Authors
Janardhan, Harish P.Milstone, Zachary J.
Shin, Masahiro
Lawson, Nathan D.
Keaney, John F. Jr.
Trivedi, Chinmay M.
UMass Chan Affiliations
UMass Metabolic NetworkDepartment of Molecular, Cell, and Cancer Biology
Division of Cardiovascular Medicine, Department of Medicine
Document Type
Journal ArticlePublication Date
2017-11-01
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Lymphedema, the most common lymphatic anomaly, involves defective lymphatic valve development; yet the epigenetic modifiers underlying lymphatic valve morphogenesis remain elusive. Here, we showed that during mouse development, the histone-modifying enzyme histone deacetylase 3 (Hdac3) regulates the formation of both lymphovenous valves, which maintain the separation of the blood and lymphatic vascular systems, and the lymphatic valves. Endothelium-specific ablation of Hdac3 in mice led to blood-filled lymphatic vessels, edema, defective lymphovenous valve morphogenesis, improper lymphatic drainage, defective lymphatic valve maturation, and complete lethality. Hdac3-deficient lymphovenous valves and lymphatic vessels exhibited reduced expression of the transcription factor Gata2 and its target genes. In response to oscillatory shear stress, the transcription factors Tal1, Gata2, and Ets1/2 physically interacted with and recruited Hdac3 to the evolutionarily conserved E-box-GATA-ETS composite element of a Gata2 intragenic enhancer. In turn, Hdac3 recruited histone acetyltransferase Ep300 to form an enhanceosome complex that promoted Gata2 expression. Together, these results identify Hdac3 as a key epigenetic modifier that maintains blood-lymph separation and integrates both extrinsic forces and intrinsic cues to regulate lymphatic valve development.Source
J Clin Invest. 2017 Nov 1;127(11):4193-4206. doi: 10.1172/JCI92852. Epub 2017 Oct 16. Link to article on publisher's siteDOI
10.1172/JCI92852Permanent Link to this Item
http://hdl.handle.net/20.500.14038/36631PubMed ID
29035278Related Resources
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This work is licensed under the Creative Commons Attribution 4.0 International License.Distribution License
http://creativecommons.org/licenses/by/4.0/ae974a485f413a2113503eed53cd6c53
10.1172/JCI92852
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Except where otherwise noted, this item's license is described as This work is licensed under the Creative Commons Attribution 4.0 International License.