Telomere fusions in cancer. In recent years, we have used whole-genome sequencing data to study the rates and spectrum of somatic telomere fusions (TFs) in over 30 different types of cancer. Our findings indicate that TFs are widespread in human tumors, with rates that vary greatly between and within different types of cancer. In addition to end-to-end fusions, we have identified unique patterns of TFs that are linked to the activity of the alternative lengthening of telomeres (ALT) pathway. One particularly exciting discovery has been the detection of TFs in the blood of cancer patients, offering a potential method for early cancer detection with high specificity and sensitivity. This is especially promising for cancer types such as pancreatic cancer and brain tumors, which currently have limited options for early detection. Through biochemical, molecular, CRISPR/Cas, and genomic (NGS) techniques, we will continue to investigate the occurrence and function of telomere fusions in various human and mouse tumors. Understanding the role of TFs in cancer will be crucial in developing targeted therapies and improving patient outcomes.

Telomere fusions (TF) in cardiomyocyte maturation and heart regeneration. Maturation in many mammalian cells, including cardiomyocytes, is accompanied by an increase in the number of chromosomes, or polyploidization. This increase in chromosome sets may contribute to the limited ability of mature cardiomyocytes to divide after a damage, as polyploid cells are often unable to undergo successful cell division. While the importance of cardiomyocyte polyploidy is well-recognized, the mechanism behind it is not understood. In recent years using a high-content imaging approach, we have discovered that approximately half of postnatal mouse cardiomyocytes that enter mitosis have discernible chromosome bridges. Furthermore, we observed that the ploidy of cardiomyocytes is tracked by an increasing number of fusions between chromosome ends, providing evidence of a direct link between TFs and cardiomyocyte polyploidization. We also found that TFs are a conserved phenomenon, present in the hearts of mice, zebrafish, pigs, and humans. Importantly, zebrafish hearts, which are able to regenerate and have mostly diploid cardiomyocytes, have few TFs. In fact, deleting telomerase to inhibit zebrafish regeneration increased the number of polyploid cardiomyocytes, supporting the idea that cardiomyocyte polyploidization impairs heart regeneration. Together these results identify TFs as a mechanism leading to chromosome bridging and polyploidization and suggest that failed cardiomyocyte cytokinesis originates from a mitotic defect. We are currently investigating whether fine-tuned regulation of telomerase avoids the presence of TFs, increases the number of diploid cardiomyocytes, and extend the cardiomyocyte proliferation and heart regeneration window. Our findings suggest that regulating the presence of TFs may be key to enhancing cardiomyocyte proliferation and heart regeneration.