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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
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) 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 -TRF2 overexpressing mice (K5TRF2/Terc-/-) -q 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. -histopathology and immunochemistry -telomere length analysis -TRF-based telomere length analysis -cell culture -gamma irradiation for DNA damage -western blot -northern blot analysis -RNA FISH -microarray analysis
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