Telomere Shortening Relaxes X Chromosome Inactivation and Forces Global Transcriptome Alterations

• Published in: Proceedings of the National Academy of Sciences - PNAS 2009-11, Vol.106 (46), p.19393-19398
• Main Authors: Schoeftner, Stefan, Blanco, Raquel, de Silanes, Isabel Lopez, Muñoz, Purificación, Gómez-López, Gonzalo, Flores, Juana M., Blasco, Maria A.
• Format: Article
• Language: English
• Subjects: Aging; Aging, Premature - genetics; Aging, Premature - metabolism; Aging, Premature - pathology; AKT protein; Animals; Biological Sciences; Cell cycle; Cell Cycle - genetics; Cell survival; Chromosomes; Deoxyribonucleic acid; DNA; DNA damage; DNA Damage - genetics; DNA repair; epigenetics; Female; Female animals; Gene expression; Gene Expression Profiling; Genes; Keratin-15; Keratin-5 - genetics; Keratinocytes; Lead; Male; Mice; Mice, Transgenic; RNA; Sex chromosomes; Skin - metabolism; Skin - pathology; Telomerase - genetics; Telomerase - metabolism; Telomere - metabolism; Telomeres; Telomeric Repeat Binding Protein 2 - genetics; Telomeric Repeat Binding Protein 2 - metabolism; TOR protein; Transcription, Genetic; Transcriptomes; Transgenes; X Chromosome Inactivation
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0909265106

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.