Translational Epigenetics Laboratory
What we do
(for the non-scientific audience)
Chartography of the senescent human genome
It is now well understood that, as human cells approach the irreversible state of senescence, the spatial organization of their chromosomes is affected. We recently described a structural hallmark of 3D chromosomal reorganization in the formation of prominent senescent-induced CTCF clusters (SICCs; see Zirkel et al., Mol Cell 2018). SICCs appear to form on the basis of “phase separation” forces and underlie the altered gene expression program of senescent cells. In parallel, we uncovered a higher-order architectural feature of senescent chromosomes that allows for the efficient coordination of gene expression with secretome production (see Sofiadis et al., Mol Syst Biol 2021). Currently, we are interested in using genome-wide screens to identify additional architectural regulators of senescent chromosomes in an effort to constrain or even reverse cellular commitment to senescence.
Fundamental principles of chromatin folding
Genomic functions like gene expression and DNA replication require a tunable 3D architecture of interphase chromatin. Work from many labs over the last decade, combining genome-wide chromosome conformation capture assays with the removal of different chromatin components, has attributed key hallmarks of this 3D architecture to the interplay between the insulator factor CTCF and the ring-shaped cohesin complex. We have contributed to this elucidation by studying the contribution of cohesin-cofactors STAG1 and STAG2 in chromatin folding (see Casa et al., Genome Res 2020). More recently, we have been investigating the role of RNA polymerase II in setting up 3D genome architecture of human chromosomes during the different phases of the cell cycle (see Zhang et al., Sci Advances 2021), and continue to do so using ultra-resolved Micro-C approaches.
The 3D genome in driving malignancy
Senescence in normal human cells can be induced in response to multiple stimuli, incl. the spontaneous and stochastic activation of oncogenes. As a result, senescence is viewed as an inherent anti-tumour mechanism in our bodies. However, we recently revealed a molecular mechanism involving 3D genome reorganization events that can fuel the “escape” individual cell clones from senescence and drive them towards a state of malignancy (see Zampetidis et al., Mol Cell 2022). This, and our work on the role of 3D genome architecture changes upon commitment to senescence, motivated us to start exploring our “rheostat” hypothesis for the maintenance of homeostasis in the face of either cell ageing or senescence (see Papantonis, Trends Genet 2021). We have now started using patient-derived organoids and stem cells in 3D and single-cell genomics assays to find how chromosomal architecture drives malignant transformation.