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Isolation of Human Lymphatic Endothelial Cells by Multi-parameter Fluorescence-activated Cell Sorting
Published on: May 1, 2015
Hdac3 regulates lymphovenous and lymphatic valve formation
Harish P Janardhan1,2, Zachary J Milstone1,2, Masahiro Shin3
1Division of Cardiovascular Medicine.
The Journal of Clinical Investigation
|October 17, 2017
Summary
Histone deacetylase 3 (Hdac3) is crucial for lymphatic valve development and maintaining blood-lymph separation. Its absence causes severe defects, leading to lethality in mice.
Area of Science:
- Vascular biology
- Epigenetics
- Developmental biology
Background:
- Lymphedema is a common lymphatic anomaly linked to defective lymphatic valve development.
- The epigenetic mechanisms governing lymphatic valve formation are not well understood.
Purpose of the Study:
- To investigate the role of epigenetic modifiers in lymphatic valve morphogenesis.
- To identify key regulators of lymphatic valve development and blood-lymph separation.
Main Methods:
- Utilized mouse models with endothelium-specific ablation of histone deacetylase 3 (Hdac3).
- Analyzed lymphatic valve development, blood-lymph separation, and gene expression patterns.
- Investigated protein-DNA and protein-protein interactions involving Hdac3, Gata2, and other transcription factors.
Main Results:
- Endothelium-specific Hdac3 ablation in mice resulted in defective lymphovenous and lymphatic valves, blood-filled lymphatics, edema, and lethality.
- Hdac3 deficiency led to reduced expression of the transcription factor Gata2 and its target genes.
- Hdac3 was recruited to a Gata2 enhancer by transcription factors (Tal1, Gata2, Ets1/2) in response to shear stress, forming an enhanceosome with Ep300 to promote Gata2 expression.
Conclusions:
- Hdac3 is a critical epigenetic modifier regulating lymphatic valve development and blood-lymph separation.
- Hdac3 integrates extrinsic cues (shear stress) and intrinsic factors to control Gata2 expression and lymphatic morphogenesis.
- These findings identify Hdac3 as a key player in maintaining vascular system integrity and lymphatic function.
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