The transcription factor grainyhead-like 2 regulates the molecular composition of the epithelial apical junctional complex
The transcription factor grainyhead-like 2 regulates the molecular composition of the epithelial apical junctional complex
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DOI：
10.1242/dev.055483
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发表时间：
2010-11-15
期刊：
影响因子：
4.6
通讯作者：
Schmidt-Ott, Kai M.
中科院分区：
文献类型：
--
作者：
Werth, Max;Walentin, Katharina;Schmidt-Ott, Kai M.
上皮细胞的分化和上皮管或层的形态发生与顶端连接复合体的建立和重塑密切相关，顶端连接复合体包括贴壁连接和紧密连接。对顶端连接复合体成分的转录调控知之甚少。在这里，我们发现转录因子颗粒样蛋白2(Grhl2)是果蝇颗粒头上皮特异性同源基因，对于黏附连接基因E-钙粘附素和紧密连接基因claudin 4(Cldn4)在几种类型的上皮细胞中的充分表达是必不可少的，包括肠道内胚层、表面外胚层和耳部上皮。我们已经培育了Grhl2突变小鼠，以证明这些隔室中顶端连接复合体的分子组成存在缺陷，这与前后神经管缺陷的发生相一致。在机制上，我们发现Grhl2与位于Cldn4核心启动子和E-cadherin基因内含子2内的顺式调控元件特异性地结合。Cldn4启动子在上皮细胞中的活性主要依赖于Grhl2的可用性和Grhl2相关顺式调控元件的完整性。在E-钙粘蛋白基因座，内含子Grhl2相关的顺式调控区通过染色质环与启动子联系，而Grhl2的缺失导致E-钙粘蛋白启动子上激活的组蛋白标志物的特异性减少。综上所述，我们的数据提供了Grhl2作为顶端连接复合体成分的靶基因相关转录激活因子的证据，从而关键地参与了上皮分化。
Differentiation of epithelial cells and morphogenesis of epithelial tubes or layers is closely linked with the establishment and remodeling of the apical junctional complex, which includes adherens junctions and tight junctions. Little is known about the transcriptional control of apical junctional complex components. Here, we show that the transcription factor grainyhead-like 2 (Grhl2), an epithelium-specific mammalian homolog of Drosophila Grainyhead, is essential for adequate expression of the adherens junction gene E-cadherin and the tight junction gene claudin 4 (Cldn4) in several types of epithelia, including gut endoderm, surface ectoderm and otic epithelium. We have generated Grhl2 mutant mice to demonstrate defective molecular composition of the apical junctional complex in these compartments that coincides with the occurrence of anterior and posterior neural tube defects. Mechanistically, we show that Grhl2 specifically associates with cis-regulatory elements localized at the Cldn4 core promoter and within intron 2 of the E-cadherin gene. Cldn4 promoter activity in epithelial cells is crucially dependent on the availability of Grhl2 and on the integrity of the Grhl2-associated cis-regulatory element. At the E-cadherin locus, the intronic Grhl2-associated cis-regulatory region contacts the promoter via chromatin looping, while loss of Grhl2 leads to a specific decrease of activating histone marks at the E-cadherin promoter. Together, our data provide evidence that Grhl2 acts as a target gene-associated transcriptional activator of apical junctional complex components and, thereby, crucially participates in epithelial differentiation.