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 (Figure 1), 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 (Figure 2).
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:
- Determine how the structure of regulatory RNPs instructs their function in brain development and neurologic diseases.
- Understand how regulatory RNPs respond to cellular signals, in particular the signals that affect neurons during at the initial stages of neurodegenerative diseases, with the primary focus on motor neuron disease.
- Define how mutations can modify protein-RNA interactions to either drive evolution of mammalian brain, or cause neurologic diseases.
|Chris Sibley (2011-) Intronic splicing regulatory elements in neuronal genes.|
|Andrea D’Ambrogio (2013-) Regulation and function of alternative 3’ UTRs.|
|Lilach Soreq (2013-) Computational study of neuronal RNA metabolism.|
|Rickie Patani (2013-) RNA metabolism in motor neuron disease.|
Sugimoto (2010-) Functional analysis of in
vivo RNA structures.
|Jan Attig (2011-) Control of mRNA life cycle: from processing to decay.|
|Ina Huppertz (2012-) Function of disordered regions in RNA-binding proteins.|
|Nejc Haberman (2013-) Computational study of protein-RNA interactions.|
|Claire Hall (2013-) Neuronal functions of intronic splicing regulatory elements.|
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
König J, Zarnack K, Luscombe NM, Ule J. (2012) Protein-RNA interactions: new genomic technologies and perspectives. Nat Rev Genet. Jan 18;13(2):77-83.
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