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TETs Regulate Proepicardial Cell Migration through Extracellular Matrix Organization during Zebrafish Cardiogenesis
Yahui Lan1, Heng Pan2, Cheng Li3
1Department of Surgery, Weill Cornell Medical College, New York, NY 10065, USA.
Cell Reports
|January 17, 2019
Summary
Ten-eleven translocation (Tet) enzymes Tet2 and Tet3 are crucial for embryonic heart development by regulating gene expression. Their activity guides epicardial progenitor cells, essential for forming the heart's atrial-ventricular canal.
Area of Science:
- Developmental Biology
- Epigenetics
- Cardiovascular Science
Background:
- Ten-eleven translocation (Tet) enzymes (Tet1/2/3) are known for 5-methylcytosine (5mC) hydroxylation, impacting DNA demethylation and gene expression.
- While mutant Tet isoforms are studied in cancer, their normal roles in organogenesis, particularly heart development, remain largely unknown.
- Understanding Tet enzyme function is critical for elucidating mechanisms of normal development and disease.
Purpose of the Study:
- To investigate the normal roles of Tet enzymes during embryonic organogenesis, focusing on cardiac development.
- To identify the specific functions of Tet2 and Tet3 in the embryonic heart and their impact on cellular recruitment and gene regulation.
- To elucidate the epigenetic mechanisms governing gene expression changes during vertebrate heart development.
Main Methods:
- Utilized compound mutant zebrafish models to analyze the functions of Tet2 and Tet3 during embryonic heart development.
- Employed a combination of DNA methylation, hydroxymethylation profiling, and transcriptomic analysis.
- Investigated the recruitment of epicardial progenitors and the development of the atrial-ventricular canal (AVC).
Main Results:
- Tet2/3 activity is essential in the embryonic heart for the recruitment of epicardial progenitors, crucial for atrial-ventricular canal (AVC) development.
- Identified Inhbaa (endocardium) and Sox9b (myocardium) as Tet2/3 demethylation targets, critical for organizing the AVC extracellular matrix (ECM).
- Demonstrated that Tet2/3-mediated gene regulation facilitates epicardial progenitor migration onto the developing heart tube.
Conclusions:
- This study reveals essential DNA demethylation modifications governed by Tet2/3 during cardiac development.
- Highlighted the temporal and lineage-specific roles of Tet enzymes in regulating gene expression critical for heart formation.
- Underscored the complex interplay between multiple cell populations and epigenetic modifications in vertebrate heart development.
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