Long non-coding RNAs in cell fate decisions – RNAFATE

Since their discovery, long non-coding RNAs (lncRNAs) have been shown to contribute to cell identity in normal and pathological situations by modulating genome expression and integrity. However, our mechanistic knowledge of their role in cell fate decisions remains largely elusive. Conserved throughout the eukaryotic kingdom, the developmental transition from mitosis to meiosis is critical for gamete production and is accompanied by profound modifications in gene expression profiles between somatic and germline cells. Based on several preliminary data and innovative approaches gathered by the consortium, this project aims at deciphering the molecular and cellular mechanisms by which distinct lncRNAs and their protein partners coordinate their action to orchestrate the cell cycle transition from mitosis to meiosis, using fission yeast as a model organism. Notably, we will:
1. determine the cis-elements and trans-acting factors governing the role of gametogenic lncRNAs. Our results support the notion that antagonistic lncRNAs tune the mitosis to meiosis switch. We will identify the cis-elements within these lncRNA moieties that mediate the binding and regulation of gametogenic effectors. Using proteomic and genetic strategies, we will further determine the repertoire of trans-acting factors that associate with the corresponding lncRNAs. Finally, we will perform mechanistic studies to assess the contribution of these cis-elements and trans-acting factors to the regulation of meiosis onset and progression.
2. investigate the mechanisms underlying the assembly and remodeling of lncRNA-containing complexes (lncRNPs) during the mitosis to meiosis switch. Our system provides a unique opportunity to study the remodeling of antagonistic lncRNPs and their consequences on meiotic gene expression. We will determine the expression profiles, post-translational modifications and localization of lncRNAs and associated factors upon synchronized meiosis induction. We will also assess whether dynamic changes in lncRNP composition upon sexual differentiation underlie the timely control of the meiotic program.
3. study the lncRNA-dependent spatial control of the meiotic program into nuclear bodies. Current data, including ours, indicate that gametogenic effectors assemble within nuclear foci overlapping lncRNA transcription sites. By combining in vivo and in vitro approaches, we will study their biophysical properties, composition (protein and RNA content) and dynamics during the mitosis to meiosis switch and will assess their physiological relevance in meiotic gene expression.
To achieve these different aims, this consortium combines unique and complementary skills in molecular biology, biochemistry, genomics, microscopy and structural biology. By addressing several general and unanswered questions in the RNA field, the realization of this project should lead to important conceptual advances in our understanding of lncRNA-mediated mechanisms and post-transcriptional regulatory networks involved in gene expression and cell fate decisions.