LONG-TERM EFFECTS OF BCG VACCINATION ON TELOMERE LENGTH AND TELOMERASE ACTIVITY
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PROVIDER: PRJNA1280003 | ENA |
REPOSITORIES: ENA
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Project description:Vaccination with Bacillus Calmette-Guérin (BCG) induces long-term innate immune memory, also called trained immunity, characterized by metabolic and epigenetic changes leading to enhanced responsiveness upon exposure to heterologous pathogens. BCG vaccination was also shown to reduce systemic inflammation. Thus, BCG counteracts two significant immunological changes associated with aging: impaired responsiveness and elevated systemic inflammation. However, if and how BCG impacts other aging-related processes in immune cells, such as telomere shortening, remains unexplored. In this study, we investigated the transcriptional impact of BCG training on telomere maintenance-related genes through RNA sequencing and determined average telomere length from whole blood via RT-qPCR before and three months after BCG vaccination in two independent human cohorts. Trained immunity response was measured by ex-vivo cytokine production induced by a heterologous stimulus three months after vaccination compared to baseline. In addition, we examined the effects of BCG on telomerase activation using an in vitro trained immunity model. In vitro BCG training upregulated processes related to telomere maintenance and telomerase localization. In vivo, we observed shorter telomeres three months after BCG vaccination in both studies. Interestingly, the induction of a trained immunity response by BCG was correlated to the change in telomere length: more telomere shortening was observed in trained immunity non-responder individuals, particularly in males. Higher testosterone concentrations before vaccination were linked to more telomere loss. In vitro, BCG training of human monocytes activated the telomerase enzyme, predominantly in females, an effect that was blocked by exogenous testosterone treatment. Overall, this study reports sex-specific long-term impacts of BCG vaccination on telomerase activity and telomere maintenance. These data add to the arguments that BCG vaccination impacts aging mechanisms, which warrants more investigation.
2025-07-28 | GSE300272 | GEO
Project description:Telomere homeostasis, crucial for various biological processes, relies on telomerase activity. We identified ZC3H15 as a novel telomerase-interacting protein. Its deletion unexpectedly increased telomerase activity but led to shortened telomeres and cellular senescence. ZC3H15 interacts with telomerase and itself, regulating telomerase activity in an RNA-dependent manner. Proximity labeling showed ZC3H15's interaction with proteins involved in organelle assembly and RNA processes. Loss of ZC3H15 sequestered TERC in the Cajal body, reducing telomerase recruitment to telomeres during S phase. These findings unveil ZC3H15's role in telomere dynamics and cellular senescence, suggesting its potential as a target for cancer therapy or anti-aging interventions.
2024-05-06 | PXD052036 |
Project description:The century-old Mycobacterium bovis Bacillus Calmette-Guerin (BCG) remains the only licensed vaccine against tuberculosis (TB). Despite this, there is still a lot to learn about the immune response induced by BCG, both in terms of phenotype and specificity. Here, we investigated the BCG-specific gene expression changes induced in PBMCs and CD4 memory T cells by BCG in individuals pre- and 8m post vaccination. We also determined whether reactivity against a peptide pool defined in individuals with controlled latent TB infection (MTB300), and with peptides homologous to peptides found in BCG, was boosted following BCG vaccination.
2021-12-06 | GSE156422 | GEO
Project description:Telomere length heterogeneity in various cell types including stem cells and cancer cells has been recognized. Cell heterogeneity also is found in pluripotent stem cells such as embryonic stem cells (ESCs). The implication and mechanisms underlying the heterogeneity remain to be defined. We have optimized a robust method that can simultaneously measure telomere length coupled with RNA-sequencing analysis (scT&R-seq) in the same human ES cell. Using this method, we show that telomere length varies with pluripotency state. Long telomere hESCs highly express TERF1/TRF1 as well as ZFP42/REX1, PRDM14 and NANOG for naïve pluripotency, in contrast to short telomere hESCs. hESCs express high telomerase activity as expected, and ubiquitously express NOP10 and DKC1, stabilizing components of telomerase complexes, regardless of telomere lengths. Moreover, new candidate genes such as MELK, MSH6 and UBQLN1 cluster with long telomeres and pluripotency network. Notably, short telomere hESCs exhibit higher oxidative phosphorylation primed for lineage differentiation, whereas long telomere hESCs show elevated glycolysis, another key feature for naïve pluripotency. Our data further suggest that telomere length is implicated in metabolism activity and pluripotency state of hESCs. Single cell analysis of telomere and RNA-sequencing can be exploited to further understand the molecular mechanisms of telomere heterogeneity.
2017-11-06 | GSE98644 | GEO
Project description:Background and Aims: Telomere dysfunction can increase tumor initiation by induction of chromosomal instability, but initiated tumor cells need to reactivate telomerase for genome stabilization and tumor progression. However, this concept has not been proven in vivo since appropriate mouse models were lacking. Here, we analyzed hepatocarcinogenesis (i) in a novel mouse model of inducible telomere dysfunction on a telomerase-proficient background, (ii) in telomerase knockout mice with chronic telomere dysfunction (G3 mTerc-/-), and (iii) in wild-type mice with functional telomeres and telomerase. Transient or chronic telomere dysfunction enhanced the rates of chromosomal aberrations during hepatocarcinogenesis, but only telomerase-proficient mice exhibited significantly increased rates of macroscopic tumor formation and cancer cell proliferation in response to telomere dysfunction. In contrast, telomere dysfunction resulted in pronounced accumulation of DNA damage, cell cycle arrest and apoptosis in telomerase-deficient liver tumors. Together, these data provide the first in vivo evidence that transient telomere dysfunction during early and late stages of tumorigenesis can promote chromosomal instability and carcinogenesis in telomerase-proficient mice in the absence of additional genetic checkpoint defects at germline level.
2012-03-31 | GSE36813 | GEO
Project description:Background and Aims: Telomere dysfunction can increase tumor initiation by induction of chromosomal instability, but initiated tumor cells need to reactivate telomerase for genome stabilization and tumor progression. However, this concept has not been proven in vivo since appropriate mouse models were lacking. Here, we analyzed hepatocarcinogenesis (i) in a novel mouse model of inducible telomere dysfunction on a telomerase-proficient background, (ii) in telomerase knockout mice with chronic telomere dysfunction (G3 mTerc-/-), and (iii) in wild-type mice with functional telomeres and telomerase. Transient or chronic telomere dysfunction enhanced the rates of chromosomal aberrations during hepatocarcinogenesis, but only telomerase-proficient mice exhibited significantly increased rates of macroscopic tumor formation and cancer cell proliferation in response to telomere dysfunction. In contrast, telomere dysfunction resulted in pronounced accumulation of DNA damage, cell cycle arrest and apoptosis in telomerase-deficient liver tumors. Together, these data provide the first in vivo evidence that transient telomere dysfunction during early and late stages of tumorigenesis can promote chromosomal instability and carcinogenesis in telomerase-proficient mice in the absence of additional genetic checkpoint defects at germline level. RNA from liver tumors derived from from DEN treated TTD+ mice TTD- mice and RNA from normal liver 48h-72h after doxycycline induced transient telomere dysfunction in TTD+ and TTD- liver were isolated and RNA was extracted. Agilent Mouse 4x44K v2 arrays were used. DNA from liver tumors and corrresponding kidney as control derived from from DEN treated TTD+ mice, TTD- mice and mTERC-/- G3 mice was isolated and extracted using Phenol/Chloroform. Agilent Mouse 4x44K and Mouse 1x244K arrays were used.
2012-03-30 | E-GEOD-36813 | biostudies-arrayexpress
Project description:Critically short telomeres activate p53-mediated apoptosis, resulting in organ failure and causing malignant transformation. Mutations in genes responsible for telomere maintenance are linked to a number of specific human diseases. We derived induced pluripotent stem cells (iPSCs) from patients with mutations in the TERT and TERC telomerase genes. Telomerase-mutant iPSCs elongated telomeres, but at a lower rate than healthy iPSCs, and the magnitude of the elongation deficit correlated with the specific mutation’s impact on telomerase activity. However, elongation significantly varied among iPSC clones harboring the same mutation, and was affected by genetic and environmental factors. iPSCs cultured in hypoxia showed increased telomere length. Potential influence of residual expression of reprogramming factors on telomerase regulation and telomere length was ruled out by excising the transgenes after successful reprogramming. Evidence for telomerase-independent telomere elongation was not observed in these cells. We demonstrate that telomerase is required for telomere elongation in iPSCs and uncover heterogeneity in telomere maintenance even between clones derived from individual patients or siblings with the same mutation, indicating that telomere phenotype may be influenced by acquired and environmental agents. Our data underscore the necessity of studying multiple clones when using iPSCs to model disease. The exon array were done to validate the pluripotent phenotype of the derived normal and telomerase mutant iPSC and to potentially identify differentially expressed genes in mutant iPSC. Objective: confirming pluripotency by comparing telomerase mutated-, control-iPSC to human ESC and to their parental somatic cells (fibroblast used for iPSC derivation) 20 samples total, 5 different fibroblast cells, 13 iPSC lines, 1 ES line (H1) from different passages
2013-02-11 | E-GEOD-42869 | biostudies-arrayexpress
Project description:Telomere maintenance is essential for genome stability, and its regulation during the cell cycle remains a critical area of research. Screening for telomerase-interacting proteins is crucial for understanding the biological processes of telomerase maturation, processing, and recruitment. Using PhastID screening with TERT during S-phase, we identify STRBP, a GEMs-associated protein, as a novel regulator of telomerase activity and telomere length. Our data demonstrate that STRBP mediates interaction with telomerase through TERRA, this interaction negatively regulates telomerase activity, thereby limiting telomere elongation. Notably, TERRA levels decrease during S-phase, potentially facilitating the recruitment of telomerase to telomeres and enabling telomere extension.
2025-10-09 | PXD069238 |
Project description:Vaccination against tuberculosis by intradermal Bacillus Calmette-Guérin (BCG) injection saves many lives, supposedly by inducing adaptive immune memory in lymphocytes. Epidemiologically, BCG vaccination is also associated with reduced childhood mortality unrelated to TB, which is attributed to innate immune memory, also termed trained immunity. We recently demonstrated improved protection against tuberculosis infection in highly susceptible rhesus macaques by mucosal BCG vaccination, correlating with a unique local but no peripheral immune profile. Here, we investigated local and peripheral innate immune function after intradermal versus mucosal vaccination with M. bovis BCG or the live attenuated, M. tuberculosis-derived candidate, MTBVAC. The results demonstrate an augmented frequency of trained immunity in monocytes after respiratory mucosal administration of live attenuated mycobacterial vaccines compared to intradermal immunization, with MTBVAC being equally potent as BCG. These results provide further support to strategies for improving TB vaccination and, more broadly, modulating innate immunity via mucosal surfaces.
2021-01-27 | GSE159046 | GEO
Project description:BCG vaccination in rhesus macaques
| PRJNA902836 | ENA