Mouse HP1γ regulates TRF1 expression and telomere stability
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1003795 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25581733_1.fastq.gz | Fastqsanger.gz | |||
| SRR25581733_2.fastq.gz | Fastqsanger.gz | |||
| SRR25581734_1.fastq.gz | Fastqsanger.gz | |||
| SRR25581734_2.fastq.gz | Fastqsanger.gz | |||
| SRR25581735_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 14 |
Similar Datasets
Project description:Telomeric Repeat-containing RNA are long non-coding RNAs generated from the telomeres. TERRAs are essential for the establishment of heterochromatin marks at telomeres, which serve for the binding of members of the Heterochromatin Protein 1protein family of epigenetic modifiers involved with chromatin compaction and gene silencing. While HP1γ is enriched on gene bodies of actively transcribed mammalian genes, it is unclear if its transcriptional role is important for HP1γ function in telomere cohesion and telomere maintenance. We aimed to study the effect of mouse HP1γ on the transcription of telomere factors and molecules that can affect telomere maintenance. We investigated the telomere function of HP1γ by using HP1γ deficient mouse embryonic fibroblastsderiving from 13.5 embryonic day embryos compared to their littermate controls. We used gene expression analysis of HP1γ deficient MEFs and validated the molecular and mechanistic consequences of HP1γ loss by telomere FISH, immunofluorescence, RT-qPCR and DNA-RNA Immunoprecipitation. Loss of HP1γ in primary MEFs led to a downregulation of various telomere and telomere-accessory transcripts, including the shelterin protein TRF1. Its downregulation is associated with increased telomere replication stress and DNA damage (γH2AX), effects more profound in females. We suggest that the source for the impaired telomere maintenance is a consequence of increased telomeric DNARNA hybrids and TERRAs arising at and from mouse chromosomes 18 and X. Our results suggest an important transcriptional control by mouse HP1γ of various telomere factors including TRF1 protein and TERRAs that has profound consequences on telomere stability, with a potential sexually dimorphic nature.
2023-08-19 | GSE240434 | GEO
Project description:TRF1, a component of the telomere shelterin complex, plays crucial roles in telomere protection, telomere length regulation, and stemness. Here, we describe a previously unknown connection between TRF1 and metabolism. Telomere attrition has been linked to obesity. Our study reveals that Trf1-deficient mice exhibit a leaner phenotype, reduced adiposity, and improved glucose tolerance, even when subjected to a high-fat diet, independently of telomere shortening. These findings uncover a previously unknown role of TRF1 in regulating metabolism. Our research not only contributes to the understanding of obesity onset but also positions TRF1 as a potential therapeutic target for combating metabolic syndrome.
2025-09-22 | GSE273596 | GEO
Project description:The naked mole rat (NMR), a long-lived and cancer resistant rodent, is highly resistant to hypoxia. Here, using robust cellular models wherein the mouse telomeric protein TRF1 is substituted by the NMR TRF1 or its mutant forms, we show that TRF1 supports maximal glycolytic capacity under low oxygen, shows increased nuclear localization and association with telomeres, and protects telomeres from replicative stress. We pinpoint this evolutionary gain of metabolic function to specific amino acid changes in the homodimerization domain of this protein. We further find that NMR TRF1 accelerates telomere shortening. These findings reveal an evolutionary strategy to adapt telomere biology for metabolic control under an extreme environment.
2021-03-02 | GSE163064 | GEO
Project description:Telomeres prevent ATM activation by sequestering chromosome termini within telomere loops (t-loops). Mitotic arrest promotes telomere linearity and a localized ATM-dependent telomere DNA damage response (DDR) through an unknown mechanism. Using unbiased interactomics, biochemical screening, molecular biology, and super-resolution imaging, we found that mitotic arrest-dependent (MAD) telomere deprotection requires the combined activities of the Chromosome passenger complex (CPC) on shelterin, and the BLM-TOP3A-RMI1/2 (BTR) complex on t-loops. During mitotic arrest, the CPC component Aurora Kinase B (AURKB) phosphorylated both the TRF1 hinge and TRF2 basic domains. Phosphorylation of the TRF1 hinge domain enhances CPC and TRF1 interaction through the CPC Survivin subunit. Meanwhile, phosphorylation of the TRF2 basic domain promotes telomere linearity, activates a telomere DDR dependent on BTR-mediated double Holliday junction dissolution, and leads to mitotic death. We identify that the TRF2 basic domain functions in mitosis-specific telomere protection and reveal a regulatory role for TRF1 in controlling a physiological ATM-dependent telomere DDR. The data demonstrate that MAD telomere deprotection is a sophisticated active mechanism that exposes telomere ends to signal mitotic stress.
2025-01-28 | PXD043281 | Pride
Project description:The heterochromatin protein 1 (HP1) family members are canonical effectors and propagators of gene repression mediated by histone H3 lysine 9 (H3K9) methylation. HP1γ exhibits an increased interaction with active transcription elongation-associated factors in embryonic stem cells (ESCs) compared to somatic cells. However, whether this association has a functional consequence remains elusive. Here we find that genic HP1γ colocalizes and enhances enrichment of transcription elongation-associated H3K36me3 rather than H3K9me3. Unexpectedly, sustained H3K36me3 deposition is dependent on HP1γ. HP1γ-deleted ESCs display reduced H3K36me3 enrichment, concomitant with decreased expression at shared genes which function to maintain cellular homeostasis. Both the H3K9me3-binding chromodomain and histone binding ability of HP1γ are dispensable for maintaining H3K36me3 levels. Instead, the chromoshadow together with the hinge domain of HP1γ that confer protein and nucleic acid-binding ability are sufficient because they retain the ability to interact with NSD1, an H3K36 methyltransferase. HP1γ-deleted ESCs have a slower self-renewal rate and an impaired ability to differentiate towards cardiac mesoderm. Our findings reveal a requirement for HP1γ in faithful establishment of transcription elongation in ESCs, which regulates pluripotency.
2020-11-01 | GSE144862 | GEO
Project description:The heterochromatin protein 1 (HP1) family members are canonical effectors and propagators of gene repression mediated by histone H3 lysine 9 (H3K9) methylation. HP1γ exhibits an increased interaction with active transcription elongation-associated factors in embryonic stem cells (ESCs) compared to somatic cells. However, whether this association has a functional consequence remains elusive. Here we find that genic HP1γ colocalizes and enhances enrichment of transcription elongation-associated H3K36me3 rather than H3K9me3. Unexpectedly, sustained H3K36me3 deposition is dependent on HP1γ. HP1γ-deleted ESCs display reduced H3K36me3 enrichment, concomitant with decreased expression at shared genes which function to maintain cellular homeostasis. Both the H3K9me3-binding chromodomain and histone binding ability of HP1γ are dispensable for maintaining H3K36me3 levels. Instead, the chromoshadow together with the hinge domain of HP1γ that confer protein and nucleic acid-binding ability are sufficient because they retain the ability to interact with NSD1, an H3K36 methyltransferase. HP1γ-deleted ESCs have a slower self-renewal rate and an impaired ability to differentiate towards cardiac mesoderm. Our findings reveal a requirement for HP1γ in faithful establishment of transcription elongation in ESCs, which regulates pluripotency.
2020-11-01 | GSE144861 | GEO
Project description:The mechanisms that regulate pluripotency and cell fate are still largely unknown. Here, we show that the Telomere Repeat Binding Factor 1 (TRF1), a component of the shelterin telomere protection complex, regulates genome-wide binding of polycomb to stem cell and pluripotency genes, thereby exerting vast epigenetic changes that contribute to maintain embryonic stem cells in a naïve state. We further show that TRF1 mediates these effects by regulating TERRA, the long-non-coding RNAs transcribed from telomeres and that are part of the telomeric chromatin. In particular, we find that TERRAs are enriched at polycomb and stem cell genes in pluripotent cells and that TRF1 abrogation results in increased TERRA levels and a higher binding of TERRA to those genes, an event that is coincidental with TRF1-dependent induction of cell-fate programs and loss of the naïve state. These results are consistent with a model in which TERRA recruits polycomb to genes important for pluripotency and differentiation in a manner that is dependent on TRF1. These unprecedented findings explain the long-standing observation that TRF1 is one of the most upregulated genes during induction of pluripotency and it is essential for the induction and maintenance of pluripotency.
2019-08-09 | GSE121759 | GEO
Project description:Telomeric repeat sequences are prone to induce replication stress and one of the core telomere binding proteins, TRF1, is thought to counteract these problems. The molecular mechanisms coming into play upon TRF1 loss were not clearly defined though. This study combines an inducible TRF1 loss with telomere-targeted proteomics to analyze the incurring changes. The results show that loss of TRF1 causes important alterations in telomere associated proteins and the new profile resembles in a number of ways that of cells in which telomeres are maintained by telomerase-independent mechanisms, named ALT. The presence of DNA repair proteins (MRN complex, the SMC5/6 complex), some increases in telomere colocalization with PML bodies, sister chromatid exchanges and clear signs of increased TERRA transcription and mitotic break-induced replication are part of these phenotypes. The data also show that these early ALT phenotypes can be differentiated from drug induced replication stress, and part of this ALT response is conserved in human cells. These studies therefore point to a critical role for TRF1 in preventing the emergence of ALT and hence immortalization of cells. Given that the details for how ALT actually is initiated remained unclear, these findings are an important step forward and will spur new research into that question.
2020-01-22 | PXD017022 | Pride
Project description:Renal tubular epithelial cells (TECs) are critical mediators of renal fibrogenesis. Telomere dysfunction has been associated with renal injury and fibrosis. However, the role of telomere dysfunction specifically in TECs in the onset and progression of renal fibrosis remains poorly understood. To investigate the impact of telomere dysfunction on renal injury and fibrosis, we generated mice depleted for the shelterin component TRF1 specifically in TECs. Genetic ablation of Trf1 caused decline in renal function, tubular injury and tubulointerstitial fibrosis eight weeks after TRF1 depletion, concomitant with excessive accumulation of extracellular matrix (ECM), cell cycle arrest at G2/M phase, and telomeric damage. Trf1Δ/Δ mice activated regenerative repair mechanism, increasing the risk of of chronic kidney disease (CKD) progression following acute kidney injury (AKI), supporting proliferation-mediated telomere shortening in tubular cells. Mechanistically, Trf1 deletion upregulated Ras–Raf–Mek–Erk, PI3k/Akt/mTOR and p38 pathways. At humane endpoint, Trf1Δ/Δ mice displayed elevated urinary albumin-to-creatinine ratio (uACR), associated with augmented interstitial fibrosis and tubular atrophy eventually leading to CKD. In folic acid (FA)-induced nephropathy, depletion of Trf1 in TECs mitigated the fibrogenic phenotype of CKD. Collectively, our study underlies the important role of TECs in the development and progression of renal fibrosis and CKD associated to dysfunctional telomeres.
2025-08-21 | GSE272068 | GEO
Project description:Naked mole rat TRF1 safeguards glycolytic capacity and telomere replication under low oxygen
| PRJNA684585 | ENA