Last month, we held the second edition of the EMBO | EMBL Symposium series ‘The ageing genome: from mechanisms to disease‘ at EMBL Heidelberg and virtually.

Ageing is a complex process affecting multiple organs. Five core molecular mechanisms, known as the ‘Primary Hallmarks of Ageing’, are believed to drive this process.

To continue the exchange on the basic/mechanistic aspects of chromosome biology within the applied and emerging field of ageing sciences, this symposium brought together an international line-up of speakers from many diverse fields across topics, who investigate genomic changes during the ageing process. An emphasis on the importance of chromatin changes and telomere dysfunction was made, keeping in mind how they also affect DNA damage and repair responses.

During the four-day conference, there were 88 on-site and 63 remote participants. The press, media partners, and 5 sponsors helped make this event a success. During two poster sessions 53 aspiring scientists presented their posters and participants voted for four winners.

We are pleased to introduce you to Dalya, Sarah, Xinran, and Shoma, and share their abstracts!

Consequences of age-related G-quadruplex formation for the fidelity of mammalian transcription

Presenter: Dalya Hiluf
Authors: Dalya Hiluf, Antonios Papadakis, Argyris Papantonis , Andreas Beyer, Robert Hänsel-Hertsch

Abstract:

DNA can adopt alternative conformations in living cells, including G-quadruplex (G4) structures (Hänsel et al., 2009, 2013). G4s are stable, four-stranded DNA configurations that can stall replication forks and impede transcription, resulting in replication stress and double-strand breaks that drive genomic instability. DNA helicases such as BRIP-1/FANCJ, WRN, and BLM efficiently resolve G4s in vitro, thus preventing such instability.
High-throughput sequencing has revealed that G4 structures are enriched in nucleosome-depleted regions (NDRs), which are controlled by transcription factors (TFs). Hence, G4 landscapes inform on transcriptional programs but also serve as epigenomic biomarkers for genome instability and gene activity (Hänsel-Hertsch et al.,
2016, 2020). Moreover, many TFs directly bind to G4s to regulate transcription, indicating
that G4 landscapes may predict TF activity (Spiegel…Hänsel-Hertsch et al., 2021).
Epigenetic alterations and genomic instability are hallmarks of aging and cancer, yet
whether these factors affect transcriptional fidelity remains unclear. Sirtuins—proteins
associated with aging—decline in activity with age and are known to regulate helicases that resolve G4s and R-loops. Dysfunction in sirtuin activity may therefore lead to helicase
failure, resulting in the accumulation of G4s and R-loops (Frobel and Hänsel-Hertsch 2024). This accumulation could stall polymerases, introduce transcriptional errors, and ultimately disrupt protein homeostasis.
We hypothesize that sirtuin dysfunction disrupts helicase activity, leading to increased G4
and R-loop levels, which in turn compromise transcription fidelity and proteostasis. To test
this hypothesis, we will perturb sirtuin activity, identify the interacting helicases, and map
genome-wide changes in G4 and R-loop structures. We will then assess the impact on
transcriptional accuracy and protein folding in a replicative senescence model. This project aims to provide mechanistic insight into how age-related decline in sirtuin function contribute to genome instability and proteostasis defects.

References

1. Hänsel R, Löhr F, Trantirek L & Dötsch V (2013) High-Resolution Insight into GOverhang
   Architecture. Journal of the American Chemical Society 135: 2816–2824
2. Hänsel-Hertsch R, Beraldi D, Lensing SV, Marsico G, Zyner K, Parry A, Di Antonio M,
   Pike J, Kimura H, Narita M et al (2016) G-quadruplex structures mark human regulatory
   chromatin. Nature genetics 48: 1267–72
3. Hänsel-Hertsch R, Simeone A, Shea A, Hui WWI, Zyner KG, Marsico G, Rueda OM,
   Bruna A, Martin A, Zhang X et al (2020) Landscape of G-quadruplex DNA structural
   regions in breast cancer. Nat Genet 52: 878–883
4. Spiegel J, Cuesta SM, Adhikari S, Hänsel-Hertsch R, Tannahill D & Balasubramanian S
   (2021) G-quadruplexes are transcription

Due to the confidentiality of the unpublished data, we cannot share the poster

Aging promotes reactivation of the barr body at distal chromosome regions

Presenter: Sarah Hoelzl
Authors: Sarah Hoelzl, Tim Hasenbein, Stefan Engelhardt, Daniel Andergassen

Abstract:

Decades ago, evidence of age-related reactivation of a single gene on the female inactive X chromosome (Xi) was observed in mice. While stable maintenance of the Xi is crucial for balancing X-linked gene dosage between the sexes, the long-term stability of the epigenetically silenced Barr body during aging remains unexplored. Here, we employed
allele-specific multi-omics approaches in a highly polymorphic mouse model to capture a
comprehensive catalog of genes that escape X chromosome inactivation throughout development and aging.

In adult tissues, we identified both constitutive and organ-specific escape genes, along with nearby cell-type-specific escape, suggesting a clustered organization of gene reactivation. With aging, escape rates substantially increased across multiple organs. This age-specific escape occurred in several distinct cell types and was enriched at distal chromosome regions, pointing to the contribution of age-associated epigenetic changes to Xi instability. Consistent with this, chromatin accessibility increased over megabase-wide domains at chromosome ends during aging and overlapped with DNA regulatory elements at escape sites, indicating that these elements may drive age-specific escape. Since several age-specific escape genes are associated with human disease, their elevated expression in females may contribute to the sex-biased development and progression observed in age-related diseases.

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Haematopoietic stem cell longevity and telomere maintenance in mouse and human

Presenter: Xinran Huang
Authors: Xinran Huang, Yavor Bozhilov, Jill Brown, Ashley Kamimae-Lanning, Duncan Baird,Adam Wilkinson, KJ Patel

Abstract:

Haematopoietic stem cells (HSCs) are a rare adult stem cell population and are mostly quiescent in vivo. It remains unclear whether HSCs can maintain their telomeres and proliferate in culture without reaching replicative senescence, as no method for stably maintaining long-term HSC cultures previously existed. Using a serum-free, polyvinyl-alcohol-based ex vivo expansion system [1], we continuously cultured primary mouse HSCs for up to six months – the longest reported HSC-derived cultures to our knowledge. Mean telomere length remained stable over time as detected by quantitative fluorescence in situ hybridisation (Q-FISH), and telomerase activity was detected throughout the culturing period. However, long-term cultures showed a reduced frequency of
immunophenotypic HSCs (Lineage- cKit+ Sca1+ CD150+ CD201+) and diminished reconstitution ability. In contrast, human CD34+ HSCs can only be expanded for one to two months in a similar ex vivo culture system [2]. When comparing early and late human HSC cultures, significant reductions in telomere lengths were detected using Q-FISH, and the initial telomere lengths of human HSC cultures correlated with their replicative potential. However,
single telomere length analysis (STELA) showed no significant changes in the telomeric end of chromosome 17p. It is possible that longer telomeres are eroded while shorter telomeres are preferentially elongated by telomerase, explaining the loss of Q-FISH signal intensities but maintenance of the shorter 17p telomeres. Ongoing Telo-Seq analysis using Oxford Nanopore long-read sequencing will provide chromosome-specific quantification of telomere lengths in human HSC cultures over time.
The discrepancy between mouse and human HSCs in their ability to maintain telomeres and expand ex vivo suggests that telomere maintenance may be a limiting factor in human HSC expansion. This work will provide further insights into HSC longevity and telomere biology, with potential therapeutic implications.
Resources:
[1] Wilkinson, A. C. et al. Long-term ex vivo haematopoietic-stem-cell expansion allows
nonconditioned transplantation. Nature 571, 117–121 (2019).
[2] Sakurai, M., Ishitsuka, K., Ito, R. et al. Chemically defined cytokine-free expansion of
human haematopoietic stem cells. Nature 615, 127–133 (2023).

Due to the confidentiality of the unpublished data, we cannot share the poster

Non-cell-autonomous control of stress surveillance by telomere deprotection

Presenter: Shoma Ishikawa
Authors: Shoma Ishikawa, Maria Khachatryan, Bjoern Schumacher

Abstract:

Telomeres are a prerequisite for the maintenance and inheritance of genetic information by protecting chromosome ends. Telomere damage signals trigger cellular senescence or cell death that acts as a cell-intrinsic barrier against unrestrained proliferation and oncogenic transformation. However, little is known about systemic responses to telomere instability and
their physiological consequences. Here, we show that depleting the telomere-binding protein complex shelterin in the germline promotes organismal healthspan and lifespan in the nematode C. elegans without overt reproductive cost. Telomere deprotection-driven longevity is mediated by the enhancement of mitophagy through the HLH-30/TFEB transcription factor and the PMK-1/p38 stress signaling in the soma. The somatic stress surveillance also controls the apoptotic elimination of germ cells depleted of shelterin, which in turn promotes longevity. In addition, activation of PMK-1-dependent stress signaling upon telomere deprotection regulates meiotic chromosome integrity thus preserving heritable euploidy. Our study highlights an unprecedented role of chromosome end protection in systemically coordinating stress surveillance mechanisms that regulate organismal survival
and reproductive fidelity, ensuring chromosome inheritance.

Due to the confidentiality of the unpublished data, we cannot share the poster

The EMBO | EMBL Symposium ‘The ageing genome: from mechanisms to disease’ took place from 10 – 13 June 2025 at the EMBL Heidelberg Advanced Training Centre and Vitual.