Personal Genome Diagnostics
Ontology highlight
ABSTRACT:
PROVIDER: EGAO00000000317 | EGA |
REPOSITORIES: EGA
Publications
Genomic analyses of gynaecologic carcinosarcomas reveal frequent mutations in chromatin remodelling genes.
Jones Siân S Stransky Nicolas N McCord Christine L CL Cerami Ethan E Lagowski James J Kelly Devon D Angiuoli Samuel V SV Sausen Mark M Kann Lisa L Shukla Manish M Makar Rosemary R Wood Laura D LD Diaz Luis A LA Lengauer Christoph C Velculescu Victor E VE
Nature communications 20140919
Malignant mixed Müllerian tumours, also known as carcinosarcomas, are rare tumours of gynaecological origin. Here we perform whole-exome analyses of 22 tumours using massively parallel sequencing to determine the mutational landscape of this tumour type. On average, we identify 43 mutations per tumour, excluding four cases with a mutator phenotype that harboured inactivating mutations in mismatch repair genes. In addition to mutations in TP53 and KRAS, we identify genetic alterations in chromati ...[more]
Similar Datasets
Project description:Double homeobox 4 (DUX4) is expressed in at the early preimplantation stage in human embryos. Here we show that induced human DUX4 expression substantially alters the non-coding chromatin accessibility of non-coding DNA and activates thousands of newly identified putative transcribed enhancer-like regions, preferentially located within ERVL-MaLR repeat elements. CRISPR activation of transcribed enhancers by C-terminal DUX4 motifs results in the increased expression of target embryonic genome activation (EGA) genes ZSCAN4 and KHDC1P1. We show that DUX4 is markedly enriched in human zygotes, followed by intense nuclear DUX4 localization preceding and coinciding with minor EGA. DUX4 knockdown in human zygotes led to changes in the EGA transcriptome but did not terminate the embryos. We also show that the DUX4 protein interacts with the Mediator complex via the C-terminal KIX binding motif. Our findings contribute to the understanding of DUX4 as a regulator of the non-coding genome.
2022-03-16 | GSE171803 | GEO
Project description:Reprogramming of histone modification regulates gene expression and mammal preimplantation development. Trimethylation of lysine 4 on histone 3 (H3K4me3) has unique landscape in mouse oocytes and early embryos. However, the dynamics and function of H3K4me3 in livestock embryos remain unclear. To address how it is reprogrammed in domestic animals, we profiled changes of H3K4me3 during bovine early embryo development. Notably, the overall signal of H3K4me3 decreased during embryonic genome activation (EGA). By utilizing ultra-low-input native ChIP-seq (ULI-NChIP-seq) technology, we observed widespread broad H3K4me3 domains in oocytes and embryos. The signal of broad H3K4me3 began to decrease after fertilization and was lowest after EGA. Along with the removal of broad H3K4me3, deposition of H3K4me3 at promoter regions enhanced gradually. Besides, the transcriptional activity and signal of promoter H3K4me3 showed positive correlation after the erasure of broad H3K4me3 at 16-cell stage. Moreover, knocking down of demethylases KDM5A, KDM5B and KDM5C caused EGA delay and blastocyst formation failure. RNA-seq analysis revealed 47.8% down-regulated genes in knockdown embryos at 8/16-cell stage were EGA genes, and 63.1% of up-regulated genes were maternal transcripts. Particularly, the positive correlation between transcriptional activity and promoter H3K4me3 during EGA was restrained when knocking down of KDM5A, KDM5B and KDM5C. Overall, our work initiatively mapped the genomic reprogramming of H3K4me3 during bovine preimplantation development, and KDM5A/B/C played roles in modulating oocyte-to-embryonic transition (OET) through timely erasure of broad H3K4me3 domains far away from promoters.
2022-03-31 | GSE189101 | GEO
Project description:Reprogramming of histone modification regulates gene expression and mammal preimplantation development. Trimethylation of lysine 4 on histone 3 (H3K4me3) has unique landscape in mouse oocytes and early embryos. However, the dynamics and function of H3K4me3 in livestock embryos remain unclear. To address how it is reprogrammed in domestic animals, we profiled changes of H3K4me3 during bovine early embryo development. Notably, the overall signal of H3K4me3 decreased during embryonic genome activation (EGA). By utilizing ultra-low-input native ChIP-seq (ULI-NChIP-seq) technology, we observed widespread broad H3K4me3 domains in oocytes and embryos. The signal of broad H3K4me3 began to decrease after fertilization and was lowest after EGA. Along with the removal of broad H3K4me3, deposition of H3K4me3 at promoter regions enhanced gradually. Besides, the transcriptional activity and signal of promoter H3K4me3 showed positive correlation after the erasure of broad H3K4me3 at 16-cell stage. Moreover, knocking down of demethylases KDM5A, KDM5B and KDM5C caused EGA delay and blastocyst formation failure. RNA-seq analysis revealed 47.8% down-regulated genes in knockdown embryos at 8/16-cell stage were EGA genes, and 63.1% of up-regulated genes were maternal transcripts. Particularly, the positive correlation between transcriptional activity and promoter H3K4me3 during EGA was restrained when knocking down of KDM5A, KDM5B and KDM5C. Overall, our work initiatively mapped the genomic reprogramming of H3K4me3 during bovine preimplantation development, and KDM5A/B/C played roles in modulating oocyte-to-embryonic transition (OET) through timely erasure of broad H3K4me3 domains far away from promoters.
2022-03-31 | GSE189100 | GEO
Project description:Embryonic genome activation (EGA) is orchestrated by an intrinsic developmental program initiated during oocyte maturation with translation of stored maternal mRNAs. Here we show that tankyrase, a poly(ADP-ribosyl) polymerase that regulates β-catenin levels, undergoes programmed translation during oocyte maturation and serves an essential role in mouse EGA. Newly translated TNKS triggers proteasomal degradation of axin, reducing targeted destruction of β-catenin and promoting β-catenin-mediated transcription of target genes, including Myc. MYC mediates ribosomal RNA transcription in 2-cell embryos, supporting global protein synthesis. Suppression of tankyrase activity using knockdown or chemical inhibition causes loss of nuclear β-catenin and global reductions in transcription and histone H3 acetylation. Chromatin and transcriptional profiling indicate that development arrests prior to the mid-2-cell stage, mediated in part by reductions in β-catenin and MYC. These findings indicate that post-transcriptional regulation of tankyrase serves as a ligand-independent developmental mechanism for post-translational β-catenin activation and is required to complete EGA.
2020-05-21 | GSE123815 | GEO
Project description:During maternal-to-embryonic transition control of embryonic development gradually switches from maternal RNAs and proteins stored in the oocyte to gene products generated after embryonic genome activation (EGA). Detailed insight into the onset of embryonic transcription is obscured by the presence of maternal transcripts. Using the bovine model system, we established by RNA sequencing a comprehensive catalogue of transcripts in germinal vesicle and metaphase II oocytes, and in embryos at the 4-cell, 8-cell, 16-cell and blastocyst stages. These were produced by in vitro fertilization of Bos t. taurus oocytes with sperm from a Bos t. indicus bull to facilitate parent-specific transcriptome analysis. Transcripts from 12.4 to 13.7 × 10^3 different genes were detected in the various developmental stages. EGA was analyzed by i) detection of embryonic transcripts which are not present in oocytes; ii) detection of transcripts from the paternal allele; and iii) detection of primary transcripts with intronic sequences. These strategies revealed (i) 220, (ii) 937, and (iii) 6,848 genes to be activated from the 4-cell to the blastocyst stage. The largest proportion of gene activation, i.e. (i) 59%, (ii) 42%, and (iii) 58%, was found in 8-cell embryos, indicating major EGA at this stage. Gene ontology analysis of genes activated at the 4-cell stage identified categories related to translation, RNA processing and transport, consistent with preparation for major EGA. Our study provides the largest transcriptome data set of bovine oocyte maturation and early embryonic development and new insight into the timing of embryonic activation of specific genes.
2014-02-09 | GSE52415 | GEO
Project description:Milk production during the early postpartum in dairy cows can impact the circulating metabolites and negatively affects embryo survival. However, the molecular consequences for the embryo during its development in the oviduct are still unknown. The objective was to determine the impact of metabolic status on embryonic genome activation (EGA) using high-throughput sequencing to generate comprehensive transcriptome profiles of bovine 16-cell stage embryos which had undergone EGA in vitro or in the oviducts of primiparous postpartum dry or postpartum lactating Holstein Friesian cows.
2023-08-30 | GSE226844 | GEO
Project description:BackgroundThe cost of genomic information has fallen steeply, but the clinical translation of genetic risk estimates remains unclear. We aimed to undertake an integrated analysis of a complete human genome in a clinical context.MethodsWe assessed a patient with a family history of vascular disease and early sudden death. Clinical assessment included analysis of this patient's full genome sequence, risk prediction for coronary artery disease, screening for causes of sudden cardiac death, and genetic counselling. Genetic analysis included the development of novel methods for the integration of whole genome and clinical risk. Disease and risk analysis focused on prediction of genetic risk of variants associated with mendelian disease, recognised drug responses, and pathogenicity for novel variants. We queried disease-specific mutation databases and pharmacogenomics databases to identify genes and mutations with known associations with disease and drug response. We estimated post-test probabilities of disease by applying likelihood ratios derived from integration of multiple common variants to age-appropriate and sex-appropriate pre-test probabilities. We also accounted for gene-environment interactions and conditionally dependent risks.FindingsAnalysis of 2.6 million single nucleotide polymorphisms and 752 copy number variations showed increased genetic risk for myocardial infarction, type 2 diabetes, and some cancers. We discovered rare variants in three genes that are clinically associated with sudden cardiac death-TMEM43, DSP, and MYBPC3. A variant in LPA was consistent with a family history of coronary artery disease. The patient had a heterozygous null mutation in CYP2C19 suggesting probable clopidogrel resistance, several variants associated with a positive response to lipid-lowering therapy, and variants in CYP4F2 and VKORC1 that suggest he might have a low initial dosing requirement for warfarin. Many variants of uncertain importance were reported.InterpretationAlthough challenges remain, our results suggest that whole-genome sequencing can yield useful and clinically relevant information for individual patients.FundingNational Institute of General Medical Sciences; National Heart, Lung And Blood Institute; National Human Genome Research Institute; Howard Hughes Medical Institute; National Library of Medicine, Lucile Packard Foundation for Children's Health; Hewlett Packard Foundation; Breetwor Family Foundation.
| S-EPMC2937184 | biostudies-literature
Project description:SYSTEMATIC PHARMACOGENOMIC ANALYSIS USING A PERSONAL GENOME OF A MALAY INDIVIDUAL
| PRJEB4210 | ENA
Project description:To determine blastomere fate and embryonic genome activation (EGA) at 5- to 8-cell stage human embryos by global gene expression profile of amplified cDNA from blastomeres at the single cell level
2010-10-30 | GSE22032 | GEO
Project description:We live in exciting times for a new generation of biomarkers being enabled by advances in the design and use of biomaterials for medical and clinical applications, from nano- to macro-materials, and protein to tissue. Key challenges arise, however, due to both scientific complexity and compatibility of the interface of biology and engineered materials. The linking of mechanisms across scales by using a materials science approach to provide structure-process-property relations characterizes the emerging field of 'materiomics,' which offers enormous promise to provide the hitherto missing tools for biomaterial development for clinical diagnostics and the next generation biomarker applications towards personal health monitoring. Put in other words, the emerging field of materiomics represents an essentially systematic approach to the investigation of biological material systems, integrating natural functions and processes with traditional materials science perspectives. Here we outline how materiomics provides a game-changing technology platform for disruptive innovation in biomaterial science to enable the design of tailored and functional biomaterials--particularly, the design and screening of DNA aptamers for targeting biomarkers related to oral diseases and oral health monitoring. Rigorous and complementary computational modeling and experimental techniques will provide an efficient means to develop new clinical technologies in silico, greatly accelerating the translation of materiomics-driven oral health diagnostics from concept to practice in the clinic.
| S-EPMC4739130 | biostudies-literature