Notre unité invite Pierre Chymkowitch, Associate Professor – Group leader: Transcriptional Regulation Of Cell Fate (Department of Biosciences – University of Oslo – Norway) à présenter ses travaux lors d’un séminaire exceptionnel.

« Understanding the Role of Mitotic Chromosome Condensation and SUMOylation in Maintaining Cellular Identity and Homeostasis ».

📆 Lundi 10 juin – 10h
📌 Bâtiment Bordeaux Biologie Santé – BBS, 2 rue Dr Hoffmann Martinot, 33000 Bordeaux
Lien zoom sur demande (sarah.lesjean@inserm.fr)

Abstract:
Preservation of gene expression patterns that define cellular identity is essential to perpetuate cellular lineages and preserve homeostasis. During this presentation I will feature published and unpublished data indicating how transcriptional and epigenetic identities are conserved throughout cell division and differentiation.
Mitotic entry correlates with the condensation of the chromosomes, changes in histone modifications, exclusion of transcription factors from DNA, and the broad downregulation of transcription. We found that preventing one chromosome to condense during mitosis causes it to fail resetting transcription. Rather, in the following interphase, the affected chromosome contains unusually high levels of the transcription machinery, resulting in abnormally high gene expression levels, including various transcription factors. This subsequently causes the activation of inducible transcriptional programs in trans, even in the absence of the relevant stimuli. Thus, mitotic chromosome condensation exerts stringent control on interphase gene expression to ensure the maintenance of cell identity across cell divisions (1).
We used adipogenesis as a model to find that SUMOylation of chromatin-bound proteins ensures the precision of gene expression and transcription factor dynamics during differentiation (2). However, the molecular mechanisms by which SUMOylation orchestrates the rewiring of transcriptional programs during initiation of differentiation remains to be established. Our unpublished data indicate that transient, pharmacological inhibition of SUMOylation in human preadipocytes is sufficient to prime and activate specific enhancers and transcription factors. This causes irreversible hypertranscription of adipogenic genes, leading to excessive fat accumulation. Given that epigenetic and transcriptional regulators are major SUMO targets, we propose that SUMOylation maintains a chromatin landscape in undifferentiated cells, which is critical to preserving the epigenetic fate of mature adipocytes, protecting against unrestricted adipogenic transcription. This implies that the inherent adipogenic capacity of human adipose stem cells may be tied to SUMOylation and suggests an epigenetic basis for the inter-individual variability in fat accumulation.
Using adipogenesis as a paradigm to uncover new molecular pathways by which SUMOylation sustains epigenetic fates, we expect to contribute to a broader understanding of how transitory disruptions in epigenetic regulation induce stable homeostatic shifts and lead to disease, like obesity and cancer (3).

1. Ramos-Alonso, L. et al. Mitotic chromosome condensation resets chromatin to safeguard transcriptional homeostasis during interphase. Proc Natl Acad Sci U S A 120, e2210593120 (2023). https://doi.org:10.1073/pnas.2210593120
2. Zhao, X. et al. Waves of sumoylation support transcription dynamics during adipocyte differentiation. Nucleic Acids Res 50, 1351-1369 (2022). https://doi.org:10.1093/nar/gkac027
3. Parreno, V. et al. Transient loss of Polycomb components induces an epigenetic cancer fate. Nature (2024). https://doi.org:10.1038/s41586-024-07328-w

Bio:

I obtained a PhD from the University of Strasbourg in 2008. My research in the group of Jean-Marc Egly, at the IGBMC, was focused on revealing the origin of gene expression defects in patients with rare genetic disorders like Xeroderma pigmentosum (1).
I then moved to Norway at the Dept. of Microbiology at Oslo Univ. Hospital. For the next eight years, I continued my research in the group of JM. Enserink on gene regulation in the model organism Saccharomyces cerevisiae. The first four years were dedicated to revealing mechanisms that synchronize cell-cycle progression and gene expression (2). In the next four years I strated investigating the mechanisms regulated by the Small Ubiquitin-like Modifier SUMO at the chromatin level during adaptive response to stress (3) and started exploring the perpetuation of epigenetic and transcriptional memory throw-out mitosis (4).
Next, I started my group at Oslo Univ. Hospital and was appointed Associate Professor at the University of Oslo, where I have been working since 2020. Our focus is unraveling the mechanisms supporting epigenetic and transcription fidelity (5) during cellular differentiation, with a particular focus on how the SUMOylation pathway supports cellular fate (6,7).

References:

1. Chymkowitch, P., Le May, N., Charneau, P., Compe, E. & Egly, J. M. The phosphorylation of the androgen receptor by TFIIH directs the ubiquitin/proteasome process. EMBO J 30, 468-479
   (2011). https://doi.org:10.1038/emboj.2010.337
2. Chymkowitch, P. et al. Cdc28 kinase activity regulates the basal transcription machinery at a subset of genes. Proc Natl Acad Sci U S A 109, 10450-10455 (2012). https://doi.org:10.1073/pnas.1200067109
3. Chymkowitch, P. et al. TORC1-dependent sumoylation of Rpc82 promotes RNA polymerase III assembly and activity. Proc Natl Acad Sci U S A 114, 1039-1044 (2017). https://doi.org:10.1073/pnas.1615093114
4. Kruitwagen, T., Chymkowitch, P., Denoth-Lippuner, A., Enserink, J. & Barral, Y. Centromeres License the Mitotic Condensation of Yeast Chromosome Arms. Cell 175, 780-795 e715 (2018). https://doi.org:10.1016/j.cell.2018.09.012
5. Ramos-Alonso, L. et al. Mitotic chromosome condensation resets chromatin to safeguard transcriptional homeostasis during interphase. Proc Natl Acad Sci U S A 120, e2210593120 (2023). https://doi.org:10.1073/pnas.2210593120
6. Zhao, X. et al. Waves of sumoylation support transcription dynamics during adipocyte differentiation. Nucleic Acids Res 50, 1351-1369 (2022). https://doi.org:10.1093/nar/gkac027
7. Bjune, J.-I. et al. Mechanisms of the FTO locus association with obesity: Irx3 controls a sumoylation-dependent switch between adipogenesis and osteogenesis. bioRxiv,
   2023.2010.2017.562662 (2023). https://doi.org:10.1101/2023.10.17.562662