Genes in the brain are very long and can be transcribed into diverse RNAs.

Introduction

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.

The conformation of human mRNAs as revealed by hiCLIP.

Figure 1: The conformation of human mRNAs as revealed by hiCLIP (from Sugimoto et al, Nature 2015). A standardized mRNA is shown at the circumference, divided into the 5' UTR, CDS and 3′ UTR, and RNA-RNA connections are shown within the circle.

Upon its transcription, each RNA molecule 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 in collaboration with the group of Nicholas Luscombe 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 in collaboration with the group of Rickie Patani by using induced pluripotent 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:

  1. How do RNA-RNA and protein-RNA interactions define the assembly of RNPs, and thereby coordinate RNA processing and regulation?
  2. How do RNPs contribute to neuronal differentiation and function?
  3. How do the RNA-protein networks evolve, and how do transposable elements and other non-canonical elements contribute to this evolution?
  4. How do mutations cause disease by disrupting the function of RNPs, and what treatments could ameliorate this?