Novel TINF2 gene mutation in dyskeratosis congenita with extremely short telomeres:A case report

BACKGROUND Dyskeratosis congenita is a rare disease characterized by bone marrow failure and a clinical triad of oral leukoplakia,nail dystrophy,and abnormal skin pigmentation.The genetics of dyskeratosis congenita include mutations in genes involved in telomere maintenance,including TINF2.CASE SUMMARY Here,we report a female patient who presented thrombocytopenia,anemia,reticulate hyperpigmentation,dystrophy in fingernails and toenails,and leukoplakia on the tongue.A histopathological study of the skin showed dyskeratocytes;however,a bone marrow biopsy revealed normal cell morphology.The patient was diagnosed with dyskeratosis congenita,but her family history did not reveal significant antecedents.Whole-exome sequencing showed a novel heterozygous punctual mutation in exon 6 from the TINF2 gene,namely,NM_001099274.1:-c.854delp.(Val285-Alafs*32).An analysis of telomere length showed short telomeres relative to the patient’s age.CONCLUSION The disease in this patient was caused by a germline novel mutation of TINF2 in one of her parents.

Human Long Telomeres and Epigenetic Marks

We have read with interest the article “Telomere length regulates TERRA levels through increased trimethylation of telomeric H3K9 and HP1α” by Arnoult and colleagues [1]. This study focuses on human telomeric chromatin structure using different techniques like Chromatin Immunoprecipitation (ChIP), cytolocalization or RT-qPCR. However, it has been performed without taking into consideration the presence of Interstitial Telomeric Sequences (ITSs) in the human genome. Some of the conclusions of the article are undoubtedly clear but there are others that might be explained in alternative ways, considering the existence of ITSs. Following, we mention some comments that arise from this interesting article.

Telomeres,telomerase and colorectal cancer

Colorectal cancer(CRC)is the third most common cancer worldwide and,despite improved treatments,is still an important cause of cancer-related deaths.CRC encompasses a complex of diseases arising from a multistep process of genetic and epigenetic events.Besides heterogeneity in the molecular and biological features of CRC,chromosomal instability is a hallmark of cancer and cancer cells may also circumvent replicative senescence and acquire the ability to sustain unlimited proliferation.Telomere/telomerase interplay is an important mechanism involved in both genomic stability and cellular replicative potential,and its dysfunction plays a key role in the oncogenetic process.The erosion of telomeres,mainly because of cell proliferation,may be accelerated by specific alterations in the genes involved in CRC,such as APC and MSH2.Although there is general agreement that the shortening of telomeres plays a role in the early steps of CRC carcinogenesis by promoting chromosomal instability,the prognostic role of telomere length in CRC is still under debate.The activation of telomerase reverse transcriptase(TERT),the catalytic component of the telomerase complex,allows cancer cells to grow indefinitely by maintaining the length of the telomeres,thus favouring tumour formation/progression.Several studies indicate that TERT increases with disease progression,and most studies suggest that telomerase is a useful prognostic factor.Plasma TERT mRNA may also be a promising marker for the minimally invasive monitoring of disease progression and response to therapy.

Telomeres and Telomerase: Molecular Views and Perspectives

Telomere, the nucleoprotein structure at the end of eukaryotic linear chromosomes is indispensable for maintaining the genome stability. Telomeric DNA loss is apparent with each cell division, which marks an endpoint to the indefinite replication of the cell by causing replicative senescence that may lead to the programmed cell death. The loss of telomere is normal in cell division and as such after 20 - 40 divisions, telomere becomes too short to facilitate the capping function. Telomere uncapping or chromosomal free end causes a potential threat to the genomic stability and thus leads to the accumulation of chromosomal abnormalities that have been known to play a role in aging and cancer. Telomerase, the ribonucleoprotein complex, and its accessory proteins are required to maintain the telomere sequence. Telomerase plays a key role in maintaining the length of telomere by adding G-rich repeat sequences. Its activity has been found to be quite high in the gametes, stem cells and most importantly tumor cells. Almost 85% of tumor cells compensate for telomere loss aided by telomerase-associated protein complex and shelter in complex or telosome. However, 5% - 10% of the cells undergo telomerase-independent mechanism. This review presents the molecular view of the telomere and telomerase along with its associated complex structures. It also discusses its contrasting role in causing cellular senescence and promoting tumorigenesis.

Short telomeres impede germ cell specification by upregulating MAPK and TGFβsignaling

Functional telomeres protect chromosome ends and play important roles in stem cell maintenance and differentiation. Short telomeres negatively impact germ cell development and can contribute to age-associated infertility. Moreover, telomere syndrome resulting from mutations of telomerase or telomere-associated genes exhibits short telomeres and reduced fertility. It remains elusive whether and how telomere lengths affect germ cell specification. We report that functional telomere is required for the coordinated germ cell and somatic cell fate decisions. Using telomerase gene Terc deficient mice as a model, we show that short telomeres restrain germ cell specification of epiblast cells but promote differentiation towards somatic lineage. Short telomeres increase chromatin accessibility to elevate TGFβ and MAPK/ERK signaling for somatic cell differentiation. Notably,elevated Fst expression in TGFβ pathway represses the BMP4-pSmad signaling pathway, thus reducing germ cell formation. Reelongation of telomeres by targeted knock-in of Terc restores normal chromatin accessibility to suppress TGFβ and MAPK signaling, thereby facilitating germ cell formation. Taken together, our data reveal that functional telomeres are required for germ cell specification by repressing TGFβ and MAPK signaling.

Superresolution imaging of telomeres with continuous wave stimulated emission depletion (STED) microscope

The significant role of telomeres in cells has attracted much attention since they were discovered.Fluorescence imaging is an effective method to study subcellular structures like telomeres.However,the diffraction limit of traditional optical microscope hampers further investigation on them.Recent progress on superresolution fluorescence microscopy has broken this limit.In this work,we used stimulated emission depletion(STED) microscope to observe fluorescence-labeled telomeres in interphase cell nuclei.The results showed that the size of fluorescent puncta representing telomeres under the STED microscope was much smaller than that under the confocal microscope.Two adjacent telomeres were clearly separated via STED imaging,which could hardly be discriminated by confocal microscopy due to the diffraction limit.We conclude that STED microscope is a more powerful tool that enable us to obtain detailed information about telomeres.

Characterization of tree shrew telomeres and telomerase

The use of tree shrews as experimental animals for biomedical research is a new practice.Several recent studies suggest that tree shrews are suitable for studying cancers,including breast cancer,glioblastoma,lung cancer,and hepatocellular carcinoma.However,the telomeres and the telomerase of tree shrews have not been studied to date.Here,we characterize telomeres and telomerase in tree shrews.The telomere length of tree shrews is approximately 23 kb,which is longer than that of primates and shorter than that of mice,and it is extended in breast tumor tissues according to Southern blot and flow-fluorescence in situ hybridization(FISH)analyses.Tree shrew spleen,bone marrow,testis,ovary,and uterus show high telomerase activities,which are increased in breast tumor tissues by telomeric repeat amplification protocol assays.The telomere length becomes shorter,and telomerase activity decreases with age.The tree shrew TERT and TERC are more highly similar to primates than to rodents.These findings lay a solid foundation for using tree shrews to study aging and cancers.

EPAS1 prevents telomeric damage-induced senescence by enhancing transcription of TRF1,TRF2,and RAD50

Telomeres are nucleoprotein structures located at the end of each chromosome,which function in terminal protection and genomic stability.Telomeric damage is closely related to replicative senescence in vitro and physical aging in vivo.As relatively long-lived mammals based on body size,bats display unique telomeric patterns,including the upregulation of genes involved in alternative lengthening of telomeres(ALT),DNA repair,and DNA replication.At present,however,the relevant molecular mechanisms remain unclear.In this study,we performed cross-species comparison and identified EPAS1,a well-defined oxygen response gene,as a key telomeric protector in bat fibroblasts.Bat fibroblasts showed high expression of EPAS1,which enhanced the transcription of shelterin components TRF1 and TRF2,as well as DNA repair factor RAD50,conferring bat fibroblasts with resistance to senescence during long-term consecutive expansion.Based on a human single-cell transcriptome atlas,we found that EPAS1 was predominantly expressed in the human pulmonary endothelial cell subpopulation.Using in vitro-cultured human pulmonary endothelial cells,we confirmed the functional and mechanistic conservation of EPAS1 in telomeric protection between bats and humans.In addition,the EPAS1 agonist M1001 was shown to be a protective compound against bleomycin-induced pulmonary telomeric damage and senescence.In conclusion,we identified a potential mechanism for regulating telomere stability in human pulmonary diseases associated with aging,drawing insights from the longevity of bats.

Role of mitophagy in the hallmarks of aging

Aging, subjected to scientific scrutiny, is extensively defined as a time-dependent decline in functions that involves the majority of organisms. The time-dependent accretion of cellular lesions is generally a universal trigger of aging, while mitochondrial dysfunction is a sign of aging. Dysfunctional mitochondria are identified and removed by mitophagy, a selective form of macroautophagy. Increased mitochondrial damage resulting from reduced biogenesis and clearance may promote the aging process. The primary purpose of this paper is to illustrate in detail the effects of mitophagy on aging and emphasize the associations between mitophagy and other signs of aging, including dietary restriction, telomere shortening, epigenetic alterations, and protein imbalance.The evidence regarding the effects of these elements on aging is still limited. And although the understanding of relationship between mitophagy and aging has been long-awaited, to analyze details of such a relationship remains the main challenge in aging studies.

Association between Dietary Collagen Consumption and Telomere Length: National Health and Nutrition Examination Survey

Background: Bioactive peptides derived from hydrolyzed collagen have broad physiological functions and beneficial effects on human health, ranging from reducing skin aging to modifying lipid metabolism. Telomere length shortening is an established biomarker of cellular aging. It is not known if collagen consumption is associated with telomere length protection. Our purpose was to investigate the relationship between dietary collagen consumption and telomere length in a nationally representative US adult population. Methods: We analyzed the data of 6173 adults aged 20 - 84 from the National Health and Nutrition Examination Survey (NHANES) 1999-2002. Multivariable linear regression and a generalized additive model with smoothing plot were used to assess the association between the total collagen consumption and log-transformed leukocyte telomere length (LTL). Results: Compared with the lowest quartile of total collagen (Q1), we found that the second quartile of collagen (Q2) consumption (1.36 - 3.40 g/1000kcal) was positively associated with telomere length (β: 0.017;95% CI: 0.006, 0.028;P = 0.022) in the females while no association in the males (β: −0.003;95% CI: −0.019, 0.012;P = 0.678) and overall population (β: 0.008;95% CI: −0.002, 0.018;P = 0.141). The association in the females is nonlinear with an inflection point of 2.5 g/1000kcal (P for non-linearity: Conclusion: In conclusion, moderate dietary collagen has a positive and nonlinear association with telomere length in US females, while no significant associations were found in the males and the overall population.

Hematopoietic stem cell transplantation of aplastic anemia by relative with mutations and normal telomere length: A case report

BACKGROUND Immunosuppressive therapy and matched sibling donor hematopoietic stem cell transplantation(MSD-HSCT)are the preferred treatments for aplastic anemia(AA).CASE SUMMARY In this report,we describe a 43-year-old male patient with severe AA who carried BRIP1(also known as FANCJ),TINF2,and TCIRG1 mutations.Screening of the family pedigree revealed the same TINF2 mutation in his mother and older brother,with his older brother also carrying the BRIP1 variant and demonstrating normal telomere length and hematopoietic function.The patient was successfully treated with oral cyclosporine A,eltrombopag,and acetylcysteine,achieving remission 4 years after receiving MSD-HSCT from his older brother.CONCLUSION This case provides a valuable clinical reference for individuals with suspected pathogenic gene mutations,normal telomere length,and hematopoietic function,highlighting them as potential donors for patients with AA.

硒化壳聚糖对NB4细胞增殖的影响及其与端粒酶活性和hTERT基因表达的关系

目的:研究硒化壳聚糖对体外培养的NB4细胞增殖的影响,探讨这种作用与端粒酶活性和hTERT基因表达的关系。方法:MTT法检测对细胞生长的抑制作用;PCR-ELISA法检测端粒酶活性;RT-PCR法检测hTERTmRNA水平。结果:硒化壳聚糖可时间剂量依赖性地抑制NB4细胞增殖,50～200mg/L硒化壳聚糖作用NB4细胞48h,可明显降低端粒酶活性和hTERTmRNA水平。结论:硒化壳聚糖可通过抑制端粒酶活性,下调hTERT基因表达来抑制NB4细胞的增殖。

Telomere dynamics in induced pluripotent stem cells:Potentials for Human disease modeling

Recent advances in reprograming somatic cells from normal and diseased tissues into induced pluripotent stem cells (iPSCs) provide exciting possibilities for generating renewed tissues for disease modeling and therapy. However, questions remain on whether iPSCs still retain certain markers (e.g. aging) of the original somatic cells that could limit their replicative potential and utility. A reliable biological marker for measuring cellular aging is telomere length, which is maintained by a specialized form of cellular polymerase known as telomerase. Telomerase is composed of the cellular reverse transcriptase protein, the integral RNA component, and other cellular proteins (e.g. dyskerin). Mutations in any of these components of telomerase can lead to a severe form of marrow def iciency known as dyskeratosis congenita (DC). This review summarizes recent f indings on the effect of cellular reprograming via iPS of normal or DC patient-derived tissues on telomerase function and consequently on telomere length maintenance. The potentials and challenges of using iPSCs in a clinical setting will also be discussed.

Telomere function in colorectal cancer

Colorectal cancer is the third most common form of cancer and the second leading cause of cancer-related death in the western world.Tumour cells acquire the hallmarks of cancer during the carcinogenic selection process.Cell immortality is one of the principal features acquired during this process which involves the stabilization of telomere length.It is achieved mainly,by telomerase activation.Thus,the discovery of telomeres and telomerase allowed an understanding of the mechanisms by which cells can become immortalized.Different studies have shown that tumour cells have shorter telomeres than nontumour cells and have detected telomerase activity in the majority of tumours.Survival studies have determined that telomere maintenance and telomerase activity are associated with poor prognosis.Taking into account all the results achieved by different groups,quantification and evaluation of telomerase activity and measurement of telomere length may be useful methods for additional biologic and prognostic staging of colorectal carcinoma.

The expressional level of tankyrase-1 gene and its regulation in colorectal cancer in a Saudi population

Tankyrase1(TNKS1)plays an essential role in cancer progression by regulating telomere length.The study aimed to determine expression of TNKS1 and its regulation in colorectal cancer(CRC)in 20 samples from Saudi patients.mRNA expression of TNKS1 in CRC and paired normal tissues was measured by qRT-PCR.Epigenetic modification of TNKS1 promoter was determined by methylation-specific PCR while somatic mutation was analyzed by Sanger sequencing in exon 10 of the gene.All cancerous and normal tissues expressed TNKS1,but level of expression in CRC tissues was significantly associated with tumor stage though no other parameters;age,gender,and tumor location,showed any correlation.Expression of TNKS1 was markedly higher in earlier(I,II)than in later(Ⅲ,Ⅳ)stages of CRC development.Both cancerous and healthy tissues had unmethylated promoters.Sanger sequencing of exon 10 masked any somatic mutation in the samples.Our findings suggest that up-regulation of TNKS1 was inversely correlated with cancer progression in CRC,indicating that TNKS1 participates in the initiation of CRC by stabilizing telomere length in the first phase of cancer progression.Mechanisms other than TNKS1 might play a role in malignant tumor progression and telomere maintenance in the late stages of CRC.

Telomere and SARS-CoV-2: A Correlation between Them

This article briefly reviews the history of coronavirus detection and states the structural characteristics and pathogenesis of the SARS-CoV-2 strain. Following the conclusion that cellular senescence is thought to contribute to SARS-CoV-2 susceptibility, this article continues to review the structure and function of telomeres. Finally, it briefly states the link between COVID-19 and telomeres caused by the SARS-CoV-2 strain.

The restriction endonuclease Tru9I is a useful tool to analyze telomere sequences separately from interstitial telomeric sequences in <i>Arabidopsis thaliana</i>

We have previously described a simple method to analyze the chromatin structure of Arabidopsis telomeres independently of that of Interstitial Telomeric Sequences (ITSs). By using this method, we found that, whereas ITSs are heterochromatic, Arabidopsis telomeres exhibit euchromatic features [1]. Some concerns have been recently raised about the accuracy of this procedure [2]. Here, we summarize these concerns and justify our experimental approaches and interpretation of results.

Research Progress of Parasite Telomerase and Its Interacting Proteins

Telomerase is a nucleoprotein that contains reverse transcriptase activity. It is reversely transcribed into DNA at the end of its chromosome using its own RNA as a template to ensure the length and stability of telomeres. Its physiological function is closely related to the life process of cells. In recent years, the research on telomeres and telomerase has become a new hotspot, people have a more in-depth research and scientific understanding of their structures and functions, and scientists have also attached great importance to the research progress of telomerase increasingly. Researchers in parasite-related research have successively discovered a large number of telomere and telomerase sequences in a variety of different parasites. These achievements have greatly facilitated the scientific research of diseases caused by parasitic infections, providing a solid research basis for the preparation of new drugs, while enriching the treatment protocols of parasitic diseases, and opening new worlds for the prevention of certain diseases and epidemic transmission. This paper reviews the current research progress of telomerase.

Senescence and longevity in amniotic fluid derived cells

Amniotic fluid stem cells(AFSC) are noncontroversial and abundant potentially transplantable cells. They are derived from fetal and amniotic sources and show osteogenic, neuronal, and adipogenic differentiation in culture. Clinical material must be expanded in culture and sorted if clinical use is desired. Cellular senescence and replicative potential for AFSC cultures has had limited study, with scant data on gene expression over time. We report changes in samples from 17 patients over multiple passages form 10 to 81 population doublings. Longevity was unrelated to telomere length in these cells. It was related to upregulation of TWIST1, which is highly expressed in stem cells, and downregulation of genes associated with apoptosis.