Transcriptional complexity at the Hoxa5 locus

从受精卵到多细胞生物的发育是一个复杂的过程，涉及许多基因在空间和时间上的精确表达。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位置。Hox基因的突变会导致一系列影响胚胎的异常现象，并在成人中引起疾病，这表明Hox基因在整个生命过程中发挥着广泛的作用。一系列复杂的不同调控模式支配着Hox基因的特定表达，这表明正确的Hox表达对生物体正常发育的重要性。其中一种模式涉及在Hox集群中发现的长非编码rna。我们的实验室对阐明哺乳动物发育过程中Hox基因表达时空模式的分子机制感兴趣。我们使用Hoxa5基因作为模型。在小鼠中，Hoxa5功能的缺失会导致影响包括骨骼、肺、肠道、甲状腺和乳腺在内的几种结构形成的缺陷，揭示了它对正常胚胎发育的关键作用。我们已经证明Hoxa5在胚胎中的特异性区域表达受几种DNA序列和转录因子的控制。产生含有Hoxa5序列的多个rna，但只有一个编码Hoxa5蛋白。其他Hoxa5转录本具有发育调节表达，但它们如何整合到发育程序中仍不清楚。我们拟通过表征Hoxa5调控元件，分析包含Hoxa5序列的长链非编码rna在Hox基因的时空限制性表达中可能发挥的作用，进一步研究Hoxa5的表达调控机制。这将通过使用分子和遗传方法来解决。我们的研究计划将有助于更好地理解Hox基因表达的精确调控，这对Hox基因的功能和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.