Andreas Beyer / Argyris Papantonis - C 4

Contribution of deteriorating RNA biosynthesis to cellular ageing

Abstract

Whereas the differential expression of genes during ageing has been studied extensively, little attention has been paid to age-associated changes in the transcription process itself. Using transcriptome data from 5 animal species we have shown that the speed of RNA polymerase II (Pol-2) elongation increases with ageing. Strikingly, these changes coincide with a loss of splicing fidelity leading to the increased expression of low-quality transcripts. In this project we plan to further analyse this phenomenon and to better elucidate molecular mechanisms. Nucleosome profiling in early- and late-passage primary human cells will reveal to what extend Pol-2 speed and co-transcriptional splicing are affected by alterations of nucleosome positioning. Second, we will profile transcriptomes in single cells, which will be a substantial leap forward. First of all, this single-cell data will allow us to quantify the cell-to-cell variability of RNA biosynthesis. Second, by correlating our RNA biosynthesis scores with expression levels of individual genes per cell, we will identify modulators impacting on the quality of these processes. Finally, we will integrate all of the above data with additional published data in order to create a model of RNA biosynthesis changes with age. Thus, taken together this project will bring us significantly closer to understanding the mechanisms leading to a reduction of transcript quality with age, which potentially contributes to age-associated tissue degeneration.

Clinical/medical relevance and sustainability in disease understanding

Our discovery that Pol-2 elongation speed increases with age (with impacts on transcript quality) has far reaching implications for our understanding of cellular ageing and age-associated decline of tissue integrity. We suspect that changes in elongation speed contribute to age-associated diseases, such as cancer. Since Pol-2 elongation speed can be modulated with small-molecule drugs, there is even a potential for therapeutically exploiting our findings in the long run.


Prof. Dr. Andreas Beyer

CECAD Cologne

Prof. Dr. Andreas Beyer

Principal Investigator C 4

andreas.beyer@uni-koeln.de

Publications - Andreas Beyer

Link to PubMed


Dr. rer. nat. Argyris Papantonis

Center for Molecular Medicine Cologne

Dr. rer. nat. Argyris Papantonis

Co-Principal Investigator C 4 /
Principal Investigator - JRG VIII

argyris.papantonis@uni-koeln.de

Publications - Argyris Papantonis

Link to PubMed