Deciphering gene regulatory networks driving aging and rejuvenation in the human endothelium at single-cell resolution

• Applicant: Dr. Felipe Francisco Lüttmann
• Subject Area: General Genetics and Functional Genome Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 561598351

Gene regulatory networks (GRNs) consist of an intricate interplay of epigenetic modalities such as transcription factors (TF), chromatin accessibility and histone modifications that modulate gene expression. By orchestrating transcriptional patterns, GRNs confer cellular identity and perturbation of GRNs causes aging. In the endothelium, aging is associated with permanent cell-cycle arrest, called senescence, which comes along with secretion of proinflammatory cytokines. This senescence-associated secretory phenotype in the vascular system enables cancer metastasis and precedes many cardio-vascular diseases. A promising approach to counteract these adverse aging-related effects is to restore GRNs to a more youthful state by the transient expression of the TFs OCT4, SOX2, KLF4 and c-Myc (OSKM). However, forced expression of OSKM is associated with an inherent risk of tumorigenesis and the effects of OSKM on senescence as well as the stochastic shifts in GRNs in individual cells remain elusive. In this project, I will use an mRNA-based approach to deliver OSKM in a temporal controlled fashion in aged human endothelial cells. To dissect the epigenetic underpinnings during OSKM-driven rejuvenation, gene expression, distribution of histone modifications and chromatin accessibility will be profiled at single-cell level. Thereby, this project aims to shed light on the dynamic shifts of GRNs and their underlying key regulators during partial reprogramming of the aged senescent human endothelium at unprecedented resolution. This knowledge shall pave the way for safer and more effective strategies to counteract age-related vascular diseases.

• DFG Programme: WBP Position