Telo-seq, a new tool, is revolutionizing the study of telomeres. It allows scientists to investigate the role of telomeres in aging and cancer in ways that were not possible before. The discoveries made using Telo-seq will pave the way for innovative treatments for age-related diseases that target telomeres.
In our cells, DNA is organized into chromosomes and protected by telomeres. As we age, these telomeres gradually shorten, leaving our chromosomes vulnerable and leading to cell death. The details of this shortening process and its effects were previously not fully understood.The issue of how telomere length changes with age and if certain chromosomes are more affected than others has been unclear until now. Scientists at the Salk Institute have created an innovative tool called Telo-seq, which is intended to transform the study of telomeres in aging and disease. This new technique, unlike existing methods, can sequence entire telomeres and accurately measure their length on each individual chromosome, rather than just the average length across all chromosomes. The researchers are currently using Telo-seq to uncover new insights into telomere dynamics.The research, which was published in Nature Communications on June 18, 2024, will have a significant impact on studies related to telomeres and their role in human health and disease. This breakthrough will likely lead to an increase in research and the development of new therapies targeting telomeres to treat age-related illnesses.
Senior author of the study, Jan Karlseder, who is a professor, chief science officer, and holds the Donald and Darlene Shiley Chair for Research on Aging at Salk, expressed how previous methods for measuring telomere length were not accurate and had low resolution. This limited the ability to test hypotheses about the role of individual telomeres in aging and cancer. However, with the new findings, these hypotheses can now be properly investigated.Karlseder and his team worked with specialists at Oxford Nanopore Technologies to integrate elements of their long-read sequencing method with new biochemistry and bioinformatics approaches. This resulted in a technique that starts at the end of each telomere and extends into the subtelomere region. By doing so, the scientists are able to determine the chromosome they are analyzing and closely examine its telomere structure and composition.
This new method has enabled the researchers to uncover previously inaccessible aspects of telomere biology. Their observations have revealed new insights into the features of telomere biology that were previously unknown to scientists.The length of telomeres on each chromosome arm in individual human samples can vary, and their shortening rates can also differ significantly. These dynamics are not consistent across different tissues and cell types within the same person, and may be influenced by factors such as stress and inflammation affecting various parts of the body. This indicates that there are potential chromosome arm-specific factors that impact telomere dynamics in aging and disease.
“Aging affects everyone differently,” says Karlseder. “We are very interested in understanding how these differences are related.”
The Telo-seq method is a powerful tool for studying telomeres and their role in aging and diseases. It can reveal differences in telomere shortening rates between individuals and chromosomes, and potentially help in slowing down this process to promote healthy aging. Additionally, Telo-seq can improve our understanding of telomere-related diseases, such as telomeropathies, which involve stem cells running out of telomere length and losing their ability to divide into new, functional cells. This can result in conditions like hair loss, immune disorders, and certain cancers. Telo-seq will enable scientists to investigate whether these diseases are inherited within families or associated with individual chromosomes, leading to more targeted interventions.determine whether a cell is using the telomerase enzyme or the ALT mechanism to repair its damaged telomeres. This allows for a better understanding of how different maintenance mechanisms affect the length and composition of telomeres. Additionally, Telo-seq provides a more efficient way for scientists and clinicians to measure telomere maintenance, which can have significant implications for cancer research and treatment.”The first author, Tobias Schmidt, a postdoctoral researcher in Karlseder’s lab, states that it is crucial to determine whether a cancer is telomerase-positive or ALT-positive. He explains that ALT-positive cancers are often more aggressive and require different treatment approaches than telomerase-positive cancers. Schmidt suggests that Telo-seq could be used as a quick and reliable diagnostic tool to identify cancer types and guide more personalized treatment plans.
In addition to its immediate clinical applications, Karlseder and Schmidt believe that Telo-seq will have a significant impact on igniting a new era of telomere research.
Karlseder and Schmidt anticipate that Telo-seq will enable them to address important questions about telomeres and their role in cancer development.”We have been able to address questions about development, aging, stem cells, and cancer that were previously impossible to answer with our new tools,” says Karsleder. “We have barely scratched the surface of what we can learn, and I believe that the knowledge we are starting to gain now is just the beginning. This is a very exciting time for telomere science.”
Additional authors on the study include Candy Haggblom, Jeffrey R. Jones, and Fred H. Gage from Salk, Kelly A. Frazer from UC San Diego, and Carly Tyer, Preeyesh Rughan, Xiaoguang Dai, Sissel Juul, and Scott Hickey from Oxford Nanopore Technologies, Inc.
This research received support from the National Institute of Aging (P30AG068635, AG0773424), the NatThe research was funded by various organizations including the National Cancer Institute, the National Institute for General Medicine, the Helmsley Charitable Trust, the Shiley-Marcos Alzheimer’s Disease Research Center at UC San Diego, the European Molecular Biology Organization, the JBP Foundation, the Paul F. Glenn Center for Biology of Aging Research at Salk Institute, and the AHA-Allen Initiative in Brain Health and Cognitive Impairment award from the American Heart Association and The Paul G. Allen Frontiers Group.
