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SPP1935 -- Deciphering the mRNP code :
RNA-bound Determinants of Post-transcriptional Gene Regulation

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laboratoriesProf. Dr. Dieterich

Christoph  Dieterich Center
University Hospital Heidelberg, Klaus-Tschira-Institute, Bioinformatics and Systems Cardiology

AZ III, Im Neuenheimer Feld 669, 69120 Heidelberg


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Deciphering the assembly, composition and function of exon junction compledxes


Mammalian gene expression involves the formation of mRNPs, which regulate processing, translation and turnover of mRNAs. The exon junction complex (EJC) is a multifunctional mRNP component, which is assembled on mRNAs during splicing in the nucleus. The interaction of the EJC component eIF4A3 with the spliceosomal protein CWC22 enables the deposition of the EJC approximately 20 nucleotides upstream of the splice junction in a sequence-independent manner. EJCs remain bound to their mRNA during and after transport to the cytoplasm and modulate many post-transcriptional steps of gene expression, including pre-mRNA splicing, mRNP packaging, mRNA transport, translation and degradation.

Significant insights into EJC biology have been obtained since its first description 15 years ago. However, important questions about the assembly of EJCs and their biological functions remain open. To address these questions, we put forward three main aims as part of this proposal.

1. Understanding the mechanism of EJC assembly is key to understand its function. Hence, we aim to identify factors and interactions that mediate EJC formation and dissect different steps and assembly intermediates of the EJC.

2. Binding of the EJC to mRNA involves mainly the four core components, but the function of the EJC during gene expression is tightly linked to its interacting protein partners. Therefore, we aim to characterize the interactions of EJC-binding proteins with the EJC and identify novel EJC-binding proteins.

3. The molecular functions of EJCs have been mainly studied with simplified reporter assays. To avoid the shortcomings of such approaches, we plan to study the cellular functions of the EJC using unbiased high-throughput assays.

A combination of low- and high-throughput assays will leverage our understanding on all possible aspects of EJC function. It is this holistic approach that will lead us to a system-wide, quantitative understanding of EJC function and will deliver hypothesis to be tested in reconstituted systems in vitro and through genomic engineering in vivo.

Focus of the group

The Dieterich Lab works on computational and statistical approaches to study
• RNA modifications (i.e. RNA editing and others)
• RNA-RNA and RNA-protein interactions
• Circular RNAs
• Control of translation
• RNA dynamics
• Data integration (OMICS & clinical data)


Cell culture, RNAi, transfection

PublicationsPUBLICATIONS :

Ivanov A; Memczak S; Wyler E; Torti F; Porath HT; Orejuela MR; Piechotta M; Levanon EY; Landthaler M; Dieterich C; Rajewsky N, 2015. Analysis of intron sequences reveals hallmarks of circular RNA biogenesis in animals. Cell Rep 10(2):170-7

Cheng J; Metge F; Dieterich C, 2015. Specific identification and quantification of circular RNAs from sequencing data. Bioinformatics. 2015 Nov 9. pii: btv656

Blin K*; Dieterich C*; Wurmus R; Rajewsky N; Landthaler M; Akalin A, 2015. DoRiNA 2.0--upgrading the doRiNA database of RNA interactions in post-transcriptional regulation. Nucleic Acids Res 43(Database issue):D160-7; * joint first authors

Aeschimann F; Xiong J; Arnold A; Dieterich C*; Grosshans H*, 2015. Transcriptome-wide measurement of ribosomal occupancy by ribosome profiling. Methods 85:75-89; * corresponding authors

Schueler M; Munschauer M; Gregersen LH; Finzel A; Loewer A; Chen W; Landthaler M; Dieterich C, 2014. Differential protein occupancy profiling of the mRNA transcriptome. Genome Biol 15(1):R15