The homeobox transcription factor HOXA9 is a regulator of SHOX in U2OS cells and chicken micromass cultures.
The homeobox transcription factor HOXA9 is a regulator of SHOX in U2OS cells and chicken micromass cultures.
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DOI：
10.1371/journal.pone.0045369
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Rappold G
中科院分区：
文献类型：
--
作者：
Durand C;Decker E;Roeth R;Schneider KU;Rappold G
同源盒基因SHOX编码一种在肢体发育过程中发挥重要作用的转录因子。人类中SHOX的突变或缺失导致Turner、Langer和Leri-Weill综合征中的身材矮小以及特发性身材矮小。在胚胎发育过程中，SHOX以复杂的时空模式表达，需要特定的调控机制。到目前为止，已知SHOX受基因两侧的两个上游启动子和几个增强子调控，但尚未鉴定出可通过结合这些调控元件来激活或抑制SHOX转录的调控因子。我们现在已经确定同源结构域蛋白HOXA 9作为U2 OS细胞中SHOX表达的正调节因子。使用荧光素酶分析，染色质免疫沉淀和电泳迁移率变动分析，我们可以缩小HOXA 9结合位点的两个AT丰富的序列内的SHOX启动子2的31 bp。在鸡微团模型中病毒诱导的Hoxa 9过表达验证了Hoxa 9对Shox的调节（负调节）。由于Hoxa 9和Shox都在发育肢芽的重叠区域表达，因此可以假设Hoxa 9和Shox在肢发育过程中的调节关系。
The homeobox gene SHOX encodes for a transcription factor that plays an important role during limb development. Mutations or deletions of SHOX in humans cause short stature in Turner, Langer and Leri-Weill syndrome as well as idiopathic short stature. During embryonic development, SHOX is expressed in a complex spatio-temporal pattern that requires the presence of specific regulatory mechanisms. Up to now, it was known that SHOX is regulated by two upstream promoters and several enhancers on either side of the gene, but no regulators have been identified that can activate or repress the transcription of SHOX by binding to these regulatory elements. We have now identified the homeodomain protein HOXA9 as a positive regulator of SHOX expression in U2OS cells. Using luciferase assays, chromatin immunoprecipitation and electrophoretic mobility shift assays, we could narrow down the HOXA9 binding site to two AT-rich sequences of 31 bp within the SHOX promoter 2. Virus-induced Hoxa9 overexpression in a chicken micromass model validated the regulation of Shox by Hoxa9 (negative regulation). As Hoxa9 and Shox are both expressed in overlapping regions of the developing limb buds, a regulatory relationship of Hoxa9 and Shox during the process of limb development can be assumed.
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