Hdac3 regulates lymphovenous and lymphatic valve formation.
Hdac3 regulates lymphovenous and lymphatic valve formation.
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DOI：
10.1172/jci92852
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发表时间：
2017-11-01
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影响因子：
--
通讯作者：
Trivedi CM
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作者：
Janardhan HP;Milstone ZJ;Shin M;Lawson ND;Keaney JF Jr;Trivedi CM
淋巴水肿是最常见的淋巴管异常，涉及淋巴管瓣发育缺陷，但淋巴管瓣形态发生的表观遗传修饰剂仍然难以捉摸。在这里，我们表明，在小鼠发育过程中，组蛋白修饰酶组蛋白脱乙酰酶3（Hdac 3）调节淋巴静脉瓣膜的形成，维持血液和淋巴管系统的分离，以及淋巴瓣膜。内皮特异性消融小鼠的Hdac 3导致充满血液的淋巴管、水肿、淋巴静脉瓣形态发生缺陷、淋巴引流不当、淋巴瓣成熟缺陷和完全致死。Hdac 3缺陷的淋巴静脉瓣膜和淋巴管表现出转录因子Gata 2及其靶基因的表达减少。在响应振荡剪切应力，转录因子Tal 1，Gata 2，和Ets 1/2物理相互作用和招聘Hdac 3进化保守的E-box-GATA-ETS复合元件的Gata 2基因内增强子。反过来，Hdac 3招募组蛋白乙酰转移酶Ep 300形成增强体复合物，促进Gata 2表达。总之，这些结果确定Hdac 3作为一个关键的表观遗传修饰剂，保持血液淋巴分离，并整合外力和内在的线索，以调节淋巴阀的发展。
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.