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

Hoxa5 位点的转录复杂性：Hoxa5 相关长非编码 RNA 作用的表征

• 批准号: RGPIN-2015-05055
• 负责人: Jeannotte, Lucie
• 金额: $ 2.19万
• 依托单位: Université Laval
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=613328
• 关键词: Transcriptional; complexity; Hoxa5; locus; Characterization

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.

从受精卵中开发多细胞生物是一个复杂的过程，涉及许多在时空中精确表达的基因。 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据了关键位置。 HOX基因的突变导致影响胚胎的异常，并引起成年人的疾病，从而指出了HOX基因在一生中的巨大作用。不同调节模式的复杂阵列控制了HOX基因的特定表达，表明正确的HOX表达对生物体的正常发育的重要性。这些模式之一涉及在整个基因组中发现的长不编码（LNC）RNA，并沿HOX基因簇呈现。我们的实验室有兴趣阐明哺乳动物发育过程中HOX基因表达的时空时期模式的分子机制。我们将HOXA5基因作为模型。我们已经表明，Hoxa5对于形成包括骨架，肺，肠道，卵巢以及甲状腺和甲状腺和甲状腺的几种结构至关重要，揭示了Hoxa5在正常发育中的关键作用。此外，我们发现胚胎中的HOXA5特异性区域表达在几个DNA序列和转录因子的控制之下。产生了多个含有HOXA5序列的RNA，但仅针对HOXA5蛋白进行编码。其他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形成。但是，它们的确切功能以及如何将其集成到发展计划中仍然未知。我们的工作假设是，HOXA5相关的LNCRNA对于胚胎发生过程中HOX基因的协调时空表达很重要，并且它们也有助于控制发育中涉及的大型基因表达程序。我们将通过分析HOXA5相关的LNCRNA在小鼠胚胎发生过程中的作用来研究HOXA5表达的控制机制。这将通过使用分子和遗传方法来解决。我们的研究计划将更好地理解HOX表达的精确调节，这对于HOX基因功能至关重要，因此对于正确的胚胎发育至关重要。