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首页> 外文期刊>Molecular and Cellular Biology >Transcriptional Autoregulation Controls Pancreatic Ptf1a Expression during Development and Adulthood
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Transcriptional Autoregulation Controls Pancreatic Ptf1a Expression during Development and Adulthood

机译：转录自动调节在发育和成年期控制胰腺Ptf1a表达。

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The basic helix-loop-helix (bHLH) transcription factor PTF1a is critical to the development of the embryonic pancreas. It is required early for the formation of the undifferentiated tubular epithelium of the nascent pancreatic rudiment and then becomes restricted to the differentiating acinar cells, where it directs the transcriptional activation of the secretory digestive enzyme genes. Here we report that the complex temporal and spatial expression of Ptf1a is controlled by at least three separable gene-flanking regions. A 14.8-kb control domain immediately downstream of the last Ptf1a exon is highly conserved among mammals and directs expression in the dorsal part of the spinal cord but has very little activity in the embryonic or neonatal pancreas. A 13.4-kb proximal promoter domain initiates limited expression in cells that begin the acinar differentiation program. The activity of the proximal promoter domain is complemented by an adjacent 2.3-kb autoregulatory enhancer that is able to activate a heterologous minimal promoter with high-level penetrance in the pancreases of transgenic mice. During embryonic development, the enhancer initiates expression in the early precursor epithelium and then superinduces expression in acinar cells at the onset of their development. The enhancer contains two evolutionarily conserved binding sites for the active form of PTF1a, a trimeric complex composed of PTF1a, one of the common bHLH E proteins, and either RBPJ or RBPJL. The two sites are essential for acinar cell-specific transcription in transfected cell lines and mice. In mature acinar cells, the enhancer and PTF1a establish an autoregulatory loop that reinforces and maintains Ptf1a expression. Indeed, the trimeric PTF1 complex forms dual autoregulatory loops with the Ptf1a and Rbpjl genes that may maintain the stable phenotype of pancreatic acinar cells.
机译：基本的螺旋-环-螺旋（bHLH）转录因子PTF1a对胚胎胰腺的发育至关重要。它是早期形成胰腺未分化的未分化管状上皮所必需的，然后限制在分化的腺泡细胞中，在那里它指导分泌型消化酶基因的转录激活。在这里，我们报告 Ptf1a 的复杂时空表达受至少三个可分离的基因侧翼区域控制。最后一个 Ptf1a 外显子下游的一个14.8-kb控制域在哺乳动物中高度保守，并指导在脊髓背侧的表达，但在胚胎或新生儿胰腺中的活性很小。一个13.4kb的近端启动子结构域在开始腺泡分化程序的细胞中启动有限的表达。近端启动子结构域的活性被相邻的2.3-kb自调节增强子所补充，该增强子能够在转基因小鼠的胰腺中以高水平的渗透性激活异源最小启动子。在胚胎发育过程中，增强子在早期前体上皮中开始表达，然后在腺泡细胞开始发育时就在其腺泡细胞中超诱导表达。增强子包含两个进化上保守的PTF1a活性形式的结合位点，这是一个由PTF1a，一种常见的bHLH E蛋白和RBPJ或RBPJL组成的三聚体复合物。这两个位点对于转染细胞系和小鼠的腺泡细胞特异性转录至关重要。在成熟的腺泡细胞中，增强子和PTF1a建立了一个自动调节环，可以增强并维持 Ptf1a 的表达。的确，三聚体PTF1复合物与 Ptf1a 和 Rbpjl 基因形成双重自调控环，可以维持胰腺腺泡细胞的稳定表型。

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