TIN2 deficiency leads to ALT-associated phenotypes and differentiation defects in embryonic stem cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA658144 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12478355_1.fastq.gz | Fastqsanger.gz | |||
| SRR12478355_2.fastq.gz | Fastqsanger.gz | |||
| SRR12478356_1.fastq.gz | Fastqsanger.gz | |||
| SRR12478356_2.fastq.gz | Fastqsanger.gz | |||
| SRR12478357_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 24 |
Similar Datasets
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.
2022-04-07 | GSE156514 | GEO
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 promyelocytic leukemia (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.
| S-EPMC9120858 | biostudies-literature
Project description:Haploinsufficiency of the progranulin (PGRN) protein is a leading cause of frontotemporal lobar degeneration (FTLD). Mouse models have been developed to study PGRN functions. However, PGRN deficiency in the commonly used C56BL/6 mouse strain background leads to very mild phenotypes, and pathways regulating PGRN deficiency phenotypes remain to be elucidated. We generated PGRN-deficient mice in the FVB/N background and compared PGRN deficiency phenotypes between C56BL/6 and FVB/N background via immunostaining, western blot, RNA-seq, and proteomics approaches. We also identified sPLA2-IIA as a novel binding partner of PGRN and demonstrated the importance of sPLA2-IIA in modifying PGRN deficiency phenotypes using inhibitor treatment and AAV-mediated overexpression in mouse models. We report that PGRN loss in the FVB/N mouse strain results in earlier onset and stronger FTLD-related and lysosome-related phenotypes. We found that PGRN interacts with sPLA2-IIA, a member of the secreted phospholipase A2 (sPLA2) family member and a key regulator of inflammation that is expressed in FVB/N but not C56BL/6 background. sPLA2-IIA inhibition rescues PGRN deficiency phenotypes and sPLA2-IIA overexpression drives enhanced gliosis and lipofuscin accumulation in PGRN-deficient mice. Additionally, RNA-seq and proteomics analysis revealed that mitochondrial pathways are upregulated in the PGRN-deficient C57BL/6 mice but not in the FVB/N mice. Our studies establish a better mouse model for FTLD-GRN and uncover novel pathways modifying PGRN deficiency phenotypes.
2025-03-20 | MSV000097392 | MassIVE
Project description:MATRIN3 deficiency leads to cGAS-STING activation
| PRJNA1092701 | ENA
Project description:MATRIN3 deficiency leads to cGAS-STING activation
| PRJNA895450 | ENA
Project description:Drosophila melanogaster alt, aluminum tubes, is differentially expressed in 14 experiment(s);
| FBgn0038535 | ExpressionAtlas
Project description:Drosophila melanogaster alt, aluminum tubes, is expressed in 4 baseline experiment(s);
| FBgn0038535 | ExpressionAtlas
Project description:MATRIN3 deficiency leads to cGAS-STING activation (NanoString)
| PRJNA895455 | ENA
Project description:<p>Many tumors maintain chromosome ends through a telomerase-independent, homologous recombination based mechanism called alternative lengthening of telomeres (ALT). While ALT occurs in only a subset of tumors, it is strongly associated with mutations in the genes encoding components of the histone H3.3 chaperone complex, ATRX and DAXX. To date the mechanistic role of ATRX and particularly DAXX mutations in potentiating ALT remains poorly understood. We identify an osteosarcoma cell line, G292, with a unique chromosomal translocation resulting in loss of DAXX function, while retaining functional ATRX. Using this distinctive resource, we demonstrate that introduction of wild type DAXX suppresses the ALT phenotype and restores localization of the ATRX/DAXX complex to PML bodies. This provides the first direct molecular evidence that ongoing DAXX deficiency is essential for maintenance of the ALT phenotype and highlights the potential for therapeutic targeting of this oncogenic pathway.</p>
| phs001495 | dbGaP
Project description:Most sarcomas have complex karyotype and are characterized by multiple chromosomal rearrangements. Moreover, sarcomas very frequently maintain their telomeres by recombination in the process called Alternative Lengthening of Telomeres (ALT) which enables their continuous growth and immortalization. Previously our group showed that orphan receptors bind specifically to the ALT telomeres and that their presence is important for the ALT mechanism. In these studies we focus on the function of orphan receptors at the telomeres and their contribution to telomeric recombination. We demonstrate that orphan receptors induce proximity of their binding sites in telomeric and genomic context and reveal novel aspects of ALT which are telomere-genome rearrangements which can underlie complexity of sarcomas. Our data perturb the dogma of telomere function in protecting the genome integrity. Here we show that in some cases telomeres may in fact drive genomic instability and chromosomal rearrangements by recombination with genomic sites. Characterization of TRF2 and orphan receptor NR2F/C2 binding sites in ALT (-) and ALT (+) cells.
2015-02-23 | E-GEOD-46237 | biostudies-arrayexpress