PHYSIOLOGICAL CAUSES AND CONSEQUENCES OF GENOME INSTABILITY

Epigenetic Regulation of Cellular Homeostasis Amid Transcription-Blocking DNA Damage During Development and Aging, project 3

The research project focuses on how epigenetic mechanisms, particularly the deposition of H3K4me2 by the MLL/COMPASS complex, are regulated in response to transcription-blocking DNA damage. It investigates how this histone modification aids in the recovery of transcription elongation and the maintenance of cellular homeostasis during both development and aging. Using *C. elegans*, the study seeks to understand the physiological consequences of genome instability, particularly how impaired or enhanced deposition of H3K4me2 influences growth and longevity .

Radiation biology and DNA repair

Prof. Jörg Kobarg (University of Campinas)

His research group investigates the role of specific proteins in processes such as DNA damage repair, cellular stress response, and cancer development. One key aspect of his work involves studying protein-protein interactions and their implications for understanding how cells maintain genomic stability under stress conditions. Prof. Kobarg’s work has significant applications in cancer biology, as it aims to identify potential therapeutic targets by exploring the molecular mechanisms that drive tumor development and progression.

While humans and house mice develop kidney failure upon injury, the spiny mouse has a unique mechanism to repair kidney injury and prevent concomitant permanent kidney failure. My aim is to decipher the unique regenerative capacity by identifying the master switches which are repressed in humans and house mice by using tubuloids of spiny mice. The master switches can be targets in future regenerative medicine applications.

We aim to explore the causes and consequences of deregulated DNA repair to explain important phenotypes observed in our novel human genome instability syndromes. Importantly, these insights will serve as a blueprint to understand the intricate relationship between the DDR, protein homeostasis and neurodegeneration. 

Environmental Stress and Chromatin Dynamics: Investigating Epigenetic Responses in C. elegans

Dr. Daphne Selvaggia Cabianca's research at the Helmholtz Institute Munich focuses on how environmental factors influence chromatin organization and function. Using *C. elegans* as a model organism, her group explores how changes in diet, temperature, and other external stimuli impact the spatial architecture of chromatin and gene expression. A key area of her work is understanding how chromatin modifications can contribute to "stress memory," enabling organisms to respond more effectively to future stress. Her lab employs advanced techniques such as CRISPR-Cas9, RNAi screens, and live-cell microscopy to investigate how metabolic changes affect chromatin states and their broader effects on organismal health.

Telomere Biology and Cancer: Unraveling the Role of Chromatin and DNA Repair in Genome Stability

Seminar talk in cooperation with the Cologne Graduate School of Ageing Research (CGA).

Dr. Roderick O'Sullivan's research at UPMC Pittsburgh focuses on understanding how telomeres, the protective caps at the ends of chromosomes, maintain genome stability. His lab investigates the proteins that regulate telomere structure and function, particularly within the Alternative Lengthening of Telomeres (ALT) pathway, which is implicated in certain cancers. By studying chromatin dynamics and DNA repair mechanisms at telomeres, O'Sullivan aims to uncover how telomere dysfunction can lead to genomic instability, a hallmark of cancer. His research also explores how modifications like poly-ADP-ribosylation impact telomere maintenance and cellular aging.

Sara and Anja are investigating how mechanical stress leads to DNA damage and affects genome mechanoprotection in cellular and organismal homeostasis. Their work focuses on uncovering the mechanisms through which physical forces trigger chromatin changes, replication stress, and DNA damage. This project aims to enhance our understanding of the role of mechanical stress in genome stability and its broader implications for tissue functionality.

A damage driven transcription stress on aging and the effect of calorie restriction, project 7

Joris investigates how chronic genome instability disrupts tissue homeostasis, focusing on transcriptional stress and its systemic impacts during aging. Using progeroid DNA-repair-deficient mouse models, he revealed that transcriptional stalling induces metabolic dysfunction and accelerates tissue degeneration, including neurodegeneration. His groundbreaking discovery of dietary restriction as a therapy shows it mitigates DNA damage, reprograms metabolism, and significantly extends lifespan, offering a translational approach to aging-related diseases.

DNA Damage Tolerance: Physiological and Cancer Therapeutic Relevance

Seminar talk by Dr. Heinz Jacobs from Netherlands Cancer Institute Antoni Van Leeuwenhoek.

DNA Damage Tolerance is Essential for Hematopoietic Stem Cell Maintenance and Mammalian Life
Stem cells are key players in central biological processes, such as tissue homeostasis, ageing, and cancer formation. Stem cell depend on genome maintenance to prevent disease formation. DNA damage tolerance (DDT) pathways enable DNA replication in the presence of replication impediments and are regulated by PCNAK164 ubiquitination and REV1. The failure to generate PcnaK164R/K164R;Rev1-/- deficient mice revealed DDT as essential for mammalian life. The compound mutation rendered hematopoietic stem cells (HSCs) and the hematopoietic precursors genetically unstable, instigating a pathological process where the associated HSC depletion culminated in a severe, embryonic-lethal anemia. Single cell RNA-sequencing of the remaining HSCs and progenitors identified CD24Ahigh and CD93low erythroid-biased progenitors (EBP) within the Lineage-, Sca1+, cKit- (LSK) population. In line, this subset was found to depend on the erythroid transcription factor Klf1. In conclusion, DDT is an essential activity within the DNA damage response network and in maintaining HSC fitness. By studying this system, we identified an erythroid-biased progenitor subset within the LSK compartment.