BCL-2 pathway counteracts aneuploidy in mammalian embryos
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB36524 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR3858700_1.fastq.gz | Fastqsanger.gz | |||
| ERR3858700_2.fastq.gz | Fastqsanger.gz | |||
| ERR3858710_1.fastq.gz | Fastqsanger.gz | |||
| ERR3858710_2.fastq.gz | Fastqsanger.gz | |||
| ERR3858720_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 60 |
Similar Datasets
Project description:BCL-2 pathway counteracts aneuploidy in mammalian embryos
| PRJEB36524 | ENA
Project description:DNA double-strand breaks (DSBs) are toxic to mammalian cells. However, during meiosis, more than 200 DSBs are generated deliberately, to ensure reciprocal recombination and orderly segregation of homologous chromosomes. If left unrepaired, meiotic DSBs can cause aneuploidy in gametes and compromise viability in offspring. Oocytes in which DSBs persist are therefore eliminated by the DNA-damage checkpoint. The checkpoint’s downstream effectors that trigger oocyte death, thereby preserving genome stability across the generations, are unknown. Here we show that the DNA-damage checkpoint eliminates oocytes via the pro-apoptotic BCL-2 pathway members Puma, Noxa and Bax. Deletion of these factors prevents oocyte elimination in recombination-repair mutants, even when the abundance of unresolved DSBs is high. Remarkably, surviving oocytes can extrude a polar body and be fertilised, despite chaotic chromosome segregation at the first meiotic division. Our findings raise the possibility that allelic variants of the BCL-2 pathway could influence the risk of embryonic aneuploidy.
2020-03-26 | E-MTAB-8752 | biostudies-arrayexpress
Project description:Preimplantation genetic diagnosis (PGD) of aneuploidy by fluorescence in situ hybridisation (FISH) has not delivered the expected clinical benefit. Many previous re-analysis studies of embryos deemed aneuploid by FISH on day 3 have found a high degree of chromosomal normalcy at the blastocyst stage. While most have interpreted this as “self correction,” there remains a lack of evidence for such a phenomenon. A more comprehensive technique for 24 chromosome aneuploidy screening was utilised here to re-evaluate blastocysts previously diagnosed as abnormal by FISH and investigate possible self correction mechanisms, including extrusion or duplication of aneuploid chromosomes resulting in uniparental isodisomy (UPID), and preferential segregation of aneuploidy to the trophectoderm (TE). Embryos that developed to a morphologically normal blastocyst after an aneuploidy diagnosis by cleavage stage FISH were biopsed into 4 sections, 3 TE and 1 inner cell mass (ICM), and randomised for evaluation by single nucleotide polymorphism (SNP) microarray based 24 chromosome aneuploidy screening (MA-PGD). Fifty-eight percent of blastocysts were euploid for all 24 chromosomes despite an aneuploid FISH result on day 3. Only 18% were consistent with the original FISH diagnosis, while the remaining 24% identified abnormalities that were different from the original FISH diagnosis. Abnormalities did not preferentially segregate to the TE and aneuploid chromosome extrusion or duplication resulting in UPID did not occur. Cleavage stage FISH is poorly predictive of aneuploidy in an embryo that develops into a morphologically normal blastocyst. Clinicians should consider re-evaluating embryos diagnosed as aneuploid by FISH that form morphologically normal blastocysts using a validated comprehensive 24 chromosome aneuploidy screening method.
2010-05-19 | GSE18932 | GEO
Project description:Preimplantation genetic diagnosis (PGD) of aneuploidy by fluorescence in situ hybridisation (FISH) has not delivered the expected clinical benefit. Many previous re-analysis studies of embryos deemed aneuploid by FISH on day 3 have found a high degree of chromosomal normalcy at the blastocyst stage. While most have interpreted this as âself correction,â there remains a lack of evidence for such a phenomenon. A more comprehensive technique for 24 chromosome aneuploidy screening was utilised here to re-evaluate blastocysts previously diagnosed as abnormal by FISH and investigate possible self correction mechanisms, including extrusion or duplication of aneuploid chromosomes resulting in uniparental isodisomy (UPID), and preferential segregation of aneuploidy to the trophectoderm (TE). Embryos that developed to a morphologically normal blastocyst after an aneuploidy diagnosis by cleavage stage FISH were biopsed into 4 sections, 3 TE and 1 inner cell mass (ICM), and randomised for evaluation by single nucleotide polymorphism (SNP) microarray based 24 chromosome aneuploidy screening (MA-PGD). Fifty-eight percent of blastocysts were euploid for all 24 chromosomes despite an aneuploid FISH result on day 3. Only 18% were consistent with the original FISH diagnosis, while the remaining 24% identified abnormalities that were different from the original FISH diagnosis. Abnormalities did not preferentially segregate to the TE and aneuploid chromosome extrusion or duplication resulting in UPID did not occur. Cleavage stage FISH is poorly predictive of aneuploidy in an embryo that develops into a morphologically normal blastocyst. Clinicians should consider re-evaluating embryos diagnosed as aneuploid by FISH that form morphologically normal blastocysts using a validated comprehensive 24 chromosome aneuploidy screening method. Affymetrix SNP arrays were processed according to the manufacturer's directions on DNA extracted from 50 cryopreserved blastocysts that were biopsied into 3 sections of trophectoderm and 1 inner cell mass section. Affymetrix SNP array analysis was successfully completed on 145 trophectoderm samples and 47 ICM samples from embryos, 8 lymphocyte samples from cell lines and 6 mixed male and female samples.
2010-05-19 | E-GEOD-18932 | biostudies-arrayexpress
Project description:Nuclear abnormalities are commonly found in human IVF embryos and are associated with DNA damage, aneuploidy, and decreased developmental potential.
2015-09-11 | GSE72150 | GEO
Project description:Nuclear abnormalities are commonly found in human IVF embryos and are associated with DNA damage, aneuploidy, and decreased developmental potential. Immunohistochemical, microscopic, and cytogenetic analysis of human IVF embryos at different developmental stages and morphologic grades.
2015-09-11 | E-GEOD-72150 | biostudies-arrayexpress
Project description:Aneuploidy represents the most prevalent form of genetic instability found in human embryos and is the leading genetic cause of miscarriage and developmental delay in newborns. Telomere DNA deficiency is associated with genomic instability in somatic cells and may play a role in development of aneuploidy commonly found in female germ cells and human embryos. To test this hypothesis, we developed a method capable of quantifying telomere DNA in parallel with 24-chromosome aneuploidy screening from the same oocyte or embryo biopsy. Aneuploid human polar bodies possessed significantly less telomere DNA than euploid polar bodies from sibling oocytes (-3.07 fold, P=0.016). This indicates that oocytes with telomere DNA deficiency are prone to aneuploidy development during meiosis. Aneuploid embryonic cells also possessed significantly less telomere DNA than euploid embryonic cells at the cleavage stage (-2.60 fold, P=0.002) but not at the blastocyst stage (-1.18 fold, P=0.340). The lack of a significant difference at the blastocyst stage was found to be due to telomere DNA normalization between the cleavage and blastocyst stage of embryogenesis and not due to developmental arrest of embryos with short telomeres. Heterogeneity in telomere length within oocytes may provide an opportunity to improve the treatment of infertility through telomere based selection of oocytes and embryos with reproductive competence.
2011-07-04 | GSE25864 | GEO
Project description:Many studies estimate that chromosomal mosaicism within the cleavage stage human embryo is high. However, comparison of two unique methods of aneuploidy screening of blastomeres within the same embryo has not been conducted and may indicate whether mosaicism is overestimated due to technical inconsistency rather than biological phenomena. The present study investigates the prevalence of chromosomal abnormality and mosaicism found with two different single cell aneuploidy screening techniques.Thirteen arrested cleavage stage embryos were studied. Each was biopsied into individual cells (n=160). The cells from each embryo were randomized into two groups. Those destined for FISH based aneuploidy screening (n=75) were fixed, 1 cell per slide. Cells for SNP microarray based aneuploidy screening (n=85) were put into individual tubes. Microarray was significantly more reliable (96%) than FISH (83%) for providing an interpretable result (P=0.004). Markedly different results were obtained when comparing microarray and FISH results from individual embryos. Mosaicism was significantly less commonly observed by microarray (4 of 13 embryos; 31%) than by FISH (13 of 13 embryos; 100%)(P=0.0005). Although FISH evaluated fewer chromosomes per cell and fewer cells per embryo, FISH still displayed significantly more unique genetic diagnoses per embryo (3.2+0.2) than microarray (1.3+0.2)(P<0.0001). This is the first prospective, randomized, blinded, and paired comparison between microarray and FISH based aneuploidy screening. Aneuploidy and mosaicism were less common with microarray. While evaluating a smaller number of chromosomes with a proportionally smaller opportunity for finding mosaicism, FISH still had a dramatically higher level of inter-cell variation in diagnosis. SNP microarray based 24 chromosome aneuploidy screening provides more complete and consistent results than FISH.
2010-05-19 | GSE20975 | GEO
Project description:Genome-wide genetic screens have identified cellular dependencies in many cancers. Using Novartis’ DRIVE and the Broad Institute’s Achilles shRNA screening datasets, we mined for targetable dependencies in kidney lineage cancer cells. Our studies identified a dependency, preferentially in kidney cancer cells versus cells of other lineages, on the BCL2L1 gene, which encodes the Bcl-xL anti-apoptotic protein. Genetic and pharmacological inactivation of Bcl-xL, but not its paralog BCL2, led to fitness defects in renal cancer cells, and also sensitized them to chemotherapeutics. Expression levels of Bcl-xL, VHL status, and p53 mutation status were insufficient to predict Bcl-xL dependence. Instead, analyzing the transcriptional hallmarks of response to Bcl-xL blockade identified an elevated mesenchymal cell state signature in Bcl-xL dependent lines. Functional studies to address if these cell state differences drive Bcl-xL dependence showed that maintaining mesenchymal characteristics was necessary to confer sensitivity to Bcl-xL loss; and, conversely, that promoting mesenchymal transition was sufficient to increase sensitivity to Bcl-xL inhibition in resistant cells. This mesenchymal signature was also observed in almost a third of human renal tumors, and is associated with worse clinical outcomes. Detachment from an organized epithelium incites protective apoptotic responses in normal cells (e.g. anoikis); however, our findings suggest that, in mesenchymal kidney cancer cells Bcl-xL activity counteracts this protective mechanism and enables tumor cell survival. Altogether, our studies uncover an unexpected link between cellular cell state and dependence on anti-apoptotic proteins, and justify the use of Bcl-xL blockade to target a clinically aggressive subset of human kidney cancers.
2022-06-15 | GSE173618 | GEO
Project description:Many studies estimate that chromosomal mosaicism within the cleavage stage human embryo is high. However, comparison of two unique methods of aneuploidy screening of blastomeres within the same embryo has not been conducted and may indicate whether mosaicism is overestimated due to technical inconsistency rather than biological phenomena. The present study investigates the prevalence of chromosomal abnormality and mosaicism found with two different single cell aneuploidy screening techniques.Thirteen arrested cleavage stage embryos were studied. Each was biopsied into individual cells (n=160). The cells from each embryo were randomized into two groups. Those destined for FISH based aneuploidy screening (n=75) were fixed, 1 cell per slide. Cells for SNP microarray based aneuploidy screening (n=85) were put into individual tubes. Microarray was significantly more reliable (96%) than FISH (83%) for providing an interpretable result (P=0.004). Markedly different results were obtained when comparing microarray and FISH results from individual embryos. Mosaicism was significantly less commonly observed by microarray (4 of 13 embryos; 31%) than by FISH (13 of 13 embryos; 100%)(P=0.0005). Although FISH evaluated fewer chromosomes per cell and fewer cells per embryo, FISH still displayed significantly more unique genetic diagnoses per embryo (3.2+0.2) than microarray (1.3+0.2)(P<0.0001). This is the first prospective, randomized, blinded, and paired comparison between microarray and FISH based aneuploidy screening. Aneuploidy and mosaicism were less common with microarray. While evaluating a smaller number of chromosomes with a proportionally smaller opportunity for finding mosaicism, FISH still had a dramatically higher level of inter-cell variation in diagnosis. SNP microarray based 24 chromosome aneuploidy screening provides more complete and consistent results than FISH. Affymetrix SNP arrays were processed according to the manufacturer's directions on DNA extracted from 13 arrested cleavage stage embryos and biopsied into individual blastomere cells. Individual blastomeres were randomized and blinded for SNP microarray analysis (n = 85). Afflymetrix SNP array analysis was successfully completed on 82 blastomeres.
2010-06-09 | E-GEOD-20975 | biostudies-arrayexpress