Department of Cell Biology, The Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Baltimore, MD 21205-2196, USA.
Development. 2013 May;140(10):2160-71. doi: 10.1242/dev.092924. Epub 2013 Apr 11.
FoxA transcription factors play major roles in organ-specific gene expression, regulating, for example, glucagon expression in the pancreas, GLUT2 expression in the liver, and tyrosine hydroxylase expression in dopaminergic neurons. Organ-specific gene regulation by FoxA proteins is achieved through cooperative regulation with a broad array of transcription factors with more limited expression domains. Fork head (Fkh), the sole Drosophila FoxA family member, is required for the development of multiple distinct organs, yet little is known regarding how Fkh regulates tissue-specific gene expression. Here, we characterize Sage, a bHLH transcription factor expressed exclusively in the Drosophila salivary gland (SG). We show that Sage is required for late SG survival and normal tube morphology. We find that many Sage targets, identified by microarray analysis, encode SG-specific secreted cargo, transmembrane proteins, and the enzymes that modify these proteins. We show that both Sage and Fkh are required for the expression of Sage target genes, and that co-expression of Sage and Fkh is sufficient to drive target gene expression in multiple cell types. Sage and Fkh drive expression of the bZip transcription factor Senseless (Sens), which boosts expression of Sage-Fkh targets, and Sage, Fkh and Sens colocalize on SG chromosomes. Importantly, expression of Sage-Fkh target genes appears to simply add to the tissue-specific gene expression programs already established in other cell types, and Sage and Fkh cannot alter the fate of most embryonic cell types even when expressed early and continuously.
FoxA 转录因子在器官特异性基因表达中发挥重要作用，例如调节胰腺中的胰高血糖素表达、肝脏中的 GLUT2 表达和多巴胺能神经元中的酪氨酸羟化酶表达。FoxA 蛋白对器官特异性基因的调节是通过与具有更有限表达域的广泛转录因子的协同调节来实现的。叉头（Fkh）是果蝇唯一的 FoxA 家族成员，它是多种不同器官发育所必需的，但对于 Fkh 如何调节组织特异性基因表达知之甚少。在这里，我们描述了 Sage，一种仅在果蝇唾液腺（SG）中表达的 bHLH 转录因子。我们表明 Sage 是 SG 后期存活和正常管形态所必需的。我们发现 Sage 的许多靶标，通过微阵列分析确定，编码 SG 特异性分泌货物、跨膜蛋白和修饰这些蛋白质的酶。我们表明 Sage 和 Fkh 都需要 Sage 靶基因的表达，并且 Sage 和 Fkh 的共表达足以在多种细胞类型中驱动靶基因的表达。Sage 和 Fkh 驱动 bZip 转录因子 Senseless（Sens）的表达，Sens 增强了 Sage-Fkh 靶基因的表达，Sage、Fkh 和 Sens 在 SG 染色体上共定位。重要的是，Sage-Fkh 靶基因的表达似乎只是简单地增加了在其他细胞类型中已经建立的组织特异性基因表达程序，并且 Sage 和 Fkh 即使在早期和连续表达时也不能改变大多数胚胎细胞类型的命运。
