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


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.
Yuasa
Shinsuke
S
Professor and Chair, Department of Regenerative Medicine and Advanced Cardiac Therapeutics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, Japan.
Onizuka
Takeshi
T
Shimoji
Kenichiro
K
Ohno
Yohei
Y
Kageyama
Toshimi
T
Yoon
Sung Han
SH
Egashira
Toru
T
Seki
Tomohisa
T
Hashimoto
Hisayuki
H
Nishiyama
Takahiko
T
Kaneda
Ruri
R
Murata
Mitsushige
M
Hattori
Fumiyuki
F
Makino
Shinji
S
Sano
Motoaki
M
Ogawa
Satoshi
S
Prall
Owen W J
OW
Harvey
Richard P
RP
Fukuda
Keiichi
K
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D019556:COS Cells; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002522:Chlorocebus aethiops; D020869:Gene Expression Profiling / Q000379:methods; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D016147:Genes, Tumor Suppressor; D018392:Genomic Imprinting; D005865:Gestational Age; D006321:Heart / Q000196:embryology*; D006330:Heart Defects, Congenital / Q000196:embryology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008817:Mice, Mutant Strains; D009024:Morphogenesis / Q000235:genetics; D009154:Mutation; D020098:Natriuretic Peptide, C-Type / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D051381:Rats; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection
D018797:Cell Cycle Proteins; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C484469:Nkx2-5 protein, mouse; C431578:Nppa protein, mouse; C498423:Plagl1 protein, mouse; D011498:Protein Precursors; D014157:Transcription Factors; D020098:Natriuretic Peptide, C-Type; D009320:Atrial Natriuretic Factor