The primary task of the nervous system is to process and store information, and we study how this is achieved at the level of RNA molecules. As an mRNA travels through the different cellular compartments, it passes through several regulatory stages. These stages are controlled by RNA-binding proteins (RBPs) and non-coding RNAs (ncRNAs), which assemble on the mRNA into a regulatory ribonucleoprotein complex (RNP). We developed iCLIP which revealed how the position of RBP-RNA interactions guides the RBP function. We characterized the function of several RBPs that are implicated in neurologic diseases, and revealed a mechanism that controls the emergence of new exons from transposable elements
Currently, we study the structure and function of regulatory RNPs in neurons and glia. Each RNP has a unique structure, which depends on the sequence-specific interactions between mRNA, RBPs and ncRNAs. To fully understand the dynamic structure of RNPs, we study them within intact cells. We integrate genomic, biochemical and computational techniques to study RNPs in brain tissue or in pluripotent stem cells that are differentiated into specific neuronal or glial cell types. Specifically, we aim to:
- How do the RNA-RNA, protein-RNA and protein-protein interactions act together to define the assembly and function of regulatory RNPs?
- How do RNPs guide the differentiation and functions of neurons or glial cells during brain development, aging or neurodegenerative diseases?
- How do mutations cause disease by disrupting the function of RNPs or RNA regulatory elements, and what treatments could ameliorate this?
The lab is currently seconded at The Francis Crick Institute. More information on current research and lab members can be here - https://www.crick.ac.uk/research/labs/jernej-ule
Lorea Blazquez*, Warren Emmett, Rupert Faraway, Simon Bajew, Andre Gohr, Nejc Haberman, Christopher R Sibley, Manuel Irimia, Jernej Ule* (2018) Exon junction complex blocks recursive splicing to promote inclusion of RS-exons, Mol Cell, Nov 1;72(3):496-509.e9.
Jan Attig*, Federico Agostini, Clare Gooding, Anob M Chakrabarti, Julian A Zagalak, Aarti Singh, Nejc Haberman, Warren Emmett, Christopher WJ Smith, Nicholas M Luscombe, Jernej Ule* (2018) Heteromeric RNP assembly at LINEs controls lineage-specific RNA processing, Cell, Aug 23;174(5):1067-1081.e17.
Soreq L; UK Brain Expression Consortium; North American Brain Expression Consortium, Rose J, Soreq E, Hardy J, Trabzuni D, Cookson MR, Smith C, Ryten M, Patani R*, Ule J* (2017) Major shifts in glial regional identity are a transcriptional hallmark of human brain aging, Cell Reports, Jan 10;18(2):557-570.
Rot G*, Wang Z, Huppertz I, Modic M, Lenče T, Hallegger M, Haberman N, Curk T, von Mering C, Ule J*. (2017) High-Resolution RNA Maps Suggest Common Principles of Splicing and Polyadenylation Regulation by TDP-43. Cell Reports. May 2;19(5):1056-1067.
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.
Tollervey JR, Wang Z, Hortobágyi T, Witten JT, Zarnack K, Kayikci M, Clark TA, Schweitzer AC, Rot G, Curk T, Zupan B, Rogelj B, Shaw CE, Ule J. (2011) Analysis of alternative splicing associated with aging and neurodegeneration in the human brain. Genome Res. Oct;21(10):1572-82.
Tollervey JR, Curk T, Rogelj B, Briese M, Cereda M, Kayikci M, König J, Hortobágyi T, Nishimura AL, Zupunski V, Patani R, Chandran S, Rot G, Zupan B, Shaw CE, Ule J. (2011) Characterizing the RNA targets and position-dependent splicing regulation by TDP-43. Nat Neurosci. Apr;14(4):452-8.