Bowler Timothy, Kosman David, Licht Jonathan D, Pick Leslie
Department of Biochemistry, Cellular and Developmental Biology, Mount Sinai Medical School, New York, NY 10029, USA.
Dev Biol. 2006 Nov 1;299(1):78-90. doi: 10.1016/j.ydbio.2006.07.007. Epub 2006 Jul 12.
Hox genes encode DNA binding transcription factors that regulate the body plans of metazoans by regulating the expression of downstream target 'realizator genes' that direct morphogenesis and growth. Although some Hox target genes have been identified, the code used by Hox proteins to select regulatory targets remains elusive. This failure is due, in part, to the overlapping and promiscuous DNA binding potential of different Hox proteins. The identification of cofactors that modulate Hox DNA binding specificity suggested that target site selection is specified by composite binding sites in the genome for a Hox protein plus its cofactor. Here we have made use of the fact that the DNA binding specificity of the Drosophila Hox protein Fushi Tarazu (Ftz) is modulated by interaction with its partner, the orphan nuclear receptor Ftz-F1, to carry out a computational screen for genomic targets. At least two of the first 30 potential target genes--apontic (apt) and sulfated (Sulf1)--appear to be bona fide targets of Ftz and Ftz-F1. apt is expressed in stripes within the Ftz domain, but posterior to engrailed (en) stripes, suggesting a parasegmental border-independent function of ftz. Ftz/Ftz-F1 activate Sulf1 expression in blastoderm embryos via composite binding sites. Sulf1 encodes a sulfatase thought to be involved in wingless (Wg) signaling. Thus, in addition to regulating en, Ftz and Ftz-F1 coordinately and directly regulate different components of segment polarity pathways in parallel.
Hox基因编码DNA结合转录因子，这些因子通过调节下游靶标“实现基因”的表达来调控后生动物的身体结构，而这些靶标基因指导形态发生和生长。尽管已经鉴定出一些Hox靶标基因，但Hox蛋白用于选择调控靶标的编码仍不清楚。这种情况部分归因于不同Hox蛋白具有重叠且混杂的DNA结合潜力。对调节Hox DNA结合特异性的辅助因子的鉴定表明，靶位点选择是由基因组中Hox蛋白及其辅助因子的复合结合位点决定的。在这里，我们利用了果蝇Hox蛋白腹片（Fushi Tarazu，Ftz）的DNA结合特异性会通过与其伴侣孤儿核受体Ftz-F1相互作用而受到调节这一事实，对基因组靶标进行了计算筛选。在前30个潜在靶标基因中，至少有两个——无桥蛋白（apontic，apt）和硫酸酯酶1（sulfated，Sulf1）——似乎是Ftz和Ftz-F1真正的靶标。apt在Ftz结构域内的条带中表达，但在成对控制基因（engrailed，en）条带的后方，这表明ftz具有不依赖于副节边界的功能。Ftz/Ftz-F1通过复合结合位点在囊胚期胚胎中激活Sulf1的表达。Sulf1编码一种硫酸酯酶，被认为参与无翅（wingless，Wg）信号传导。因此，除了调节en之外，Ftz和Ftz-F1还能协调并直接并行调节节段极性通路的不同组分。
