Transcriptional complexity at the Hoxa5 locus: Characterization of the role of the Hoxa5-associated long noncoding RNAs

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基因的突变导致了一系列影响胚胎并导致成人疾病的异常，准确地指出了HOX基因在一生中的大范围作用。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。其中一种模式涉及在基因组中发现的、沿Hox基因簇存在的长非编码(LNC)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。我们已经证明了Hoxa5对包括骨骼、肺、肠道、卵巢、甲状腺和乳腺在内的几种结构的形成是必不可少的，揭示了Hoxa5对正常发育的关键作用。此外，我们还发现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。其他与Hoxa5相关的lncRNA具有发育调节的表达，这表明它们也参与了胚胎的形成。然而，它们的确切功能以及它们如何整合到发展计划中仍不清楚。我们的工作假设是，与Hoxa5相关的lncRNAs在胚胎发育过程中对于HOX基因的时空协调表达是重要的，它们也有助于调控参与发育的大规模基因表达程序。我们将通过分析Hoxa5相关的lncRNAs在小鼠胚胎发育过程中所起的作用来进一步研究Hoxa5表达的调控机制。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，从而对正确的胚胎发育至关重要。

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, pinpointing 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 noncoding (lnc) RNAs found throughout the genome and present along the Hox gene 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. We have shown that Hoxa5 is essential for the formation of several structures including the skeleton, the lung, the gut, the ovary, and the thyroid and mammary glands, revealing the crucial role of Hoxa5 for normal development. Moreover, we have discovered 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 for the HOXA5 protein. The other Hoxa5-associated lncRNAs possess a developmentally-regulated expression suggesting that they are also involved in embryo formation. However, their exact function and how they are integrated in the developmental program remain unknown. Our working hypothesis is that the Hoxa5-associated lncRNAs are important for the coordinated spatio-temporal expression of the Hox genes during embryogenesis and they also contribute to the control of large-scale gene expression programs involved in development. We will pursue our study of the control mechanisms of Hoxa5 expression by analyzing the role played by Hoxa5-associated lncRNAs during mouse embryogenesis. 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 the correct embryo development.**