title: Telomere shortening relaxes X chromosome inactivation and forces global transcriptome alterations.
abstract: Telomeres are heterochromatic structures at chromosome ends essential for chromosomal stability. Telomere shortening and the accumulation of dysfunctional telomeres are associated with organismal aging. Using telomerase-deficient TRF2-overexpressing mice (K5TRF2/Terc(-/-)) as a model for accelerated aging, we show that telomere shortening is paralleled by a gradual deregulation of the mammalian transcriptome leading to cumulative changes in a defined set of genes, including up-regulation of the mTOR and Akt survival pathways and down-regulation of cell cycle and DNA repair pathways. Increased DNA damage from dysfunctional telomeres leads to reduced deposition of H3K27me3 onto the inactive X chromosome (Xi), impaired association of the Xi with telomeric transcript accumulations (Tacs), and reactivation of an X chromosome-linked K5TRF2 transgene that is subjected to X-chromosome inactivation in female mice with sufficiently long telomeres. Exogenously induced DNA damage also disrupts Xi-Tacs, suggesting DNA damage at the origin of these alterations. Collectively, these findings suggest that critically short telomeres activate a persistent DNA damage response that alters gene expression programs in a nonstochastic manner toward cell cycle arrest and activation of survival pathways, as well as impacts the maintenance of epigenetic memory and nuclear organization, thereby contributing to organismal aging.
authors.affiliation: Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre (CNIO), Madrid 28029, Spain.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schoeftner
authors.forename: Raquel
authors.initials: R
authors.lastname: Blanco
authors.forename: Isabel
authors.initials: I
authors.lastname: Lopez de Silanes
authors.forename: Purificación
authors.initials: P
authors.lastname: Muñoz
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Gómez-López
authors.forename: Juana M
authors.initials: JM
authors.lastname: Flores
authors.forename: Maria A
authors.initials: MA
authors.lastname: Blasco
mesh_terms: D019588:Aging, Premature / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D004249:DNA Damage / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D053569:Keratin-15; D053555:Keratin-5 / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D012867:Skin / Q000378:metabolism* / Q000473:pathology; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D016615:Telomere / Q000378:metabolism*; D035341:Telomeric Repeat Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D049951:X Chromosome Inactivation
chemical_list: D053569:Keratin-15; D053555:Keratin-5; C492053:Krt15 protein, mouse; C534796:TRF2 protein, mouse; D035341:Telomeric Repeat Binding Protein 2; D019098:Telomerase