Transcriptional complexity at the Hoxa5 locus

Hoxa5 位点的转录复杂性

基本信息

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：
2012
资助国家：
加拿大
起止时间：
2012-01-01 至 2013-12-31
项目状态：
已结题

来源：
https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=505980
关键词：
Transcriptional complexity Hoxa5 locus

项目摘要

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.

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，这表明HOX基因在一生中的作用范围很大。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。这些模式之一涉及整个HOX簇中发现的长期非编码RNA。我们的实验室有兴趣阐明哺乳动物发育过程中HOX基因表达的时空时期模式的分子机制。我们将HOXA5基因作为模型。在小鼠中，缺乏HOXA5功能会导致缺陷，影响了几种结构的形成，包括骨架，肺，肠道，甲状腺和乳腺，揭示了其在正常胚胎发育中的关键作用。我们已经表明，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，但只有一个编码HOXA5蛋白。其他HOXA5转录本具有开发调节的表达，但是如何将它们整合到发育计划中仍然未知。我们建议通过表征HOXA5调节元件，并分析包含HOXA5序列的长期非编码RNA可能在空间和时间限制的HOX基因表达中发挥作用的作用来追求对HOXA5表达的控制机制的研究。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构图。