RNA Modifications & Regulation
Our research programme aims to decipher the molecular mechanisms behind RNA modifications and regulation, as well as their link to ageing and age-related diseases. Our interdisciplinary team employs functional genomics techniques to decode regulatory elements in RNA sequences and has developed high-throughput approaches such as iCLIP and miCLIP2 to map protein-RNA interactions and detect m6A RNA modifications. We seek to unravel the fundamental biological processes that control RNA regulation and the perturbations that lead to age-related diseases such as neurodegeneration and cancer.
Our past achievements include discovering that RNA regulation is extensively modulated by the interactions between RNA-binding proteins. We generated the first maps of the RNA regulatory elements that control specific splicing decisions and decoded their actions in CART-19 therapy resistance in leukaemia. We also found that the RNA-binding protein Makorin acts as a sensor for faulty RNAs, which could be a mechanism contributing to robustness during ageing and in age-related diseases. Recently, we discovered that m6A RNA modifications mediate X-to-autosome dosage compensation in mammals, a mechanism which could balance sex-specific differences during ageing and in disease.
Currently, we are focused on understanding the mechanisms of splicing regulation in ageing and disease, dissecting the roles of m6A RNA modifications in gene expression and dosage compensation, and investigating mechanisms of RNA quality control. Our ultimate goal is to contribute significantly to decoding the molecular principles that govern RNA regulation in human physiology and age-related diseases and guide the development of specific treatments.
Positions held
- Since 2013: Group Leader, Institute of Molecular Biology (IMB), Mainz
- 2008 - 2013: Postdoctoral Researcher, MRC Laboratory of Molecular Biology, Cambridge, UK
Education
- 2008: PhD in Biology, Phillipps University, Marburg
- 2003: Diploma in Biology, Ludwig Maximilians University, Munich
Selected publications by Julian König
Cortés-López M*, Schulz L*, Enculescu M*, Paret C, Spiekermann B, Quesnel-Vallières M, Torres-Diz M, Unic S, Busch A, Orekhova A, Kuban M, Mesitov M, Mulorz MM, Shraim R, Kielisch F, Faber J, Barash Y, Thomas-Tikhonenko A, Zarnack K#, Legewie S# and König J# (2022) High-throughput mutagenesis identifies mutations and RNA-binding proteins controlling CD19 splicing and CART-19 therapy resistance. Nat Commun, 13:5570 (*indicates joint contribution, #indicates joint correspondence) Link
Körtel N*, Rücklé C*, Zhou Y*, Busch A, Hoch-Kraft P, Sutandy FXR, Haase J, Pradhan M, Musheev M, Ostareck D, Ostareck-Lederer A, Dieterich C, Hüttelmaier S, Niehrs C, Rausch O, Dominissini D, König J# and Zarnack K# (2021) Deep and accurate detection of m6A RNA modifications using miCLIP2 and m6A boost machine learning. Nucleic Acids Res, 49:e92–e92 (*indicates joint contribution, #indicates joint correspondence) Link
Hildebrandt A, Brüggemann M, Rücklé C, Boerner S, Heidelberger JB, Busch A, Hänel H, Voigt A, Möckel MM, Ebersberger S, Scholz A, Dold A, Schmid T, Ebersberger I, Roignant JY, Zarnack K#, König J# and Beli P# (2019) The RNA-binding ubiquitin ligase MKRN1 functions in ribosome-associated quality control of poly(A) translation. Genome Biol, 20:216 (#indicates joint correspondence) Link
Braun S*, Enculescu M*, Setty ST*, Cortés-López M, de Almeida BP, Sutandy FXR, Schulz L, Busch A, Seiler M, Ebersberger S, Barbosa-Morais NL, Legewie S#, König J# and Zarnack K# (2018) Decoding a cancer-relevant splicing decision in the RON proto-oncogene using high-throughput mutagenesis. Nat Commun, 9:3315 (*indicates joint contribution, #indicates joint correspondence) Link
Sutandy FXR*, Ebersberger S*, Huang L*, Busch A, Bach M, Kang HS, Fallmann J, Maticzka D, Backofen R, Stadler PF, Zarnack K, Sattler M, Legewie S# and König J# (2018) In vitro iCLIP-based modeling uncovers how the splicing factor U2AF2 relies on regulation by cofactors. Genome Res, 28:699–713 (*indicates joint contribution, #indicates joint correspondence) Link
Posttranscriptional regulation plays a critical role in development and tissue identity. The information in the RNA sequence and how it is read and interpreted by RNA-binding proteins is commonly referred to as the ‘ribonucleoprotein (RNP) code’. Cracking this code and understanding the underlying regulatory networks remain long-standing goals of RNA biologists.
To decipher the RNP code, I previously developed iCLIP, a technique that provides genome-wide maps of protein-RNA interactions with single-nucleotide resolution. Our group uses iCLIP to address the following key questions: What is the organisation of cis-regulatory elements? How do proteins act together in RNP assembly? How do RNPs control gene regulation in early development? By cracking the RNP code, we aim to better understand human biology and disease.
Positions held
- Since 2013: Group Leader, Institute of Molecular Biology (IMB), Mainz
- 2008 - 2013: Postdoctoral Researcher, MRC Laboratory of Molecular Biology, Cambridge
Education
- 2008: PhD in Biology, Phillip University, Marburg
- 2003: Diploma in Biology, Ludwig Maximilian University, Munich
Selected publications by Julian König
Kang HS*, Sánchez-Rico C*, Ebersberger S, Sutandy FXR, Busch A, Welte T, Stehle R, Hipp C, Schulz L, Buchbender A, Zarnack K, König J# and Sattler M# (2020) An autoinhibitory intramolecular interaction proof-reads RNA recognition by the essential splicing factor U2AF2. Proc Natl Acad Sci, 117:7140–7149 (*indicates joint contribution, #indicates joint correspondence) Link
Buchbender A, Mutter H, FX Sutandy R, Körtel N, Hänel H, Busch A, Ebersberger S and König J (2019) Improved library preparation with the new iCLIP2 protocol. Methods, doi:10.1016/j.ymeth.2019.10.003 Link
Braun S*, Enculescu M*, Setty ST*, Cortés-López M, de Almeida BP, Sutandy FXR, Schulz L, Busch A, Seiler M, Ebersberger S, Barbosa-Morais NL, Legewie S#, König J# and Zarnack K# (2018) Decoding a cancer-relevant splicing decision in the RON proto-oncogene using high-throughput mutagenesis. Nat Commun, 9:3315 (*indicates joint contribution, #indicates joint correspondence) Link
Hildebrandt A, Alanis-Lobato G, Voigt A, Zarnack K, Andrade-Navarro MA, Beli P and König J (2017) Interaction profiling of RNA-binding ubiquitin ligases reveals a link between posttranscriptional regulation and the ubiquitin system. Sci Rep, 7:16582 Link
König J, Zarnack K, Luscombe NM and Ule J (2012) Protein–RNA interactions: New genomic technologies and perspectives. Nat Rev Genet, 13:77–83 Link