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.aging ͉ chromosome X inactivation ͉ DNA damage ͉ epigenetics ͉ telomeres D ysfunctional, critically short telomeres elicit a DNA damage response (DDR) that triggers senescence or apoptosis in mammalian cells, two processes that are associated with organismal aging (1-9). Mice with a targeted deletion of the RNA component of telomerase (Terc Ϫ/Ϫ ) display accelerated telomere shortening, premature loss of tissue renewal, and decreased longevity (3,(7)(8)(9). DNA damage signals originating from critically short telomeres in these mice is in line with current models proposing a causative role for DNA damage in organismal aging (10-13). Interestingly, epigenetic alterations at heterochromatic regions are proposed to lead to changes in gene expression associated with aging (14-16). In S. cerevisiae, induction of DNA double-strand breaks (DSBs) or cellular stress causes a dramatic redistribution of telomeric silent information regulator (Sir) proteins and yKU proteins (17-19), thus linking changes in telomere chromatin to global epigenetic alterations. Sir complex relocalization is known to alter the expression of stress response genes, survival factors, and ribosomal biogenesis (20,21). In functional analogy to yeast, mammalian SIRT1 is redistributed upon induction of DNA damage, causing broad alterations in global gene expression (22). Collectively, these findings suggest that agingrelated DNA damage drives gene expression alterations that could promote the development of aging pathologies.An important question to determine is how the various types of DNA damage impact gene expression changes associated with organismal a...

Androgen Receptor Interacts with Telomeric Proteins in Prostate Cancer Cells

“…Interestingly, these changes, viz. chromosome instability and altered gene expression, can result from disruption of telomeric complexes (22,23). Our observations that AR interacts with telomeric proteins (Figs.…”

TERRA transcripts are bound by a complex array of RNA-binding proteins

“…Several biological processes as well as cellular stresses have been described to infl uence TERRA levels and their nuclear localization and accumulation including the telomeric chromatin stage, telomere length, heat shock, exogenously infl icted DNA damage, as well as ontogenesis and cancer 6,8,32 (reviewed in Schoeft ner and Blasco 9 ). However, the TERRA-bound factors controlling all of these processes remain largely unknown.…”

Genome-wide analysis ofin vivoTRF1 binding to chromatin restricts its location exclusively to telomeric repeats

“…16,17 It is also known that gradual reduction in the telomere length associated to aging is linked to global deregulation of the transcriptome and loss of maintenance of epigenetic silencing mechanisms. 18 In line with extra-telomeric roles for shelterin proteins, Taz1, the fission yeast ortholog of mammalian TRF1 and TRF2, is also involved in telomere protection and recruitment of Rap1 to telomeres 19,20 and was recently described to bind to the internal telomeric repeats and play an essential role in the "replication timing control" (RTC), with about half of late origins and almost all origins in subtelomeric regions being regulated by the Taz1-mediated mechanism. 21 In agreement with this, a recent study reported restricted abilities of TRF1 and TRF2 proteins in binding extratelomeric sites of the genome in human tumor cell lines, most of them ITSs.…”