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Long noncoding RNAs: Impact on Gene Regulatory Networks

Project description

Role of long, non-coding RNAs in gene regulation

Tens of thousands of loci in mammalian genomes produce long non-coding RNAs (lncRNAs): these transcripts with lengths exceeding 200 nucleotides are not translated into proteins. At present, only a small fraction of lncRNAs have been proved biologically relevant, despite accumulating evidence that most are likely to be functional. The EU-funded IncImpact project will employ an arsenal of modern tools (from molecular biology, computational biology, high-throughput screens, cell biology and mouse genetics) to uncover the functions of lncRNAs. The project will focus on three classes of lncRNAs regulating gene expression at a distance in cis position, affecting the activity of proximal promoters, or modulating the function of the proteins that regulate mRNAs post-transcriptionally. The research has potential to characterise new lncRNAs with similar modes of action and identify general principles underlying how lncRNA gene loci impact gene-regulatory networks and gene expression in mammalian cells.

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.

Host institution

WEIZMANN INSTITUTE OF SCIENCE
Net EU contribution
€ 2 000 000,00
Address
HERZL STREET 234
7610001 Rehovot
Israel

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Activity type
Higher or Secondary Education Establishments
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Total cost
€ 2 000 000,00

Beneficiaries (1)