Transcriptional complexity at the Hoxa5 locus

从受精卵到多细胞生物体的发育是一个复杂的过程，涉及许多基因在空间和时间上精确表达。Hox基因编码控制其他基因表达的蛋白质。它们在决定胚胎形成的遗传等级中占据关键地位。Hox基因的突变会导致一系列影响胚胎的异常，并导致成年人的疾病，这表明Hox基因在整个生命中的作用范围很大。一系列复杂的不同调控模式控制Hox基因的特异性表达，表明正确的Hox表达对生物体正常发育的重要性。这些模式之一涉及在整个Hox簇中发现的长非编码RNA。我们的实验室有兴趣在阐明的分子机制负责的时空模式的Hox基因表达在哺乳动物的发展。我们使用Hoxa5基因作为模型。在小鼠中，缺乏Hoxa 5功能导致影响包括骨骼、肺、肠道、甲状腺和乳腺在内的几种结构形成的缺陷，揭示了其对正常胚胎发育的关键作用。我们已经表明，Hoxa5在胚胎中的特定区域表达是在几个DNA序列和转录因子的控制下。产生多个含有Hoxa5序列的RNA，但只有一个编码HOXA 5蛋白。其他Hoxa5转录物具有发育调控的表达，但它们如何整合到发育程序中仍然未知。我们建议继续我们的研究Hoxa5表达的控制机制，通过表征的Hoxa5调控元件，并通过分析的作用，长的非编码RNA包含Hoxa5序列可能发挥在空间和时间上限制的Hox基因的表达。这将通过使用分子和遗传方法来解决。我们的研究计划将导致更好地了解Hox表达的精确调控，这对Hox基因功能至关重要，因此对正确的胚胎模式至关重要。

The development of a multicellular organism from the fertilized egg is a complex process involving numerous genes expressed precisely in space and time. Hox genes encode proteins that control the expression of other genes. They occupy a key position in the genetic hierarchy dictating the formation of the embryo. Mutations in Hox genes result in a panoply of anomalies affecting the embryo and causing diseases in the adult, indicative of the large range of action of Hox genes throughout life. A complex array of different modes of regulation governs the specific expression of Hox genes indicative of the importance of correct Hox expression for the normal development of the organism. One of these modes involves the long non-coding RNAs found throughout the Hox clusters. Our laboratory is interested in elucidating the molecular mechanisms responsible for the spatio-temporal pattern of Hox gene expression during mammalian development. We use the Hoxa5 gene as a model. In the mouse, the lack of Hoxa5 function results in defects affecting the formation of several structures including the skeleton, the lung, the gut, the thyroid and mammary glands, revealing its crucial role for normal embryonic development. We have shown that the Hoxa5 specific regional expression in the embryo is under the control of several DNA sequences and transcriptional factors. Multiple RNAs containing Hoxa5 sequences are produced but only one encodes the HOXA5 protein. The other Hoxa5 transcripts possess a developmentally-regulated expression but how they are integrated in the developmental program remains unknown. We propose to pursue our study of the control mechanisms of Hoxa5 expression by characterizing the Hoxa5 regulatory elements and by analyzing the role that the long non-coding RNAs encompassing Hoxa5 sequences may play in the spatially and temporally-restricted expression of Hox genes. This will be addressed by using molecular and genetic approaches. Our research program will lead to a better understanding of the precise regulation of Hox expression, which is essential for Hox gene function and hence for correct embryo patterning.