Histone deacetylase 3 (hdac3) is specifically required for liver development in zebrafish
Histone deacetylase 3 (hdac3) is specifically required for liver development in zebrafish
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DOI：
10.1016/j.ydbio.2008.02.034
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发表时间：
2008-05-01
影响因子：
2.7
通讯作者：
Ge, Ruowen
中科院分区：
文献类型：
--
作者：
Farooq, Muhammad;Sulochana, K. N.;Ge, Ruowen
历史性脱乙酰酶 (HDAC) 是关键的转录调节因子，通过组蛋白/转录因子脱乙酰化和修饰染色质结构发挥作用。在这项工作中，我们发现丙戊酸 (VPA) 对 HDAC 的化学抑制主要通过抑制规范、出芽和分化来导致斑马鱼肝脏发育受损。外分泌胰腺的形成也受到抑制，但内分泌胰腺没有受到抑制。 VPA 引起的肝脏缺陷与总 HDAC 酶活性的抑制相关，但与血管生成抑制无关。吗啉代的基因敲除表明，hdac3是肝脏形成所特别需要的，而hdac1则是斑马鱼多种发育过程（包括肝脏/外分泌胰腺形成）更普遍需要的。此外，hdac3而非hdac1的过度表达部分挽救了VPA诱导的小肝脏。 hdac3 调节斑马鱼肝脏生长的一种机制是通过抑制生长分化因子 11 (gdf11)，它是 hdac3 的独特靶标，也是转化生长因子 β 家族的成员。同时过表达或吗啉敲低表明 hdac3 和 gdf11 在斑马鱼肝脏发育中发挥拮抗作用。这些结果揭示了 hdac3 在肝脏发育中的新颖且特定的作用以及 hdac1 和 hdac3 在斑马鱼胚胎发育中的不同功能。 (c) 2008 Elsevier Inc. 保留所有权利。
Historic deacetylases (HDACs) are key transcription regulators that function by deacetylating histones/transcription factors and modifying chromatin structure. In this work, we showed that chemical inhibition of HDACs by valproic acid (VPA) led to impaired liver development in zebrafish mainly by inhibiting specification, budding, and differentiation. Formation of exocrine pancreas but not endocrine pancreas was also inhibited. The liver defects induced by VPA correlate with suppressed total HDAC enzymatic activity, but are independent of angiogenesis inhibition. Gene knockdown by morpholino demonstrated that hdac3 is specifically required for liver formation while hdac1 is more globally required for multiple development processes in zebrafish including liver/exocrine pancreas formation. Furthermore, overexpression of hdac3 but not hdac1 partially rescued VPA induced small liver. One mechanism by which hdac3 regulates zebrafish liver growth is through inhibiting growth differentiation factor 11 (gdf11), a unique target of hdac3 and a member of the transforming growth factor beta family. Simultaneous overexpression or morpholino knockdown showed that hdac3 and gdf11 function antagonistically in zebrafish liver development. These results revealed a novel and specific role of hdac3 in liver development and the distinct functions between hdac1 and hdac3 in zebrafish embryonic development. (c) 2008 Elsevier Inc. All rights reserved.