4210 results for "*geneti*"

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• scATAC Gene scores

  Gene score matrices generated with ArchR based on chromatin profiles

  Study EGAS50000001993

• GLASS-NL DNA-Methylation

  Study EGAS00001007546

• Chromosomal mutational signatures of DNA damaging agents at single cell resolution

  The chromosomal scale mutational spectrum of small molecules that interact with DNA has been hard to study at scale, as mutational events are distributed in location and occur in parallel in different cells. Here, we present a framework that pairs phylogenetic ancestry reconstruction with mutational signature decomposition to characterise recent, cell-private CNA mutational processes at single-cell resolution. We used this framework to characterize the cell-wise “foreground” of contemporaneous CNAs induced by strand-break inducing chemotherapeutic drugs of different mechanisms. We demonstrate that platinum salts, G-quadruplex stabilizers and topoisomerase II inhibitors, although mechanistically distinct, converge on a mutational signature dominated by telomere-bounded copy-number gain and losses. This signature is observed in different genetic backgrounds and in vivo, in drug treated patient derived-xenograft tumours. We also observe a high rate of endogenous telomere-bounded mutational foreground in BRCA1 deficient cells. We show that the single cell genome derived signature exposures are drug dose-dependent, and use this to identify the decay of mutational load after drug withdrawal. We observe that both cisplatin and a G4 binder molecule (CX5461) exhibit foreground mutational signature persistence up to 3 weeks after drug withdrawal, suggesting that residual effects of exposure may last longer than anticipated. Finally, extending the framework to serially drug-treated patient-derived xenograft (PDX) models, we show that telomere-bounded CNA signature exposure is associated with tumour response across and resistance states exhibit only background levels of mutational signatures. This is consistent with loss of mutational activity on the genome, as opposed to acquired tolerance to chromosomal mutations as a mechanism for some forms of chemotherapeutic drug resistance. Together our results show that scWGS can identify contemporaneous chromosomal mutation patterns induced by small molecules in human tissues.

  Study EGAS50000002035

• Multi-faceted metastasis decoding: clonal fitness, site pressure, and transcriptional modulation

  The dynamics of unique pressures that evolve metastasis fitness due to genetic and non-genetic components in relationship to primary versus metastatic site has remained difficult to decipher due to the highly complex and intertwined relationship of these features to the heterogeneous clonal structures within tumors. To simplify this problem, we generated serially passaged patient-derived xenografts (PDX) that developed reproducible metastasis and examined them for robust clonal selection using DLP+ single cell genome sequencing. This clonal composition analysis identified a simpler PDX model of metastases that displayed very high intra-PDX clonal competitive fitness, marked with dominant and differential clonal sweeps at metastatic and primary sites by different clones. Further testing this fitness using the different combinations of clones’ transplantation, re-confirmed this high clonal selectivity of a metastatically fit clone at metastatic sites compared to the primary site, hence revealing copy number aberration (CNA) clonal state dependent fixed metastasis fitness. Overall, by testing 9 PDX lines we found two lines with reproducible metastasis which identified a model that simplified the complexities of tumor evolution during metastasis and revealed the dominant role of favorable CNA clonal structure in fixating fitness.

  Study EGAS50000001515

• Transcriptome Analysis Offers a Comprehensive Illustration of the Genetic Background of Pediatric Acute Myeloid Leukemia

  Study EGAS00001003701

• ATACseq of CD4 and CD8 T cells from CLL patients and age-matched HD

  This study investigates chromatin accessibility landscapes in CD4+ and CD8+ T cells from patients with chronic lymphocytic leukemia (CLL) and age-matched healthy donors (HD). Briefly, peripheral blood T cells were isolated using magnetic bead-based negative selection, with CD4+ or CD8+ fractions further purified by FACS sorting. Samples were either used at baseline or after 2 days of acd3-cd28 stimulation in vitro. ATAC-seq libraries were generated using the Omni-ATAC protocol and sequenced as paired-end reads on an Illumina NovaSeq platform. Data were processed using the ENCODE ATAC-seq pipeline, including quality control, adapter trimming, alignment to the GRCh38 reference genome, duplicate removal, and assessment of library quality metrics. Accessible chromatin regions were identified by peak calling, followed by differential accessibility analysis between CLL and HD samples using DESeq2 within DiffBind. The study aims to define disease-associated regulatory changes in T cell subsets in CLL, with emphasis on epigenetic alterations underlying T cell dysfunction we report in out in vitro readouts.

  Study EGAS50000001902

• Terminal differentiation program of CD8 T cells guides immunotherapeutic options for CLL patients

  Chronic lymphocytic leukemia (CLL) remains incurable and autologous T-cell-based therapies induce durable remissions in only a minority of patients. Although poor T-cell performance in CLL has been attributed to exhaustion, T cells from CLL patients retain cytokine production and lack key transcriptional markers of exhaustion, suggesting an alternative state of differentiation. Here, we performed an integrated phenotypic, epigenetic and functional analysis of circulating CD8⁺ T cells from treatment-naive CLL patients to define the nature and therapeutic relevance of terminal differentiation in CLL. CD8⁺ T cells from treatment-naive CLL patients were enriched for a terminally differentiated, CD27⁻CD28⁻CD57⁺KLRG1⁺ population with several senescence-associated features, including increased cell size, granularity, β-galactosidase activity, and reduced basal autophagy. However, these cells lacked key hallmarks of irreversible senescence. Instead, CLL T cells mounted robust but transient proliferative bursts and developed activation-associated γH2AX signals followed by impaired persistence and increased cell death upon repeated activation. Especially CD57⁺ T cells were vulnerable and incompatible with the experimental steps required for CAR T-cell manufacturing. The potent, acute effector function of these cells could, however, be harnessed by bispecific T-cell engagers, which induced effective cytolysis of both cell lines and primary CLL targets by these T cells. Collectively, our data support a model in which CD8+ T-cell dysfunction in CLL reflects accumulation of short-lived, terminally differentiated effector cells rather than canonical exhaustion or irreversible senescence. This state limits durable persistence required for CAR T-cell approached while preserving acute cytotoxicity relevant for bispecific antibody-based therapies in CLL.

  Dac EGAC50000001042

• DAC_RNA-seq of murine osteosarcoma cell line genetically modified for CYR61

  Data access committee for RNA-seq of murine osteosarcoma cell line genetically modified for CYR61

  Dac EGAC50000000352

• BLUEPRINT Hematopoietic Stem/Progenitor Cell Methylomes

  An optimized whole genome bisulfite sequencing protocol (µWGBS, Farlik et al. 2015 Cell Reports) was used to establish DNA methylation profiles of FACS-purified stem and progenitor cells types of the human blood lineage. Most cell types were sorted from the peripheral blood of three donors with eight pools of ten cells, two pools of 50 cells, and one pool of 1000 cells. HSCs and MPPs were also sorted from fetal liver (HSCs only), cord blood, and bone marrow. Single-cell methylomes using the scWGBS protocol (Farlik et al. 2015 Cell Reports) were established for six cell types (HSC, MPP, CMP, GMP, CLP, MLP0). Gene expression profiling using the Smart-seq2 protocol (Picelli et al. 2013 Nature Methods) was done for nine stem/progenitor cell types (HSC, MPP, CMP, GMP, CLP, MLP0, MLP1, MLP2, MLP3).

  Study EGAS00001002070

• Genetic, epigenetic and fragmentomic profiling of plasma cell-free DNA in cancer patients

  The primary goal of the study is to explore the temporal changes in cfDNA profiles in liver cancer patients undergoing therapeutic treatment. Serial blood collection and plasma cfDNA analysis were performed in patients with liver cancer, including patients with primary hepatocellular carcinoma, or those with secondary liver metastasis. Various molecular features of cfDNA were studied, including tumor fraction, epigenetic and fragmentomic analysis.

  Study EGAS50000002022