Conserved and Unique Features of Terminal Telomeric Sequences in ALT-Positive Cancer Cells
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ABSTRACT:
PROVIDER: PRJNA1287540 | ENA |
REPOSITORIES: ENA
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Project description:A significant portion of human cancers utilize a recombination-based pathway, Alternative Lengthening of Telomeres (ALT), to maintain telomere length. Targeting the ALT is of growing interest as a cancer therapy, yet a substantial knowledge gap remains regarding the basic features of telomeres in ALT-positive cells. To address this, we adopted END-seq, an unbiased sequencing-based approach, to define the identity and regulation of the terminal sequences of chromosomes in ALT cells. Our data reveal that the terminal portions of chromosomes in ALT cells contain canonical telomeric sequences with the same 5’ terminus bias (-ATC) observed in non-ALT cells. Furthermore, as reported for non-ALT cells, POT1 is required to preserve the precise regulation of the 5’ end in cells that maintain telomere length using the ALT pathway. Thus, the regulation of the terminal 5’ of chromosomes occurs independently of the mechanism of telomere elongation. Additionally, we employed an S1 endonuclease-based sequencing method to determine the presence and origin of single-stranded regions within ALT telomeres. These data shed light on conserved and unique features of ALT telomeres.
2025-07-13 | GSE301770 | GEO
Project description: Not available
| S-EPMC12157469 | biostudies-literature
Project description: Not available
| S-EPMC12316455 | biostudies-literature
Project description:Telomere is a highly refined system for maintaining the stability of linear chromosomes. Most telomeres rely on simple repetitive sequences and telomerase enzymes, but in some species or telomerase-defective situations, alternative telomere lengthening (ALT) mechanism is utilized to protect chromosomal ends. Telomere loss can induce telomere recombination by which specific sequences can be recruited into telomeres. However, canonical telomeric repeat-based telomeres have been found in mammals. Here, we show that mammalian telomeres can also be completely reconstituted using a non-telomeric unique sequence. We found that a specific subtelomeric element, named as mouse template for ALT (mTALT), is utilized for repairing telomeric DNA damage and composing new telomeric sequences in mouse embryonic stem cells. We found a high-level of non-coding mTALT transcript despite the heterochromatic nature of mTALT-based telomere. After ALT activation, the increased HMGN1, a non-histone chromosomal protein, contributed to maintaining telomere stability by regulating telomeric transcriptions. Our findings reveal novel molecular features of potential telomeric sequences which can reconstitute telomeres during cancer formation and evolution.
2020-07-17 | MSV000085772 | MassIVE
Project description:The up-regulation of a telomere maintenance mechanism (TMM) is an essential step in cancer progression to escape dysfunctional telomeres, senescence and apoptosis. Paediatric brain tumors frequently exhibit Alternative Lengthening of Telomere (ALT) as active TMM, but the mechanisms involved in the induction of ALT in brain tumor cells are not clear. Here, we report a model of juvenile zebrafish brain tumor that progressively develops ALT. We discovered that reduced expression of tert and increase in Terra expression precedes ALT development. Additionally, tumors show persistent telomeric DNA damage and loss of heterochromatin marks. Comparative analysis of gene expression after the rescue of ALT with telomerase and analysis of telomerase positive paediatric brain cancers showed normalization of telomeric heterochromatin and maintenance of telomere length, with reduced expression of genes of the pre-replicative complex as hallmark. Thus our study identifies telomere maintenance mechanisms as major drivers of DNA replication and chromatin status at telomeres in brain cancers.
2022-07-01 | GSE134135 | GEO
Project description:Telomere maintenance is indispensable for perpetuated cell division, but telomeres are not necessarily composed of a fixed sequence. Here we report the establishment of a model for alternative lengthening of telomeres (ALT) in mouse embryonic stem cells (mESCs) in which telomeres are reconstructed with an internal ALT template. Longitudinal whole-genome analyses of ALT mESCs showed that pre-amplification of the template into a telomeric region was a prerequisite for ALT activation, and that extensive copy number variations became concentrated in subtelomeric regions. Epigenomic analysis revealed the heterochromatic structure of the ALT telomeres, except for an insulator region within the ALT template. Quantitative proteomics followed by single-cell RNA-sequencing and functional assays revealed that HMGN1 protected new telomeres by regulating telomere repeat-containing RNA transcription and R loop formation in ALT mESCs. These findings implicate an evolutionarily conserved ALT mechanism driven by an internal template and provide a molecular basis underlying telomere evolution.
2020-12-30 | GSE147914 | GEO
Project description:Telomere maintenance is indispensable for perpetuated cell division, but telomeres are not necessarily composed of a fixed sequence. Here we report the establishment of a model for alternative lengthening of telomeres (ALT) in mouse embryonic stem cells (mESCs) in which telomeres are reconstructed with an internal ALT template. Longitudinal whole-genome analyses of ALT mESCs showed that pre-amplification of the template into a telomeric region was a prerequisite for ALT activation, and that extensive copy number variations became concentrated in subtelomeric regions. Epigenomic analysis revealed the heterochromatic structure of the ALT telomeres, except for an insulator region within the ALT template. Quantitative proteomics followed by single-cell RNA-sequencing and functional assays revealed that HMGN1 protected new telomeres by regulating telomere repeat-containing RNA transcription and R loop formation in ALT mESCs. These findings implicate an evolutionarily conserved ALT mechanism driven by an internal template and provide a molecular basis underlying telomere evolution.
2020-12-30 | GSE147915 | GEO
Project description:Telomere maintenance is indispensable for perpetuated cell division, but telomeres are not necessarily composed of a fixed sequence. Here we report the establishment of a model for alternative lengthening of telomeres (ALT) in mouse embryonic stem cells (mESCs) in which telomeres are reconstructed with an internal ALT template. Longitudinal whole-genome analyses of ALT mESCs showed that pre-amplification of the template into a telomeric region was a prerequisite for ALT activation, and that extensive copy number variations became concentrated in subtelomeric regions. Epigenomic analysis revealed the heterochromatic structure of the ALT telomeres, except for an insulator region within the ALT template. Quantitative proteomics followed by single-cell RNA-sequencing and functional assays revealed that HMGN1 protected new telomeres by regulating telomere repeat-containing RNA transcription and R loop formation in ALT mESCs. These findings implicate an evolutionarily conserved ALT mechanism driven by an internal template and provide a molecular basis underlying telomere evolution.
2020-12-30 | GSE147912 | GEO
Project description:Telomere maintenance is indispensable for perpetuated cell division, but telomeres are not necessarily composed of a fixed sequence. Here we report the establishment of a model for alternative lengthening of telomeres (ALT) in mouse embryonic stem cells (mESCs) in which telomeres are reconstructed with an internal ALT template. Longitudinal whole-genome analyses of ALT mESCs showed that pre-amplification of the template into a telomeric region was a prerequisite for ALT activation, and that extensive copy number variations became concentrated in subtelomeric regions. Epigenomic analysis revealed the heterochromatic structure of the ALT telomeres, except for an insulator region within the ALT template. Quantitative proteomics followed by single-cell RNA-sequencing and functional assays revealed that HMGN1 protected new telomeres by regulating telomere repeat-containing RNA transcription and R loop formation in ALT mESCs. These findings implicate an evolutionarily conserved ALT mechanism driven by an internal template and provide a molecular basis underlying telomere evolution.
2020-12-30 | GSE147913 | GEO
Project description:Telomere maintenance is indispensable for perpetuated cell division, but telomeres are not necessarily composed of a fixed sequence. Here we report the establishment of a model for alternative lengthening of telomeres (ALT) in mouse embryonic stem cells (mESCs) in which telomeres are reconstructed with an internal ALT template. Longitudinal whole-genome analyses of ALT mESCs showed that pre-amplification of the template into a telomeric region was a prerequisite for ALT activation, and that extensive copy number variations became concentrated in subtelomeric regions. Epigenomic analysis revealed the heterochromatic structure of the ALT telomeres, except for an insulator region within the ALT template. Quantitative proteomics followed by single-cell RNA-sequencing and functional assays revealed that HMGN1 protected new telomeres by regulating telomere repeat-containing RNA transcription and R loop formation in ALT mESCs. These findings implicate an evolutionarily conserved ALT mechanism driven by an internal template and provide a molecular basis underlying telomere evolution.
2020-12-30 | GSE160487 | GEO