title: SIRT1 is necessary for proficient telomere elongation and genomic stability of induced pluripotent stem cells.
abstract: The NAD-dependent deacetylase SIRT1 is involved in chromatin silencing and genome stability. Elevated SIRT1 levels in embryonic stem cells also suggest a role for SIRT1 in pluripotency. Murine SIRT1 attenuates telomere attrition in vivo and is recruited at telomeres in induced pluripotent stem cells (iPSCs). Because telomere elongation is an iPSC hallmark, we set out to study the role of SIRT1 in pluripotency in the setting of murine embryonic fibroblasts reprogramming into iPSCs. We find that SIRT1 is required for efficient postreprogramming telomere elongation, and that this effect is mediated by a c-MYC-dependent regulation of the mTert gene. We further demonstrate that SIRT1-deficient iPSCs accumulate chromosomal aberrations and show a derepression of telomeric heterochromatin. Finally, SIRT1-deficient iPSCs form larger teratomas that are poorly differentiated, highlighting a role for SIRT1 in exit from pluripotency. In summary, this work demonstrates a role for SIRT1 in the maintenance of pluripotency and modulation of differentiation.
authors.affiliation: Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre (CNIO), Melchor Fernández Almagro 3, 28029 Madrid, Spain.
authors.forename: Maria Luigia
authors.initials: ML
authors.lastname: De Bonis
authors.affiliation: Transgenic Mice Unit, Biotechnology Program, Spanish National Cancer Centre (CNIO), Melchor Fernández Almagro 3, 28029 Madrid, Spain.
authors.forename: Sagrario
authors.initials: S
authors.lastname: Ortega
authors.affiliation: Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre (CNIO), Melchor Fernández Almagro 3, 28029 Madrid, Spain.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Blasco
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D065150:Cellular Reprogramming; D042002:Chromatin Assembly and Disassembly; D058750:Epithelial-Mesenchymal Transition; D042822:Genomic Instability; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism* / Q000637:transplantation; D016014:Linear Models; D008677:Metaphase; D051379:Mice; D008819:Mice, Nude; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D016615:Telomere / Q000378:metabolism*
chemical_list: D018398:Homeodomain Proteins; D016271:Proto-Oncogene Proteins c-myc; D019098:Telomerase; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1