Regulation and Function of Human Telomere-Position-Effects

• Applicant: Dr. Kathrin Jäger
• Subject Area: Biogerontology and Geriatric Medicine
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 570620554

Telomeres are repetitive nucleotide sequences at chromosome ends. Long telomeres can silence genes located megabases away via a looping mechanism known as telomere position effect over long distances (TPE-OLD). This contrasts with the classical telomere position effect observed in yeast and Drosophila, which relies on heterochromatin spreading near the telomere. While a tumor-suppressive role has been proposed for TPE-OLD, its physiological relevance remains poorly understood. Preliminary, unpublished data indicate that TBP, encoding the TATA-binding protein and known for its high positional conservation across species, is regulated by TPE-OLD. TBP is of particular interest due to (1) its essential role in transcription initiation as part of the TFIID complex, (2) its proximity to the telomere (<200 kb), potentially allowing classical spreading mechanisms, and (3) previous indications that it is subject to telomere-independent, likely epigenetic, regulation. This first-year project will investigate TBP expression and chromosomal positioning across a panel of human fibroblast cell lines spanning a wide age range—from newborns to centenarians—to model chronological and replicative aging. The following questions will be addressed: Does TBP expression follow the TPE-OLD pattern (repression by long telomeres and reactivation with high population doublings but not in stress-induced senescence)? Are donor age–dependent effects detectable? Could differential CpG methylation contribute to TPE-OLD regulation? Follow-up studies will address the role of epigenetics in telomere-mediated gene silencing and examine whether disruptions in telomere–gene interactions, such as CAG repeat expansions, are involved in chronic disorders like amyotrophic lateral sclerosis or Hutchinson–Gilford progeria. The methods include telomerase-mediated immortalization, 3D-FISH, HiPore-C for topological mapping, chromosome-specific telomere length measurement, and methylation analysis using nanopore sequencing and array-based approaches. The overall aim is to elucidate the mechanisms and functional implications of TPE-OLD. These studies may improve our understanding of age-related gene regulation and inform novel approaches to mitigate chronic age-associated diseases.

• DFG Programme: Research Grants