Transcriptional regulation by long noncoding RNAs

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In order to generate a diversity of tissues and respond to their environment, cells need to activate and repress the expression of defined genes with exquisite specificity. This process involves the activity of multiple proteins, such as transcription factors and chromatin modifiers, that act to regulate the genome in a coordinated fashion. Over the last decade, we've come to realize that cells produce tens of thousands of long RNAs, termed lncRNAs, that do not encode proteins. A model is now emerging whereby many of these lncRNAs are thought to be involved in regulating gene expression by interacting with chromatin and proteins and influence their function either by acting as a scaffold to help their assembly into complexes, mediating their recruitment to specific loci, or by inhibiting their binding and activity. However, deciphering which lncRNAs are able to directly regulate gene expression has proven challenging and a mechanistic understanding of how lncRNAs could accomplish these tasks has remained elusive. This raises interesting questions such as whether there are functional domains within lncRNAs that mediate their interaction with transcription factors or chromatin modifiers and how to find and characterize them. It also requires applying new technologies allowing to probe and manipulate lncRNA activity. Using a novel CRISPR-based approach, we recently found a lncRNA able to activate expression when directly tethered to a defined locus. This has important implications and suggests an RNA-dependent transcriptional regulatory function, where the lncRNA likely interacts and helps recruit specific proteins to target genes. In this project, we want to define the regulatory principles of lncRNAs by identifying those with transcriptional regulatory activity, directly test their function and dissecting the specific RNA domains as well as interacting protein partners that mediate their function. Results from this project will provide valuable insight to better understand how these enigmatic RNAs can affect genome regulation and help determine whether there are modular RNA sequence-dependent effects and subgroups of lncRNAs that regulate gene expression. This project will also enable the establishment of a general approach to identify and characterize other mammalian ncRNA domains and guide the design of novel tools aimed at controlling gene expression.