Long-range telomere regulation of gene expression: Telomere looping and telomere position effect over long distances (TPE-OLD)

Kim, Wanil; Shay, Jerry W.

doi:10.1016/j.diff.2017.11.005

Cited by 59 publications

(53 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…GABPA along with the histone acetyl transferase BRD4 was also noted to bind the hTERT promoter with mutation(s) inducing permissive chromatin state 53 . Together, with the presence of tandem G-quadruplexes in the hTERT near promoter, the likelihood of Gquadruplex-dependent mechanisms of transcription factor association resulting in permissive/restrictive chromatin conformation has been discussed by several groups 42,43,67,68 .…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Human Telomerase Expression is under Direct Transcriptional Control of the Telomere-binding-factor TRF2

Sharma

Mukherjee

Roy

et al. 2020

Preprint

View full text Add to dashboard Cite

Tight regulatory mechanisms to maintain repression of human Telomerase (hTERT), the sole protein that synthesizes telomeres, is crucial for normal adult somatic cells. In contrast, enhanced telomerase activity and resulting pathological maintenance of telomeres, is widely understood as causal in >90% of human cancers. These implicate underlying mechanisms connecting hTERT regulation and telomeres, possibly through telomeric proteins, that remain unclear. In light of of recent work by us and others showing non-telomeric function of the telomere-binding protein TRF2, here we examined whether and how TRF2 affected hTERT regulation. Direct binding of TRF2spanning ~450 bp of the hTERT promoter from the Transcriptional Start Site (TSS)led to TRF2-dependent recruitment of the polycomb repressor complex PRC2 in both normal and cancer cells. This induced repressor histone modifications resulting in TRF2-dependent hTERT repression.Mutations in the hTERT promoter, found frequently in aggressive glioblastoma and reported to destabilize the G-quadruplex structure, resulted in loss of TRF2 binding and consequent hTERT over-expression. Conversely, using G-quadruplex-stabilizing ligands we regained TRF2 binding, hTERT re-suppression, in highly proliferating glioblastoma cells with telomerase hyperactivation due to hTERT promoter mutations. Together, results herein demonstrate direct control of hTERT through TRF2 in a G-quadruplex-dependent mannerimplicating mechanisms of how telomerase regulation might be linked to telomeres in normal and cancer cells. IntroductionTelomeres, comprising of (GGGTTA) n repeats in complex with telomere-binding proteins, at the end of human chromosomes are essential for genome stability 1-6 . The only protein that can replicate telomeric DNA is telomerase -a ribonucleoprotein complex of the reverse transcriptase (hTERT) and RNA the template (hTERC). In adult somatic cells, hTERT is kept trasncriptionally repressed.Resulting loss of telomeres with each replication cycle leads to replicative senescence, much like a 'molecular clock' that helps maintain cellular homeostasis. Deregulation or loss of hTERT repression, which results in aberrant maintenance of telomeres, has been causally associated to initiation/progression of more than 90% human cancers 7,8 . Although, these suggest tight control of telomerase might be linked to telomeres -the role of telomeres or telomere-binding factors in regulation of hTERT remains poorly explored.Relatively recent work by others and us showing non-telomeric binding of telomere-binding proteins, TRF1, TRF2 and RAP1, is of interest in this context. Genome wide RAP1 association has been reported in mouse and human cells while TRF1/TRF2 binding has been demonstrated in human cells 9-11 . Notably, we found about 20000 TRF2 binding sites spread throughout the genome where TRF2-mediated promoter epigenetics and gene regulation was evident. A large fraction of the TRF2 binding sites coincided with potential DNA secondary structure G-quadruplex-forming sequences 12 .Further, ...

show abstract

Section: Discussionmentioning

confidence: 99%

“…Kb downstream of hTERT exon reported to engage telomeres through looping of the 5p chromosome (Kim et al, 2016) as positive control 43 . The GAPDH promoter was used as negative control.…”

Section: Trf2 Binding On the Htert Promoter Can Be Independent Of Telmentioning

confidence: 99%

Human Telomerase Expression is under Direct Transcriptional Control of the Telomere-binding-factor TRF2

Sharma

Mukherjee

Roy

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…This gene silencing appears to be an evolutionarily conserved strategy found in several species from yeast to humans that allows metabolic adjustment to changes to environmental conditions [107,108]. These genes are activated by decreasing the TPE when TLs become shorter (but much before a DNA damage response is induced [107,109]), providing a mechanism by which organismal performance can be programmed according to TL length [110,111]. Overall, these functions suggest that TLs are regulators of cell function, sensors of energetic stress and mediators of life-history tradeoffs.…”

Section: The Metabolic Telomere Attrition Hypothesismentioning

confidence: 99%

Telomere attrition: metabolic regulation and signalling function?

2019

View full text Add to dashboard Cite

Stress exposure can leave long-term footprints within the organism, like in telomeres (TLs), protective chromosome caps that shorten during cell replication and following exposure to stressors. Short TLs are considered to indicate lower fitness prospects, but why TLs shorten under stressful conditions is not understood. Glucocorticoid hormones (GCs) increase upon stress exposure and are thought to promote TL shortening by increasing oxidative damage. However, evidence that GCs are pro-oxidants and oxidative stress is causally linked to TL attrition is mixed . Based on new biochemical findings, we propose the metabolic telomere attrition hypothesis: during times of substantially increased energy demands, TLs are shortened as part of the transition into an organismal ‘emergency state’, which prioritizes immediate survival functions over processes with longer-term benefits. TL attrition during energy shortages could serve multiple roles including amplified signalling of cellular energy debt to re-direct critical resources to immediately important processes. This new view of TL shortening as a strategy to resolve major energetic trade-offs can improve our understanding of TL dynamics. We suggest that TLs are master regulators of cell homeostasis and propose future research avenues to understand the interactions between energy homeostasis, metabolic regulators and TL.

show abstract

“…Translocated genome segments can activate chromosome position effects that may disturb gene expression either by altering the number or location of regulatory elements or by changing the architectural landscape of a gene or a genic cluster [34][35][36]. In the present case, the Xp22.33p22.31 translocated segment does not include the X-inactivation center (XIC).…”

Section: Discussionmentioning

confidence: 89%

Unbalanced X;9 translocation in an infertile male with de novo duplication Xp22.31p22.33

Roumelioti

Louizou²,

Karras

et al. 2019

J Assist Reprod Genet

View full text Add to dashboard Cite

Purpose Male carriers of an X-autosome translocation are generally infertile, regardless of the position of the breakpoint on the X chromosome while the pathogenicity of Xp22.3 subtelomeric duplications is under debate. To shed light into this controversy, we present a rare case, of an azoospermic male with no other significant clinical findings, in whom classical cytogenetics revealed additional unbalanced chromosomal material, at the telomere of the long arm of one homolog of chromosome 9. Methods In peripheral blood specimens of the index case and his parents, we performed GBanding, Inverted-DAPI Banding, AgNOR staining, Telomere specific Fluorescence in Situ Hybridization (FISH), Molecular karyotyping by Multi-color FISH, whole genome SNP microarrays, sub-telomeric MLPA, and transcription analysis of the expression of KAL1 gene by RT-PCR. Results Multi-color FISH revealed an unbalanced translocation involving the short arm of chromosome X. SNP microarray analysis combined to classical cytogenetics and MLPA demonstrated a de novo 8.796 Mb duplication of Xp22.31-p22.33. Compared to three control specimens, the patient presented significantly elevated expression levels of KAL1 mRNA in peripheral blood, suggesting transcriptional functionality of the duplicated segment. Conclusions The duplicated segment contains the pseudo-autosomal region PAR1 and more than 30 genes including SHOX, ARSE, STS, KAL1, and FAM9A and is not listed as polymorphic. Our data advocate that duplications of the Xp22.3 region may not be associated with a clinical consequence.

show abstract

Long-range telomere regulation of gene expression: Telomere looping and telomere position effect over long distances (TPE-OLD)

Cited by 59 publications

References 55 publications

Human Telomerase Expression is under Direct Transcriptional Control of the Telomere-binding-factor TRF2

Human Telomerase Expression is under Direct Transcriptional Control of the Telomere-binding-factor TRF2

Telomere attrition: metabolic regulation and signalling function?

Unbalanced X;9 translocation in an infertile male with de novo duplication Xp22.31p22.33

Contact Info

Product

Resources

About