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

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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.**