Center for Molecular Medicine Cologne

Beyer, Andreas - C 04

Mechanisms of age-associated decline in splicing fidelity


The gradual decline of cellular functions is a major factor contributing to tissue degeneration and ageing associated diseases, such as chronic kidney disease. Despite its importance for many diseases, we lack understanding about the molecular mechanisms underlying such progressive functional loss. Clearly, improving our insight about the causes will help to develop preventative measures and possibly better treatments of common complex diseases.

Recent work by us and others has demonstrated that the age-associated decline of cellular functions is associated with the decline of RNA splicing fidelity.

We have shown that during ageing the speed of RNA Pol-II elongation increases, which leads to increased errors during transcription and splicing (Figure 1). Further, we could show that slowing down transcription improves the quality of transcripts and extends lifespan in different metazoan species. However, we lack understanding about the molecular factors contributing to this functional decline.

Figure 1

Our Aims

In this project we aim to

  1. identify tissue-specific and tissue-independent splicing ‘mistakes’ at high single-cell resolution,
  2. identify molecular co-factors improving or worsening splicing fidelity, and
  3. thus better understand effects of splicing fidelity on cellular fitness.

We propose to tackle the above questions by performing extensive single-cell profiling in order to associate the emergence of specific splicing events with other molecular co-factors, such as the expression of splicing regulators, Pol-II components and chromatin regulators.

These experiments will be conducted in livers and kidneys from mice of different age and lifespan-extending interventions (dietary restriction). Importantly, we will employ innovative technologies that will allow us to profile chromatin states and RNA levels in the same cells, which will enable the direct correlation of chromatin state changes with splicing and gene expression changes. This project will heavily rely on single-cell bioinformatic methods developed in the Beyer lab.

Previous Work

We have recently shown that an increase in RNA Pol-II elongation speed during ageing contributes to a decline of cellular and organismal fitness. Further, we and others (e.g. Heintz et al. 2017, Nature) have shown that transcript quality declines with age, including increasing numbers of splicing errors in nascent transcripts, the increased formation of circular RNAs, and increasing errors in the RNA sequence itself (mismatches with the DNA template).

We have also shown that lifespan extending interventions such as dietary restriction (DR) and genetically slowing down Pol-II elongation speed rescues these effects at least partially. We could show that slowing down Pol-II extends lifespan in worm and fly and it improved transcript quality, including reduced formation of (most likely) spurious exon-exon junctions.

  • Debès C*, Leote AC*, Beyer A (2019) Computational approaches for the systematic analysis of ageing-associated molecular alterations (Review). Drug Discov. Tod.: Disease Mod. 27:51-59;
  • Cédric Debès, Sebastian Grönke, Özlem Karalay, Luke Tain, Shuhei Nakamura, Oliver Hahn, Carina Weigelt, Anne Zirkel, Konstantinos Sofiadis, Lilija Brant, Bernd Wollnik, Torsten Kubacki, Martin Späth, Bernhard Schermer, Thomas Benzing, Roman-Ulrich Müller, Argyris Papantonis, Adam Antebi, Linda Partridge, Andreas Beyer. doi:
  • Hahn O, […], Beyer A#, Partridge L#. (2018) Hepatic gene body hypermethylation is a shared epigenetic signature of murine longevity. PLoS Genet. 14(11):e1007766.
  • Hahn O, […], Beyer A#, Reik W#, Partridge L# (2017) Dietary restriction protects from age-associated DNA methylation and induces epigenetic reprogramming of lipid metabolism. Genome Biol. 18:56.
  • Leote, Wu, Beyer (2019). Regulatory network-based imputation of dropouts in single-cell RNA sequencing data. doi: 10.1371/journal.pcbi.1009849
  • Grossbach J, Gillet L, Clement-Ziza M, Schmalohr CL, Schubert OT, Schutter M, Mawer JSP, Barnes CA, Bludau I, Weith M, Tessarz P, Graef M, Aebersold R, and Beyer A (2022). The impact of genomic variation on protein phosphorylation states and regulatory networks. Mol Syst Biol18, e10712. doi:10.15252/msb.202110712.
  • Huth M, Santini L, Galimberti E, Ramesmayer J, Titz-Teixeira F, Sehlke R, Oberhuemer M, Stummer S, Herzog V, Garmhausen M, Romeike M, Chugunova A, Leesch F, Holcik L, Weipoltshammer K, Lackner A, Schoefer C, von Haeseler A, Buecker C, Pauli A, Ameres SL, Smith A, Beyer A, and Leeb M (2022). NMD is required for timely cell fate transitions by fine-tuning gene expression and regulating translation. Genes Dev36, 348-367. doi:10.1101/gad.347690.120.
  • Leote AC, Wu X, and Beyer A (2022). Regulatory network-based imputation of dropouts in single-cell RNA sequencing data. PLoS Comput Biol18, e1009849. doi:10.1371/journal.pcbi.1009849.
  • Cappelletti V, Hauser T, Piazza I, Pepelnjak M, Malinovska L, Fuhrer T, Li Y, Dorig C, Boersema P, Gillet L, Grossbach J, Dugourd A, Saez-Rodriguez J, Beyer A, Zamboni N, Caflisch A, de Souza N, and Picotti P (2021). Dynamic 3D proteomes reveal protein functional alterations at high resolution in situ. Cell184 (2), 545-559 e22. doi:10.1016/j.cell.2020.12.021.
  • Charmpi K, Chokkalingam M, Johnen R, and Beyer A (2021). Optimizing network propagation for multi-omics data integration. PLoS Comput Biol17(11), e1009161. doi:10.1371/journal.pcbi.1009161.
                                                                                                                                                            • Lackner A, Sehlke R, Garmhausen M, Giuseppe Stirparo G, Huth M, Titz-Teixeira F, van der Lelij P, Ramesmayer J, Thomas HF, Ralser M, Santini L, Galimberti E, Sarov M, Stewart AF, Smith A, Beyer A, and Leeb M (2021). Cooperative genetic networks drive embryonic stem cell transition from naive to formative pluripotency. EMBO J40 (8), e105776. doi:10.15252/embj.2020105776.
                                                                                                                                                            • Santini L, Halbritter F, Titz-Teixeira F, Suzuki T, Asami M, Ma X, Ramesmayer J, Lackner A, Warr N, Pauler F, Hippenmeyer S, Laue E, Farlik M, Bock C, Beyer A, Perry ACF, and Leeb M (2021). Genomic imprinting in mouse blastocysts is predominantly associated with H3K27me3. Nat Commun12 (1), 3804. doi:10.1038/s41467-021-23510-4.
                                                                                                                                                                                                                                                                                                                        • Tain LS, Sehlke R, Meilenbrock RL, Leech T, Paulitz J, Chokkalingam M, Nagaraj N, Gronke S, Frohlich J, Atanassov I, Mann M, Beyer A, and Partridge L (2021). Tissue-specific modulation of gene expression in response to lowered insulin signalling in Drosophila. Elife10. doi:10.7554/eLife.67275.
                                                                                                                                                                                                                                                                                                                                          • Tognetti M, Gabor A, Yang M, Cappelletti V, Windhager J, Rueda OM, Charmpi K, Esmaeilishirazifard E, Bruna A, de Souza N, Caldas C, Beyer A, Picotti P, Saez-Rodriguez J, and Bodenmiller B (2021). Deciphering the signaling network of breast cancer improves drug sensitivity prediction. Cell Syst12 (5), 401-418 e12. doi:10.1016/j.cels.2021.04.002.
                                                                                                                                                                                                                                                                                                                                          • Braun F, Rinschen M, Buchner D, Bohl K, Plagmann I, Bachurski D, Richard Spath M, Antczak P, Gobel H, Klein C, Lackmann JW, Kretz O, Puelles VG, Wahba R, Hallek M, Schermer B, Benzing T, Huber TB, Beyer A, Stippel D, Kurschat CE, and Muller RU (2020). The proteomic landscape of small urinary extracellular vesicles during kidney transplantation. Journal of extracellular vesicles 10 (1), e12026. doi: 10.1002/jev2.12026
                                                                                                                                                                                                                                                                                                                                          • Charmpi K, Guo T, Zhong Q, Wagner U, Sun R, Toussaint NC, Fritz CE, Yuan C, Chen H, Rupp NJ, Christiansen A, Rutishauser D, Ruschoff JH, Fankhauser C, Saba K, Poyet C, Hermanns T, Oehl K, Moore AL, Beisel C, Calzone L, Martignetti L, Zhang Q, Zhu Y, Martinez MR, Manica M, Haffner MC, Aebersold R, Wild PJ, and Beyer A (2020). Convergent network effects along the axis of gene expression during prostate cancer progression. Genome biology 21 (1), 302. doi: 10.1186/s13059-020-02188-9
                                                                                                                                                                                                                                                                                                                                          • Johnsen M, Kubacki T, Yeroslaviz A, Spath MR, Morsdorf J, Gobel H, Bohl K, Ignarski M, Meharg C, Habermann B, Altmuller J, Beyer A, Benzing T, Schermer B, Burst V, and Muller RU (2020). The Integrated RNA Landscape of Renal Preconditioning against Ischemia-Reperfusion Injury. J Am Soc Nephrol 31 (4), 716-30. doi: 10.1681/ASN.2019050534.
                                                                                                                                                                                                                                                                                                                                          • Kamrad S, Grossbach J, Rodriguez-Lopez M, Mulleder M, Townsend S, Cappelletti V, Stojanovski G, Correia-Melo C, Picotti P, Beyer A, Ralser M, and Bahler J (2020). Pyruvate kinase variant of fission yeast tunes carbon metabolism, cell regulation, growth and stress resistance. Mol Syst Biol 16 (4), e9270. doi: 10.15252/msb.20199270.
                                                                                                                                                                                                                                                                                                                                          Prof. Dr. Andreas Beyer CMMC Cologne
                                                                                                                                                                                                                                                                                                                                          Prof. Dr. Andreas Beyer

                                                                                                                                                                                                                                                                                                                                          CECAD Cologne

                                                                                                                                                                                                                                                                                                                                          CMMC - PI - C 04

                                                                                                                                                                                                                                                                                                                                          Publications - Andreas Beyer

                                                                                                                                                                                                                                                                                                                                          Link to PubMed