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Zac1 is an essential transcription factor for cardiac morphogenesis
Shinsuke Yuasa1, Takeshi Onizuka, Kenichiro Shimoji
1Professor and Chair, Department of Regenerative Medicine and Advanced Cardiac Therapeutics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, Japan.
Circulation Research
|February 20, 2010
Summary
Zac1 is a novel cardiac transcription factor crucial for heart development. Its absence leads to severe heart defects and lethality in mice, linking imprinted genes to congenital heart disease.
Area of Science:
- Cardiovascular Biology
- Developmental Biology
- Epigenetics
Background:
- Transcriptional networks governing heart development are not fully understood.
- Several key cardiac transcription factors have been identified, but gaps remain in knowledge.
Purpose of the Study:
- To identify novel cardiac transcription factors using gene chip analysis.
- To investigate the molecular and functional role of Zac1 (a zinc finger-type transcription factor) in heart development.
Main Methods:
- Gene chip analysis to identify candidate factors.
- Luciferase reporter assays to assess promoter activity.
- In vitro and in vivo DNA-binding and protein-association studies.
- Analysis of genetically modified mice with Zac1 locus interruption.
Main Results:
- Zac1 exhibits strong cardiac expression from early developmental stages.
- Zac1 directly binds to and activates cardiac-specific promoters (ANF, BNP, alphaMHC).
- Zac1 synergizes with Nkx2-5, forming a physical complex crucial for cardiac gene regulation.
- Zac1 is a maternally imprinted gene involved in heart development.
- Zac1 deficiency in mice causes heart defects, increased apoptosis, and embryonic lethality.
Conclusions:
- Zac1 is an essential component of the cardiac gene regulatory network.
- Defects in Zac1, an imprinted gene, can lead to congenital heart disease.
- This study establishes a mechanistic link between imprinted gene networks and heart development abnormalities.
