Principal Supervisor: Dr Michael Tellier
Secondary Supervisor(s): Dr Yolanda Markaki
University of Registration: University of Leicester
BBSRC Research Themes:
Cellular senescence, which is characterised by a proliferation arrest, is a driver of ageing (1). Several stresses can induce cellular senescence, including persistent DNA damage, telomere dysfunction, and oncogene activation. We previously found that a deregulation of expression of long non-coding (lnc)RNAs can also promote cellular senescence, due to sustained DNA damage from transcription/replication conflicts (2). Interestingly, we found that during cellular senescence, a subgroup of lncRNAs located next to DNA replication initiation regions are getting activated and resulting in DNA damage and transcription/replication conflicts. These results indicate that the activation of this subgroup of lncRNAs could play a role in the promotion and/or maintenance of cellular senescence.
The project is therefore to elucidate in a fibroblast cell culture model the regulation and the role played by this subgroup of lncRNAs in cellular senescence. This will include several interconnected lines of enquiries:
- When are these lncRNAs activated? Is it before or after cellular senescence?
- How are these lncRNAs getting activated? Are they expression regulated by one or more cellular stresses?
- Are these lncRNAs consistently promoting DNA damage via transcription/replication conflicts?
- How is their activation related to other changes in the nucleus during cellular senescence, such as 3D genome organization, RNA polymerase II activity, and nucleosome packaging?
- In the cascade of dysregulations occurring in the nucleus leading to cellular senescence, where is the activation of these lncRNAs located?
This project will equip the candidate with a unique combination of expertise in cutting-edge experimental approaches and data analyses.
- Di Micco R et al. Cellular senescence in ageing: from mechanisms to therapeutic opportunities. Nature Reviews Molecular Cell Biology, 2020.
- Nojima T*, Tellier M*, et al. Deregulated Expression of Mammalian lncRNA through Loss of SPT6 Induces R-Loop Formation, Replication Stress, and Cellular Senescence. Molecular Cell, 2018.
- Grigoryan A et al, LaminA/C regulates epigenetic and chromatin architecture changes upon aging of hematopoietic stem cells. Genome Biology, 2018.
- Genomics and transcriptomic approaches
- Bioinformatics analyses
- Live-cell imaging / super-resolution microscopy (3)
- Cell culture
- CRISPR/Cas9 genome editing
- Standard molecular biology techniques (cloning, co-immunoprecipitation …)