Transcriptional complexity at the Hoxa5 locus

Hoxa5 位点的转录复杂性

• 批准号: 194559-2010
• 负责人: Jeannotte, Lucie
• 金额: $ 2.4万
• 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: 2013
• 资助国家: 加拿大
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=523230
• 关键词: Transcriptional; complexity; Hoxa5; locus

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.

从受精卵发育成多细胞生物是一个复杂的过程，涉及在空间和时间上精确表达的大量基因。 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等级中占据着关键位置。 Hox 基因突变会导致一系列异常现象，影响胚胎并导致成人疾病，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节模式控制着 Hox 基因的特定表达，表明正确的 Hox 表达对于生物体正常发育的重要性。其中一种模式涉及在 Hox 簇中发现的长非编码 RNA。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 功能的缺乏会导致影响骨骼、肺、肠道、甲状腺和乳腺等多种结构形成的缺陷，这揭示了其对正常胚胎发育的关键作用。我们已经证明胚胎中 Hoxa5 的特异性区域表达受到多种 DNA 序列和转录因子的控制。产生了多种含有 Hoxa5 序列的 RNA，但只有一种编码 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然未知。我们建议通过表征 Hoxa5 调控元件并分析包含 Hoxa5 序列的长非编码 RNA 在 Hox 基因的空间和时间限制表达中可能发挥的作用来继续研究 Hoxa5 表达的控制机制。这将通过使用分子和遗传学方法来解决。我们的研究计划将有助于更好地了解 Hox 表达的精确调控，这对于 Hox 基因功能以及正确的胚胎模式至关重要。