NCRNAX · Regulation and function of non-coding RNAs in epigenetic processes: the paradigm of X-chromosome inactivation

Some 150 years after the emergence of genetics, epigenetic mechanisms are increasingly understood to be fundamental players in phenotype transmission and development. In addition, epigenetic alterations are now linked to several human diseases including cancers. A common feature of many epigenetic phenomena, for which X-chromosome inactivation (XCI) is the paradigm, is the implication of non-coding RNAs (ncRNAs). Regulatory ncRNAs belong to 2 major classes: (i) long ncRNAs, which can be transcribed from a single strand as well as in the opposite orientation when they may overlap with either protein-coding or non-coding genes. Both sense (Xist) and antisense (Tsix) ncRNAs control the initiation of XCI; and (ii) short ncRNAs, such as si- or miRNAs, which interfere, through different pathways, with gene function. The aim of this project is to gain insights into the regulation and function of ncRNAs in the control of gene expression program, using XCI as a model system. We propose to combine molecular genetics, embryology and cell biology to (1) decipher the transcriptional control of Xist and the coordinate regulation of the Xist/Tsix sense/antisense tandem in relation to developmental programs; (2) functionally characterise a novel ncRNA on the X chromosome which nests several miRNAs and for which preliminary data suggest a role in XCI and (3) develop a system to extend our knowledge of the regulatory stages of XCI in human through the use of human embryonic stem cells. Our comprehensive analysis of the function and regulation of ncRNAs in XCI has important implications for our understanding of the numerous diseases associated with abnormal patterns of inactivation and is a critical prerequisite to any subsequent therapeutic approaches. This project is in absolute adequacy with the future “Epigenetic and Cell Fate “ host centre co-headed by Prs. Lalande and Viegas-Pequignot, a large-scale initiative expected to strengthen French and European research in Epigenetics.