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Telomeres reforged with non-telomeric sequences in mouse embryonic stem cells (WGS)

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE147914 | GEO | 2020/12/30

REPOSITORIES: GEO

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Telomeres reforged with non-telomeric sequences in mouse embryonic stem cells (Iso-seq)

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

Telomeres reforged with non-telomeric sequences in mouse embryonic stem cells (RNA-seq)

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Mammalian telomeres reforged with non-telomeric sequences

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.

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TIN2 deficiency leads to ALT-associated phenotypes and differentiation defects in embryonic stem cells

Project description:Telomere integrity is critical for embryonic development and core telomere-binding proteins such as TIN2 are key to maintaining telomere stability. Here we report that homozygous Tin2S341X resulted in embryonic lethality in mice and reduced expression of Tin2 in the derived mouse embryonic stem cells (mESCs). Homozygous mutant mESCs were able to self-renew and remain undifferentiated but displayed many phenotypes associated with alternative lengthening of telomeres (ALT), including excessively long and heterogeneous telomeres, increased ALT-associated PML bodies, and unstable chromosomal ends. These cells also showed upregulation of Zscan4 expression and elevated targeting of DAXX/ATRX and H3K9me3 marks on telomeres. Furthermore, the mutant mESCs were impeded in their differentiation capacity. Upon differentiation, DAXX/ATRX and PML bodies disassociated from telomeres in these cells, where elevated DNA damage was also apparent. Our results reveal differential responses to telomere dysfunction in mESCs versus differentiated cells and highlight the critical role of TIN2 in embryonic development.

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NR2C/F orphan receptors induce telomere-genome rearrangements in ALT

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m6A RNA modification of TERRA lncRNA drives R-Loop formation and is required for telomere maintenance in ALT tumors [III]

Project description:Telomerase-negative tumors can maintain telomere length by alternative lengthening of telomeres (ALT) but the mechanism of telomere maintenance in ALT cells is not well understood. A significant portion of the relapse Neuroblastoma (NB) tumors are positive for ALT which suggests better dissecting the ALT mechanism could provide novel therapeutic opportunities. TERRA RNA which is derived from the telomere ends is localized to telomeres in R-loop dependent manner and is essential for telomere maintenance. In the present study, we provide evidence that RNA modification at the N6 position of internal adenosine (m6A) in TERRA RNA by methyl transferase METTL3 is essential for telomere maintenance in ALT cells and loss of TERRA m6A/METTL3 leads to accumulation of DNA damage over telomere. Our data suggest that m6A modification in TERRA RNA is required for R-loop formation and telomere targeting of TERRA. We observed that R-loop enriched TERRA is abundantly m6A modified and m6A mediated recruitment of hnRNPA2B1 to TERRA RNA is essential for R-loop formation. Together our study suggests that m6A-mediated R-loop formation could be a widespread mechanism utilized by other chromatin-interacting lncRNAs. We also show treating ALT positive NB cells with small molecule METTL3 inhibitor leads to compromised telomere targeting of TERRA and accumulation of DNA damage over telomere, suggesting METTL3 inhibition could be a therapeutic opportunity for ALT positive NB.

2023-12-13 | GSE240690 | GEO