, Tomohisa

AU - Hashimoto, Hisayuki

AU - Nishiyama, Takahiko

AU - Kaneda, Ruri

AU - Murata, Mitsushige

AU - Hattori, Fumiyuki

AU - Makino, Shinji

AU - Sano, Motoaki

AU - Ogawa, Satoshi

AU - Prall, Owen W J

AU - Harvey, Richard P.

AU - Fukuda, Keiichi

PY - 2010/4

Y1 - 2010/4

N2 - 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.

AB - 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.

KW - Heart development

KW - Transcription factor

KW - Zac1/Plagl1

UR - http://www.scopus.com/inward/record.url?scp=77950992264&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77950992264&partnerID=8YFLogxK

U2 - 10.1161/CIRCRESAHA.109.214130

DO - 10.1161/CIRCRESAHA.109.214130

M3 - Article

VL - 106

SP - 1083

EP - 1091

JO - Circulation Research

JF - Circulation Research

SN - 0009-7330

IS - 6

ER -