lncImpact SIGNED

Project "lncImpact" data sheet

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 Project objective

Tens of thousands of loci in mammalian genomes produce long RNAs that do not go on to produce functional proteins, and are collectively called long noncoding RNAs (lncRNAs). A growing number of these have been shown to be important in various biological processes and human diseases. How lncRNA genes function and, specifically, how their production, maturation, or RNA products affect other gene regulatory processes remains poorly understood and is the focus of this proposal.

We will build on a rich arsenal of tools from molecular biology, computational biology, high-throughput screens, cell biology, and mouse genetics, develop new methodologies, and dissect the rules underlying the functions of three lncRNA circuit classes that we identified as representatives of large groups of lncRNAs. Namely, lncRNAs that: (i) regulate gene expression in cis at a distance; (ii) affect the activity of proximal promoters; or (iii) modulate the function of RNA binding proteins that regulate mRNAs post-transcriptionally. We propose a roadmap in which we will use minimal synthetic systems to build on the insights from the representative circuits, identify yet uncharacterized lncRNAs with similar modes of action, and derive a codebook of how lncRNA gene loci impact gene regulatory networks and sculpt gene expression in mammalian cells.

The proposed research has the potential of producing conceptual breakthroughs including: (1) Understanding how RNA production poises genomic loci for timely gene activation upon cues for neuroregeneration and learning. (2) Recipes for therapeutic perturbations that will tune promoter activity for balancing gene expression in haploinsufficient or over-producing cells. (3) Decoding how a single lncRNA species can disrupt a network of post-transcriptional control by RNA binding proteins.