Epigenetic transgenerational inheritance of paternal DNA damage

1 PhD projects offered in the IPP winter call 2023/2024

Scientific Background

DNA damage poses a major threat to genome stability, chromosomal integrity, and cellular function. To ensure a successful process of DNA repair, chromatin serves as a platform and is dynamically changed during the DNA damage response (DDR), as described by the Access-Repair-Restore model. As a crucial part of chromatin, histones are post-translationally modified via methylation, ubiquitination, and acetylation to regulate DDR-related chromatin functions. Importantly, in contrast to the transient process of DNA repair, many histone modifications can leave a long-term epigenetic memory in cells and can be passed down to further generations, raising the question of whether DNA damage could reshape the epigenome in the damaged cells and even affect their descendants.

Epigenetic modifications are renowned for its role in the transgenerational inheritance of various traits such as longevity, diabetes and obesity. However, whether DNA damage-induced epigenetic alteration can lead to a transgenerational effect is still unknown. Previous studies based on epidemiological data cannot reach a clear conclusion, as contradictory observations were obtained from the children born in the vicinity of the nuclear power plants. Moreover, genetic studies on the progeny of the clean-up workers from the Chernobyl accident and survivors of the atomic bomb in Hiroshima and Nagasaki showed no evidence of a transgenerational effect. In contrast, a recent study showed that paternal exposure to chemotherapy before conception correlates with rare genetic diseases in the progeny, raising the question of whether paternal DNA damage can lead to a transgenerational effect.

Due to the complexity of human epigenetics, we used C. elegans as a model to study the role of histone modifications on genome stability and transgenerational inheritance.

PhD Project: “Transgenerational epigenetic memory of paternal DNA damage”

The transgenerational effect of DNA damage has been previously studied through epidemiological and genetic approaches, but these have yielded contradictory results. Recently, we identified a novel mechanism that underlies the transgenerational genetic and epigenetic effects of paternal DNA damage. Using sex-separated C. elegans strains, we found that paternal, but not maternal, exposure to ionizing radiation (IR) leads to transgenerational embryonic lethality. This lethality is caused by the persistence of DNA double-strand breaks (DSBs) in the F1 generation, where a highly enriched heterochromatin structure blocks the accessibility of homologous recombination (HR) repair machinery. This project will investigate how DNA damage in sperm alters the epigenome of the offspring, and whether these changes in the epigenome can affect genome stability and longevity of the subsequent generations. Via answering these questions, we aim to identify potential therapeutic approaches to improve the genome stability of the worms carrying paternally inherited DNA DSBs.

If you are interested in this project, please select Wang as your group preference in the IPP application platform.

Publications relevant to this project

Wang, S., Meyer, D.H. & Schumacher, B. Inheritance of paternal DNA damage by histone-mediated repair restriction. Nature 613, 365–374 (2023).

Panier, S., Wang, S., Schumacher, B.  Genome instability and DNA repair in somatic and reproductive aging. Annu Rev Pathol. (In press) (2023).