Mots-Clés
Cellular senescence
aging
epigenetics
transcriptome
DNA accessibility
gene regulatory network
Description
Context
Cellular senescence (CS) is a complex stress response implicated in multiple age-related diseases, including diabetes, cancer, and Alzheimer’s disease. As a result, the elimination or reprogramming of senescent cells has proven beneficial in treating aged mouse models, and several senotherapeutics are currently being tested in clinical trials. The senescent phenotype arises from profound, dynamic remodeling of the epigenetic and transcriptomic landscape, orchestrated by a hierarchical network of transcription factors (TFs). Despite substantial advances in determining the molecular mechanisms regulating CS, a comprehensive framework that can explain and predict CS dynamics is still lacking.
Objectives
This project aims to unravel how epigenetic mechanisms control gene expression in cells
undergoing senescence. Our laboratory has generated matched datasets of gene expression, chromatin accessibility, and histone modifications from RAS-driven oncogene-induced senescence (RAS-OIS) in fibroblasts, myofibroblasts, and mesenchymal stem cells. These data will enable us to infer TF–chromatin binding events that control gene transcription in silico and to quantitatively assess age-related signatures using state-of-the-art molecular aging clocks.
The successful candidate will utilize both in-house and publicly available repositories containing bulk and single-cell datasets to infer the underlying gene-regulatory networks in the context of CS.
We will explore multiple approaches to integrate these datasets, which will be tailored to the
candidate’s skills and preferences. These approaches include, but are not limited to:
- TF interaction network analysis over time;
- TF enrichment from target gene sets;
- Machine learning methods for exploratory and predictive analyses, focusing on
explainable architectures.
Relevant team publications
Martínez-Zamudio, R. I., Roux, P. F., de Freitas, J. A. N., Robinson, L., Doré, G., Sun, B., … & Bischof, O. (2020). AP-1 imprints a reversible transcriptional programme of senescent cells. Nature cell biology, 22(7), 842-855. https://doi.org/10.1038/s41556-020-0529-5
Martínez-Zamudio, R. I., Stefa, A., Freitas, J. A. N. L. F., Vasilopoulos, T., Simpson, M., Doré, G., … & Herbig, U. (2023). Escape from oncogene-induced senescence is controlled by POU2F2 and memorized by chromatin scars. Cell Genomics, 3(4). https://doi.org/10.1016/j.xgen.2023.100293
Computational Modeling of Aging-Related Gene Networks: A Review. Freitas, J. A. N. L. F., &
Bischof, O. Frontiers in Applied Mathematics and Statistics. 10:1380996. DOI:
10.3389/fams.2024.1380996
Team
The SENCODE Team (SENescence, Vulnerability, and ChrOnic DisEases) is a research team at Institut Mondor de Recherche Biomédicale in Créteil, France, led by Geneviève Derumeaux. We investigate how cellular senescence — the process of permanent cell aging — contributes to chronic diseases, with particular focus on pulmonary conditions (pulmonary hypertension and COPD) and cardiometabolic disorders (heart failure with preserved ejection fraction related to obesity). Composed of researchers, clinical faculty, practitioners, postdoctoral fellows, and doctoral students affiliated with UMR U955 INSERM-UPEC and the Faculté de Santé de Créteil, SENCODE works to understand how senescent cells accumulate and damage tissues to develop new therapeutic approaches for age-related diseases.
https://imrb.inserm.fr/equipes/g-derumeaux/