Genome-wide methylation profiling of sporadic Pancreatic Neuroendocrine Tumors
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Annunziata Di Domenico
PROVIDER: E-MTAB-7924 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:Pancreatic neuroendocrine tumors (PanNETs) account for 1-3% of all neoplasms of the pancreas. Epigenetic changes seem to be the main drivers of PanNET tumorigenesis. Indeed, the most frequent mutated genes in PanNETs are DAXX (Death domain associated protein 6), ATRX (Transcriptional Regulator ATRX) and MEN1 (menin 1), which are all involved in epigenetic regulation. The objective of the project is to study the epigenetic changes undergoing in PanNETs. Specifically, we aimed at investigating whether do exist biologically important epigenetic differences in PanNET, useful for a clinically relevant classification.
2022-11-30 | E-MTAB-11965 | biostudies-arrayexpress
Project description:Pancreatic neuroendocrine tumors (PanNETs) account for 1-3% of all neoplasms of the pancreas. Epigenetic changes seem to be the main drivers of PanNET tumorigenesis. Indeed, the most frequent mutated genes in PanNETs are DAXX (Death domain associated protein 6), ATRX (Transcriptional Regulator ATRX) and MEN1 (menin 1), which are all involved in epigenetic regulation. The objective of the project is to study the epigenetic changes undergoing in PanNETs. Specifically, we aimed at investigating whether do exist biologically important epigenetic differences in PanNET, useful for a clinically relevant classification.
2022-11-30 | E-MTAB-11962 | biostudies-arrayexpress
Project description:In mammals, DNA methylation is essential for protecting repetitive sequences from aberrant transcription, translocation, and homologous recombination. However, DNA hypomethylation occurs during specific developmental stages (e.g. preimplantation embryos) and in certain cell types (e.g., primordial germ cells). The absence of dysregulated repetitive elements in these cells suggests the existence of alternative mechanisms that prevent genome instability triggered by DNA hypomethylation. In this report, we seek to elucidate the factors that play a critical role in ensuring genome stability by focusing on DAXX and ATRX, two proteins that have been linked to transcriptional control and epigenetic regulation. We carried out ChIP-seq and RNA-seq analyses to compare the genome-wide binding and transcriptome profiles of DAXX and ATRX in mouse ES (mES) cells triple knocked out for the three mammalian DNA methyltransferases (DNMTs) (TKO cells) to those in wildtype mES cells. Our data indicate that DAXX and ATRX are distinct in their chromatin-binding profiles and highly co-enriched at tandem repetitive elements. Global DNA hypomethylation, as was the case in TKO cells, further promoted the recruitment of the DAXX/ATRX complex to tandem repeat sequences including IAP (intracisternal A‐particle) retrotransposons and telomeres. Inhibition of DAXX or ATRX in cells with hypomethylated genomes (e.g., TKO cells, mES cells cultured in ground-state conditions, and preimplantation embryos) increased aberrant transcriptional de-repression of repeat elements and dysfunction at telomeres. Furthermore, we provide evidence that DAXX/ATRX-dependent silencing may occur through DAXX’s interaction with SUV39H1 and increased H3K9me3 on repetitive sequences. Our study suggests that DAXX and ATRX are important for safeguarding the genome, particularly in silencing repetitive elements in the absence of DNA methylation. We tested the hypothesis that the DAXX/ATRX complex participates in protecting repetitive elements in the absence of DNA methylation. To this end, we investigated genome-wide chromatin targeting of DAXX and ATRX in wildtype mES cells, and in mES cells that exhibit extensive loss of DNA methylation due to homozygous knockout of all three DNA.
2015-07-15 | E-GEOD-70811 | biostudies-arrayexpress
Project description:Pancreatic neuroendocrine tumors (PanNETs) are a heterogeneous group of tumors that exhibit an unpredictable and broad spectrum of clinical presentations and biological aggressiveness. Surgical resection is still the only curative therapeutic option for localized PanNET but the majority of patients are diagnosed at an advanced and metastatic stage with limited therapeutic options. Key factors limiting the development of new therapeutics are the extensive heterogeneity of PanNETs and the lack of appropriate clinically relevant models. In that context, genomic sequencing of human PanNETs revealed recurrent mutations and structural alterations in several tumor suppressors. Here, we demonstrated that combined loss of MEN1, ATRX, and PTEN, tumor suppressors commonly mutated in human PanNETs, triggers pancreatic neuroendocrine tumorigenesis in mice. Histopathological evaluation and gene expression analyses of the developed tumors confirm the presence of PanNET hallmarks and significant overlap in gene expression patterns found in human disease. Thus, we postulate that the presented novel genetically defined neuroendocrine-specific tumor mouse is the first clinically relevant immunocompetent in vivo PanNET model.
2024-04-17 | GSE248606 | GEO
Project description:This study evaluate the methylation profile of 84 clinically sporadic pancreatic neuroendocrine tumors (PanNETs) with associated clinical and genomic information. We identified three subgroups of PanNETs, termed T1, T2 and T3, with distinct patterns of methylation. The T1 subgroup was enriched for functional tumors and ATRX, DAXX and MEN1 wild-type genotypes. The T2 subgroup contained tumors with mutations in ATRX, DAXX and MEN1 and recurrent patterns of chromosomal losses in half of the genome with no association between regions with recurrent LOH and methylation levels. T2 tumors were larger and had lower methylation in the MGMT gene body, which showed positive correlation with gene expression. The T3 subgroup harboured mutations in MEN1 with recurrent LOH of chromosome 11, was enriched for grade G1 tumors and showed histological parameters associated with better prognosis. Our results suggest a role for methylation in both driving tumorigenesis and potentially stratifying prognosis in PanNETs. These set of normal adjacent pancreata was compared to ICGC pancreatic neuroendocrine tumour methylation. We identified CpG sites located in promoter regions with low levels of methylation (beta value <0.3) in all normal adjacent pancreata and from those selected the most variable probes with a standard deviation >0.20 of DNA methylation levels across all tumors to identify sub-groups.
2021-02-16 | GSE149395 | GEO
Project description:Objective: Daxx is a protein with multiple functions and is essential for embryonic development. Daxx knockout embryos fail to develop properly and exhibit lethal phenotype around E6.5. One of the important functions is as a histone chaperone for the histone H3 variant, H3.3. Daxx interacts with Atrx to form a protein complex that deposits H3.3 into heterochromatic regions of the genome, including centromeres, telomeres and repeat loci. Here, we investigated how histone chaperone function of Daxx contributes to the embryonic development. Methods: We developed two Daxx mutant alleles in the mouse germline which abolish the interactions between Daxx and Atrx (DaxxY130A), Daxx and H3.3 (DaxxS226A). We set up mating between either heterozygous DaxxY130A or heterozygous DaxxS226A individually and looked for the viability of homozygous mutants at different development stages. We also performed bulk RNA-seq on tissues from the two mutant embryos and analyzed the changes in gene expression and transposable elements (TE). Results: We found that the interaction between Daxx and Atrx is dispensable for viability in both the pre- and post-natal setting as homozygous Daxx-Y130A mutants are both viable and fertile. The loss of the Atrx interaction, however, does cause dysregulated expression of both endogenous retroviruses and nearby protein coding genes. On the contrary, the interaction between Daxx and H3.3 is not required for embryonic development but is essential for postnatal viability. Transcriptome analysis of embryonic tissues demonstrates that this interaction is important for silencing endogenous retroviruses and for maintaining proper hematopoiesis. Conclusions: The histone chaperone function of Daxx is dispensable for embryonic development but important for hematopoiesis, which is independent of the interaction with Atrx. Moreover, both the interactions with Atrx and with H3.3 is important for regulation of ERV expression. Overall, these results clearly demonstrate that Daxx and H3.3 have both Atrx-dependent and independent functions, advancing our understanding of this epigenetic regulatory complex.
2023-05-01 | GSE223912 | GEO
Project description:The histone variant H3.3 is incorporated in a replication-independent manner at heterochromatic regions by the ATRX-DAXX histone chaperone complex. Here, we present a high-resolution x-ray crystal structure of an interaction surface between ATRX and DAXX. We used single amino acid substitutions in DAXX that abrogate formation of the complex to explore ATRX-dependent and -independent functions of DAXX. We found that the repression of specific murine endogenous retroviruses is dependent on DAXX, but not on ATRX. In support, we reveal the existence of two biochemically distinct DAXX-containing complexes: The ATRX-DAXX complex involved in gene repression and telomere chromatin structure, and a DAXX-SETDB1-KAP1-HDAC1 complex that represses endogenous retroviruses independently of ATRX and H3.3 incorporation into chromatin. We found that histone H3.3 stabilizes DAXX protein levels and affects DAXX-regulated genes independently of its incorporation into nucleosomes. Our findings represent the first description of a nucleosome-independent function for the H3.3 histone variant.
2017-08-31 | GSE102688 | GEO
Project description:DAXX and ATRX are tumor suppressor proteins that form a complex with histone H3.3 chaperone and are frequently mutated in cancers with the alternative lengthening of telomeres (ALT), such as pediatric glioblastoma. Rapid loss of function of either DAXX or ATRX are not by themselves sufficient to induce the ALT phenotype. However, cells lacking DAXX or ATRX can be readily selected for ALT-like features. Here, we show that a key feature of ALT selected DAXX and ATRX null glioblastoma cells is the attenuation of p53 function. RNA-seq analysis of DAXX or ATRX null U87 glioblastoma cells with ALT-like features revealed that p53 pathway is among perturbed. ALT-selected DAXX and ATRX-null cells had aberrant response to DNA damaging agent etoposide. Both DAXX and ATRX-null ALT cells showed a loss of p53 binding at a subset of response elements. Complementation of DAXX null cells with wt DAXX rescued p53 binding and transcription, while the tumor associated mutation L130R, that disrupts ATRX binding, was incapable of rescuing p53 chromatin binding. We show that histone H3.3 binding is reduced in DAXX-null cells especially at subtelomeric p53 binding sites and telomere repeats. These findings indicate that DAXX and ATRX function to enable p53 chromatin binding through modulation of histone H3.3 binding, especially at sub-telomeric sites.
2022-07-19 | GSE186442 | GEO
Project description:DAXX and ATRX are tumor suppressor proteins that form a complex with histone H3.3 chaperone and are frequently mutated in cancers with the alternative lengthening of telomeres (ALT), such as pediatric glioblastoma. Rapid loss of function of either DAXX or ATRX are not by themselves sufficient to induce the ALT phenotype. However, cells lacking DAXX or ATRX can be readily selected for ALT-like features. Here, we show that a key feature of ALT selected DAXX and ATRX null glioblastoma cells is the attenuation of p53 function. RNA-seq analysis of DAXX or ATRX null U87 glioblastoma cells with ALT-like features revealed that p53 pathway is among perturbed. ALT-selected DAXX and ATRX-null cells had aberrant response to DNA damaging agent etoposide. Both DAXX and ATRX-null ALT cells showed a loss of p53 binding at a subset of response elements. Complementation of DAXX null cells with wt DAXX rescued p53 binding and transcription, while the tumor associated mutation L130R, that disrupts ATRX binding, was incapable of rescuing p53 chromatin binding. We show that histone H3.3 binding is reduced in DAXX-null cells especially at subtelomeric p53 binding sites and telomere repeats. These findings indicate that DAXX and ATRX function to enable p53 chromatin binding through modulation of histone H3.3 binding, especially at sub-telomeric sites.
2022-07-19 | GSE186440 | GEO
Project description:DAXX and ATRX are tumor suppressor proteins that form a complex with histone H3.3 chaperone and are frequently mutated in cancers with the alternative lengthening of telomeres (ALT), such as pediatric glioblastoma. Rapid loss of function of either DAXX or ATRX are not by themselves sufficient to induce the ALT phenotype. However, cells lacking DAXX or ATRX can be readily selected for ALT-like features. Here, we show that a key feature of ALT selected DAXX and ATRX null glioblastoma cells is the attenuation of p53 function. RNA-seq analysis of DAXX or ATRX null U87 glioblastoma cells with ALT-like features revealed that p53 pathway is among perturbed. ALT-selected DAXX and ATRX-null cells had aberrant response to DNA damaging agent etoposide. Both DAXX and ATRX-null ALT cells showed a loss of p53 binding at a subset of response elements. Complementation of DAXX null cells with wt DAXX rescued p53 binding and transcription, while the tumor associated mutation L130R, that disrupts ATRX binding, was incapable of rescuing p53 chromatin binding. We show that histone H3.3 binding is reduced in DAXX-null cells especially at subtelomeric p53 binding sites and telomere repeats. These findings indicate that DAXX and ATRX function to enable p53 chromatin binding through modulation of histone H3.3 binding, especially at sub-telomeric sites.
2022-07-19 | GSE207046 | GEO