Common Telomere Changes during In Vivo Reprogramming and Early Stages of Tumorigenesis

Reprogramming of differentiated cells into induced pluripotent stem cells has been recently achieved in vivo in mice. Telomeres are essential for chromosomal stability and determine organismal life span as well as cancer growth. Here, we study whether tissue dedifferentiation induced by in vivo reprogramming involves changes at telomeres. We find telomerase-dependent telomere elongation in the reprogrammed areas. Notably, we found highly upregulated expression of the TRF1 telomere protein in the reprogrammed areas, which was independent of telomere length. Moreover, TRF1 inhibition reduced in vivo reprogramming efficiency. Importantly, we extend the finding of TRF1 upregulation to pathological tissue dedifferentiation associated with neoplasias, in particular during pancreatic acinar-to-ductal metaplasia, a process that involves transdifferentiation of adult acinar cells into ductal-like cells due to K-Ras oncogene expression. These findings place telomeres as important players in cellular plasticity both during in vivo reprogramming and in pathological conditions associated with increased plasticity, such as cancer.We are indebted to R. Serrano for expert mouse colony manage- ment and the Comparative Pathology Unit at CNIO for technical assistance. We are grateful to Dr. Ana Losada for providing us with SA1 antibody. We thank Ana Carolina Moises da Silva for her assistance in setting-up RNA-FISH experiments. Work in the laboratory of M.A.B. is funded by the Spanish Ministry of Economy and Competiveness (PLAN RETOS SAF2013-45111-R) and by the Fundacion Botın.S