Telomere shortening relaxes X chromosome inactivation and forces global transcriptome alterations

doi:10.1073/pnas.0909265106

Telomere shortening relaxes X chromosome inactivation and forces global transcriptome alterations

^aTelomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre (CNIO), Madrid 28029, Spain;
^bBioinformatics Unit, Structural Biology and Biocomputing Program, Spanish National Cancer Centre (CNIO), Madrid 28029, Spain; and
^cAnimal Surgery and Medicine Department, Facultad de Veterinaria, Universidad Complutense de Madrid, Madrid 28040, Spain

↵²Present address: Programa de Epigenética y Biología del Cáncer, Institut Català d'Oncología (ICO), Gran Via s/n, 08907 L′Hospitalet de Llobregat, Barcelona, Spain.

Edited by Jasper Rine, University of California, Berkeley, CA, and approved September 16, 2009
↵¹S.S. and R.B contributed equally to this work. (received for review August 18, 2009)

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.

Footnotes

³To whom correspondence should be addressed. E-mail: mblasco{at}cnio.es
Author contributions: S.S. and M.A.B. designed research; S.S., R.B., I.L.d.S., and J.M.F. performed research; P.M. contributed new reagents/analytic tools; S.S., R.B., I.L.d.S., G.G.-L., J.M.F., and M.A.B. analyzed data; and S.S. and M.A.B. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0909265106/DCSupplemental.