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Hdac3 regulates lymphovenous and lymphatic valve formation
The Journal of Clinical Investigation ( IF 15.9 ) Pub Date : 2017-10-16 , DOI: 10.1172/jci92852 Harish P. Janardhan , Zachary J. Milstone , Masahiro Shin , Nathan D. Lawson , John F. Keaney , Chinmay M. Trivedi
The Journal of Clinical Investigation ( IF 15.9 ) Pub Date : 2017-10-16 , DOI: 10.1172/jci92852 Harish P. Janardhan , Zachary J. Milstone , Masahiro Shin , Nathan D. Lawson , John F. Keaney , Chinmay M. Trivedi
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.
中文翻译:
Hdac3调节淋巴静脉和淋巴阀的形成
淋巴水肿是最常见的淋巴异常,涉及淋巴瓣发育不良。然而,淋巴阀形态发生的表观遗传修饰因子仍然难以捉摸。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基酶3(Hdac3)调节两个淋巴管瓣的形成,从而维持血液和淋巴血管系统以及淋巴瓣的分离。Hdac3在小鼠中的内皮特异性消融导致淋巴血管充血,水肿,淋巴管瓣膜形态发生不良,淋巴引流不当,淋巴管成熟不良和完全致死性。缺乏Hdac3的淋巴静脉瓣膜和淋巴管显示出转录因子Gata2及其靶基因的表达降低。为了响应振荡剪切应力,转录因子Tal1,Gata2和Ets1 / 2与Hdac3物理相互作用并募集到Gata2内基因增强子的进化保守E-box-GATA-ETS复合元件。反过来,Hdac3募集了组蛋白乙酰转移酶Ep300,形成了增强Gata2表达的增强体复合物。总之,这些结果确定了Hdac3是维持血液-淋巴分离并整合外在力和内在线索以调节淋巴阀发育的关键表观遗传修饰剂。
更新日期:2017-11-02
中文翻译:
Hdac3调节淋巴静脉和淋巴阀的形成
淋巴水肿是最常见的淋巴异常,涉及淋巴瓣发育不良。然而,淋巴阀形态发生的表观遗传修饰因子仍然难以捉摸。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基酶3(Hdac3)调节两个淋巴管瓣的形成,从而维持血液和淋巴血管系统以及淋巴瓣的分离。Hdac3在小鼠中的内皮特异性消融导致淋巴血管充血,水肿,淋巴管瓣膜形态发生不良,淋巴引流不当,淋巴管成熟不良和完全致死性。缺乏Hdac3的淋巴静脉瓣膜和淋巴管显示出转录因子Gata2及其靶基因的表达降低。为了响应振荡剪切应力,转录因子Tal1,Gata2和Ets1 / 2与Hdac3物理相互作用并募集到Gata2内基因增强子的进化保守E-box-GATA-ETS复合元件。反过来,Hdac3募集了组蛋白乙酰转移酶Ep300,形成了增强Gata2表达的增强体复合物。总之,这些结果确定了Hdac3是维持血液-淋巴分离并整合外在力和内在线索以调节淋巴阀发育的关键表观遗传修饰剂。