A gene needs to express itself in order to contribute to cellular functions. This requires information from the gene to be transcribed from DNA into an RNA molecule. Upon its transcription, each RNA molecule then undergoes processing, such as splicing and 3' end processing, and passes through many stages of quality control and regulation.
Ribonucleoprotein complexes (RNP form when proteins bind to an RNA molecule, and they coordinate all of the stages that the RNA passes through.
We develop techniques that integrate biochemistry and computational biology to obtain a comprehensive map of interactions between a proteins and their RNA partners within our cells. We developed the individual-nucleotide resolution UV crosslinking and immunoprecipitation of protein-RNA complexes (iCLIP), and a related method called hiCLIP, which reveals the RNA-RNA contacts and higher-order conformation of RNPs. We use these methods to study how the sequence and structure of RNAs defines the composition and function of RNPs.
Cells can change their gene expression by modulating the composition of RNPs. Moreover, genetic studies have identified mutations that disrupt RNPs, which often cause neurologic diseases, particularly the motor neuron disease, also referred to as amyotrophic lateral sclerosis (ALS). We study this disease by using embryonic stem cells with specific genetic mutations, and differentiating them into motor neurons. We wish to understand how these mutations affect the assembly of RNPs, thereby initiating the molecular cascade leading to disease.
We study the following questions:
- How do RNA-RNA, protein-RNA and protein-protein interactions guide the assembly of RNPs, and thereby coordinate RNA regulation?
- How does RNA regulation contribute to brain development and function?
- How do changes in RNA binding sites, especially those driven by transposable elements and cryptic splice sites, contribute to the evolution of RNA-protein networks?
- How do various RNA features yield the multivalent interactions that enable the condensation of RNPs?
- How do mutations or post-translational modifications in disordered regions of RNA-binding proteins alter their condensation propensity and thereby their RNA regulatory repertoire?
- How does RNP condensation enable feedback regulation that promotes cellular homeostasis, and how is this perturbed upon aging and neurodegeneration?
- How can we develop new therapeutic approaches to reestablish cellular homeostasis by modulating RNPs?