Telomere shortening relaxes X chromosome inactivation and forces global transcriptome alterations

2015-01-13

Telomere shortening relaxes X chromosome inactivation and forces global transcriptome alterations

"C:\Users\kurtw_000\Box Sync\DocDR\2014\01-30-2014d1027\Telomere shortening relaxes X chromosome inactivation and forces global transcriptome alterations.pdf"

Abstract
Telomeres are heterochromatic structures at chromosome ends es-
sential for chromosomal stability. Telomere shortening and the ac-
cumulation of dysfunctional telomeres are associated with organis-
mal aging. Using telomerase-de?cient 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 de?ned
set of genes, including up-regulation of the mTOR and Akt survival
pathways and down-regulation of cell cycle and DNA repair path-
ways. 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 accumu-
lations (Tacs), and reactivation of an X chromosome-linked K5TRF2
transgene that is subjected to X-chromosome inactivation in female
mice with suf?ciently long telomeres. Exogenously induced DNA
damage also disrupts Xi-Tacs, suggesting DNA damage at the origin
of these alterations. Collectively, these ?ndings 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.



Telomere shortening relaxes X chromosome inactivation and forces global transcriptome alterations
"C:\Users\kurtw_000\Box Sync\DocDR\2014\01-30-2014d1027\Telomere shortening relaxes X chromosome inactivation and forces global transcriptome alterations.pdf"

Some Notes
Collectively, these ?ndings 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.