Final Report Summary - TEL STEM CELL (FROM TELOMERE CHROMATIN TO STEM CELL BIOLOGY)
We have established that genetic manipulations that lead to a faster rate of telomere shortening (telomerase-deficiency) could accelerate ageing, while genetic modifications that slow down the rate of telomere shortening (by telomerase activation) delay ageing and extend longevity. Our results have led to the hypothesis that organismal ageing is mainly caused by telomere shortening and to propose that therapeutic strategies aimed to activate telomerase could be effective in both disease treatment and prevention. Our findings are proof of principle that telomere shortening with ageing due to telomerase deficiency is one of the main causes of ageing and disease in the adult organism, and that telomerase reactivation is sufficient to delay ageing and age-related diseases and to increase longevity, establishing thus telomere length and telomerase activity as one of the Hallmarks of Ageing.
We have generated gain-of-function and loss-of-function conditional mouse models for all the telomeric proteins. Using the former tools we have discovered that telomeric proteins are responsible for premature ageing and increased cancer risk. Our functional studies focusing on mouse models with altered expression of the telomeric proteins TRF1 and TPP1 constitute the demonstration for the first time ever that a telomeric protein can act both as a tumour suppressor and as an anti-ageing factor. We have also identified POT1 as the first member of telomeric proteins to be mutated in human cancer, favouring the acquisition of the malignant features of chronic lymphocytic leukaemia cells. The telomeric protein RAP1, in addition to binding to telomeric repeats, also binds to extra-telomeric sites and regulates gene expression resulting in protection from metabolic syndrome and obesity. Finally, the generation of conditional mouse models for the deletion of telomeric proteins has also allowed us to generate mouse models for the so called "telomere syndromes", which are human diseases characterised by severe telomere defects owing to mutations in telomerase or some of the telomeric proteins, that include aplasic anaemia and idiopathic pulmonary fibrosis.
We were the first to study the regulation of telomerase activity and telomere length and telomere chromatin during the process of induced pluripotency to generate induced pluripotent stem (iPS) cells. We found that telomerase activity is needed for the effective generation of iPS cells and that the telomeric protein TRF1 is essential for induction and maintenance of pluripotency (and, also, that it is a stem cell marker). We have also identified the molecular mechanisms by which short telomeres or any other kind of DNA damage limit nuclear reprogramming.