Transcriptional complexity at the Hoxa5 locus

从受精卵发育成多细胞生物体是一个复杂的过程，涉及大量在空间和时间上精确表达的基因。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层次结构中占有关键地位。HOX基因的突变会导致一系列影响胚胎的异常，并在成人中引起疾病，这表明HOX基因在一生中的广泛作用。一系列复杂的不同调控模式调控着HOX基因的特定表达，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簇中发现的长的非编码RNA。我们的实验室致力于阐明哺乳动物发育过程中HOX基因表达的时空模式的分子机制。我们使用Hoxa5基因作为模型。在小鼠中，Hoxa5功能的缺失导致了影响骨骼、肺、肠道、甲状腺和乳腺等几个结构形成的缺陷，揭示了Hoxa5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个DNA序列和转录因子的控制。产生了多个包含Hoxa5序列的RNA，但只有一个编码HOXA5蛋白。其他Hoxa5转录本具有发育调节的表达，但它们如何整合到发育程序中仍不清楚。我们建议通过鉴定Hoxa5调控元件和分析包含Hoxa5序列的长非编码RNA在HOX基因的空间和时间受限表达中所起的作用，来继续我们对Hoxa5表达调控机制的研究。这将通过使用分子和遗传方法来解决。我们的研究计划将使我们更好地了解HOX表达的精确调控，这对HOX基因的功能至关重要，从而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.