Jernej Ule

RNA Networks Laboratory

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 undergoes processing, such as splicing and 3' end processing, and passes through many stages of quality control and regulation. The coordinators of these stages are ribonucleoprotein complexes (RNP), which form when multiple proteins bind to an RNA molecule. 

We develop techniques that integrate biochemistry and computational biology to obtain a comprehensive map of interactions between a specific protein and its 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 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.

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.

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. (Click to view larger image)

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 contacts define the assembly of RNPs, and thereby coordinate RNA processing and regulation?
  2. How do RNPs modulate neuronal functions in response to neuronal differentiation or synaptic activity?
  3. How does evolution tinker with the RNA regulatory circuits? What is the role of transposable elements and non-canonical splicing in evolution?
  4. How do mutations cause disease by disrupting the function of RNPs, and what treatments could ameliorate this?

Selected Publications

Sibley RC, Blazquez L, Ule J (2016) Lessons from non-canonical splicing. Nature Reviews Genetics, May 31 

Sibley RC, Emmett W, Blazquez L, Faro A, Haberman N, Briese M, Trabzuni D, Ryten M, Hardy J, UK Brain Expression Consortium, Modic M, Curk T, Wilson SW, Plagnol V, Ule J (2015) Recursive splicing in long vertebrate genes. Nature, May 21;521(7552):371-5.

Sugimoto Y, Vigilante A, Darbo E, Zirra A, Militti C, D'Ambrogio A, Luscombe N, Ule J (2015) hiCLIP reveals the in vivo atlas of mRNA secondary structures recognized by Staufen 1. Nature, Mar 26;519(7544):491-4.

Zarnack K, König J, Tajnik M, Martincorena I, Stévant I, Reyes A, Anders S, Luscombe NM, Ule J (2013) Direct competition between hnRNP C and U2AF65 protects the transcriptome from the uncontrolled exonization of Alu elements. Cell, Jan 31;152(3):453-66

Jernej Ule

jernej.ule@crick.ac.uk
+44 (0)203 796 3137

  • Qualifications and History

  • 2004 PhD, Rockefeller University, New York
  • 2004 Post Doctoral Fellow, Rockefeller University, New York
  • 2006 Group Leader, Medical Research Council, Laboratory of Molecular Biology, UK
  • 2013 Group Leader, Department of Molecular Neuroscience, UCL Institute of Neurology
  • 2016 Group Leader, the Francis Crick Institute, London, UK