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Telomeres in Development, Senescence and Genome Instability

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: 30 August 2024 | Viewed by 7072

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Special Issue Editor

Dr. Alla Kalmykova

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Guest Editor

Head of Laboratory of Developmental Epigenetics, Koltzov Institute of Developmental Biology of RAS, 119334 Moscow, Russia
Interests: telomeres; development; germline; epigenetics
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Special Issue Information

Dear Colleagues,

Telomere biology, as a special area of biology, was brought to light in 1971–1973 by the brilliant prediction of Alexey Olovnikov (1936–2022) about the under-replication of the ends of linear chromosomes. In his telomeric theory of aging, Alexey Olovnikov also determined the key role of telomeres in various fundamental processes, such as cell death, cancer, and aging. Indeed, telomere functions are closely linked to many cellular processes, in particular through the telomere signalling mechanisms, although their molecular basis remains poorly understood. Telomere shortening and telomere dysfunction are the hallmarks of cellular senescence, aging and oncogenesis, highlighting the importance of telomere state in genome stability. The aim of this Special Issue is to bring together research and methodological articles, reviews and opinions of the authors studying the diverse and fascinating field of telomere biology.

Topics include, but are not limited to, the following:

Telomere disorders and cell death;
Telomeres and genome stability;
Epigenetics of telomeres in development and aging;
Mechanisms of telomere signalling;
Telomeres in aging and senescence;
Telomeropathies and laminopathies;
Telomere protection mechanisms in development;
Telomeres in non-model organisms;
Telomere length control in germline and stem cells;
Novel methods of telomere analysis.

Dr. Alla Kalmykova
Guest Editor

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Published Papers (6 papers)

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Research

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15 pages, 3426 KiB

Open AccessArticle

Reprogramming Chromosome Ends by Functional Histone Acetylation

by W. Alex Meltzer, Aditi Gupta, Phyo Nay Lin, Robert A. Brown, Daniel S. Benyamien-Roufaeil, Raju Khatri, Anup A. Mahurkar, Yang Song, Rodney J. Taylor and Michal Zalzman

Int. J. Mol. Sci. 2024, 25(7), 3898; https://doi.org/10.3390/ijms25073898 - 31 Mar 2024

Viewed by 686

Abstract

Cancers harness embryonic programs to evade aging and promote survival. Normally, sequences at chromosome ends called telomeres shorten with cell division, serving as a countdown clock to limit cell replication. Therefore, a crucial aspect of cancerous transformation is avoiding replicative aging by activation of telomere repair programs. Mouse embryonic stem cells (mESCs) activate a transient expression of the gene Zscan4, which correlates with chromatin de-condensation and telomere extension. Head and neck squamous cell carcinoma (HNSCC) cancers reactivate ZSCAN4, which in turn regulates the phenotype of cancer stem cells (CSCs). Our study reveals a new role for human ZSCAN4 in facilitating functional histone H3 acetylation at telomere chromatin. Next-generation sequencing indicates ZSCAN4 enrichment at telomere chromatin. These changes correlate with ZSCAN4-induced histone H3 acetylation and telomere elongation, while CRISPR/Cas9 knockout of ZSCAN4 leads to reduced H3 acetylation and telomere shortening. Our study elucidates the intricate involvement of ZSCAN4 and its significant contribution to telomere chromatin remodeling. These findings suggest that ZSCAN4 induction serves as a novel link between ‘stemness’ and telomere maintenance. Targeting ZSCAN4 may offer new therapeutic approaches to effectively limit or enhance the replicative lifespan of stem cells and cancer cells. Full article

(This article belongs to the Special Issue Telomeres in Development, Senescence and Genome Instability)

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19 pages, 3319 KiB

Open AccessArticle

3D Super-Resolution Nuclear Q-FISH Imaging Reveals Cell-Cycle-Related Telomere Changes

by Tatiana V. Pochechueva, Niko Schwenzer, Tobias Kohl, Sören Brandenburg, Gesa Kaltenecker, Bernd Wollnik and Stephan E. Lehnart

Int. J. Mol. Sci. 2024, 25(6), 3183; https://doi.org/10.3390/ijms25063183 - 10 Mar 2024

Viewed by 856

Abstract

We present novel workflows for Q-FISH nanoscopy with the potential for prognostic applications and resolving novel chromatin compaction changes. DNA-fluorescence in situ hybridization (DNA-FISH) is a routine application to visualize telomeres, repetitive terminal DNA sequences, in cells and tissues. Telomere attrition is associated with inherited and acquired diseases, including cancer and cardiomyopathies, and is frequently analyzed by quantitative (Q)-FISH microscopy. Recently, nanoscopic imaging techniques have resolved individual telomere dimensions and their compaction as a prognostic marker, in part leading to conflicting conclusions still unresolved to date. Here, we developed a comprehensive Q-FISH nanoscopy workflow to assess telomeres with PNA telomere probes and 3D-Stimulated Emission Depletion (STED) microscopy combined with Dynamic Intensity Minimum (DyMIN) scanning. We achieved single-telomere resolution at high, unprecedented telomere coverage. Importantly, our approach revealed a decrease in telomere signal density during mitotic cell division compared to interphase. Innovatively expanding FISH-STED applications, we conducted double FISH targeting of both telomere- and chromosome-specific sub-telomeric regions and accomplished FISH-STED in human cardiac biopsies. In summary, this work further advanced Q-FISH nanoscopy, detected a new aspect of telomere compaction related to the cell cycle, and laid the groundwork for future applications in complex cell types such as post-mitotic neurons and muscle cells. Full article

(This article belongs to the Special Issue Telomeres in Development, Senescence and Genome Instability)

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12 pages, 1333 KiB

Open AccessArticle

A Nested PCR Telomere Fusion Assay Highlights the Widespread End-Capping Protection of Arabidopsis CTC1

by María I. Vaquero-Sedas and Miguel A. Vega-Palas

Int. J. Mol. Sci. 2024, 25(1), 672; https://doi.org/10.3390/ijms25010672 - 4 Jan 2024

Viewed by 851

Abstract

Telomeres protect the ends of linear eukaryotic chromosomes from being recognized as DNA double-strand breaks. Two major protein complexes are involved in the protection of telomeres: shelterin and CST. The dysfunction of these complexes can challenge the function of telomeres and lead to telomere fusions, breakage–fusion–bridge cycles, and cell death. Therefore, monitoring telomere fusions helps to understand telomeres biology. Telomere fusions are often analyzed by Fluorescent In Situ Hybridization (FISH) or PCR. Usually, both methods involve hybridization with a telomeric probe, which allows the detection of fusions containing telomeric sequences, but not of those lacking them. With the aim of detecting both types of fusion events, we have developed a nested PCR method to analyze telomere fusions in Arabidopsis thaliana. This method is simple, accurate, and does not require hybridization. We have used it to analyze telomere fusions in wild-type and mutant plants altered in CTC1, one of the three components of the Arabidopsis CST telomere capping complex. Our results show that null ctc1-2 mutant plants display fusions between all telomeric regions present in Arabidopsis chromosomes 1, 3 and 5, thus highlighting the widespread end-capping protection achieved by CTC1. Full article

(This article belongs to the Special Issue Telomeres in Development, Senescence and Genome Instability)

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14 pages, 2266 KiB

Open AccessArticle

Comparative Application of Terminal Restriction Fragment Analysis Tools to Large-Scale Genomic Assays

by Liliia R. Abdulkina, Inna A. Agabekian, Liia R. Valeeva, Olga S. Kozlova, Margarita R. Sharipova and Eugene V. Shakirov

Int. J. Mol. Sci. 2023, 24(24), 17194; https://doi.org/10.3390/ijms242417194 - 6 Dec 2023

Cited by 2 | Viewed by 902

Abstract

The analysis of telomere length is an important component of many studies aiming to characterize the role of telomere maintenance mechanisms in cellular lifespan, disease, or in general chromosome protection and DNA replication pathways. Several powerful methods to accurately measure the telomere length from Southern blots have been developed, but their utility for large-scale genomic studies has not been previously evaluated. Here, we performed a comparative analysis of two recently developed programs, TeloTool and WALTER, for the extraction of mean telomere length values from Southern blots. Using both software packages, we measured the telomere length in two extensive experimental datasets for the model plant Arabidopsis thaliana, consisting of 537 natural accessions and 65 T-DNA (transfer DNA for insertion mutagenesis) mutant lines in the reference Columbia (Col-0) genotype background. We report that TeloTool substantially overestimates the telomere length in comparison to WALTER, especially for values over 4500 bp. Importantly, the TeloTool- and WALTER-calculated telomere length values correlate the most in the 2100–3500 bp range, suggesting that telomeres in this size interval can be estimated by both programs equally well. We further show that genome-wide association studies using datasets from both telomere length analysis tools can detect the most significant SNP candidates equally well. However, GWAS analysis with the WALTER dataset consistently detects fewer significant SNPs than analysis with the TeloTool dataset, regardless of the GWAS method used. These results imply that the telomere length data generated by WALTER may represent a more stringent approach to GWAS and SNP selection for the downstream molecular screening of candidate genes. Overall, our work reveals the unanticipated impact of the telomere length analysis method on the outcomes of large-scale genomic screens. Full article

(This article belongs to the Special Issue Telomeres in Development, Senescence and Genome Instability)

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16 pages, 4353 KiB

Open AccessArticle

Telomere Length in Human Spermatogenic Cells as a New Potential Predictor of Clinical Outcomes in ART Treatment with Intracytoplasmic Injection of Testicular Spermatozoa

by Anna A. Pendina, Mikhail I. Krapivin, Yanina M. Sagurova, Irina D. Mekina, Evgeniia M. Komarova, Andrei V. Tikhonov, Arina V. Golubeva, Alexander M. Gzgzyan, Igor Yu. Kogan and Olga A. Efimova

Int. J. Mol. Sci. 2023, 24(13), 10427; https://doi.org/10.3390/ijms241310427 - 21 Jun 2023

Cited by 1 | Viewed by 936

Abstract

Predicting the clinical outcomes of intracytoplasmic sperm injection (ICSI) cycles that use the testicular spermatozoa of azoospermic patients presents a challenge. Thus, the development of additional approaches to assessing the competence of a testicular-sperm-derived embryo without causing damage to gametes or the embryo is necessary. One of the key parameters in determining such developmental competence is telomere length (TL). We aimed to analyze TLs in spermatogenic cells from the testicular biopsy samples of azoospermic patients and determine how this parameter influences embryo competence for pre- and post-implantation development. Using Q-FISH, we studied the TL of the chromosomes in spermatogonia and spermatocytes I from the TESE biopsy samples of 30 azoospermic patients. An increase in TL was detected during the differentiation from spermatogonia to spermatocytes I. The patients’ testicular spermatozoa were used in 37 ICSI cycles that resulted in 22 embryo transfers. Nine pregnancies resulted, of which, one was ectopic and eight ended in birth. The analysis of embryological outcomes revealed a dependence between embryo competence for development to the blastocyst stage and the TL in spermatogenic cells. The TLs in spermatogonia and spermatocytes I in the testicular biopsy samples were found to be higher in patients whose testicular sperm ICSI cycles resulted in a birth. Therefore, the length of telomeres in spermatogenic cells can be considered as a potential prognostic criterion in assessing the competence of testicular-sperm-derived embryos for pre- and post-implantation development. The results of this study provide the basis for the development of a laboratory test for the prediction of testicular sperm ICSI cycle outcomes. Full article

(This article belongs to the Special Issue Telomeres in Development, Senescence and Genome Instability)

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Review

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16 pages, 1794 KiB

Open AccessReview

Telomere Checkpoint in Development and Aging

by Alla Kalmykova

Int. J. Mol. Sci. 2023, 24(21), 15979; https://doi.org/10.3390/ijms242115979 - 5 Nov 2023

Viewed by 1796

Abstract

The maintenance of genome integrity through generations is largely determined by the stability of telomeres. Increasing evidence suggests that telomere dysfunction may trigger changes in cell fate, independently of telomere length. Telomeric multiple tandem repeats are potentially highly recombinogenic. Heterochromatin formation, transcriptional repression, the suppression of homologous recombination and chromosome end protection are all required for telomere stability. Genetic and epigenetic defects affecting telomere homeostasis may cause length-independent internal telomeric DNA damage. Growing evidence, including that based on Drosophila research, points to a telomere checkpoint mechanism that coordinates cell fate with telomere state. According to this scenario, telomeres, irrespective of their length, serve as a primary sensor of genome instability that is capable of triggering cell death or developmental arrest. Telomeric factors released from shortened or dysfunctional telomeres are thought to mediate these processes. Here, we discuss a novel signaling role for telomeric RNAs in cell fate and early development. Telomere checkpoint ensures genome stability in multicellular organisms but aggravates the aging process, promoting the accumulation of damaged and senescent cells. Full article

(This article belongs to the Special Issue Telomeres in Development, Senescence and Genome Instability)

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