Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1215776 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Genetic and epigenetic intra-tumoral heterogeneity cooperate to shape the evolutionary course of cancer. In addition to genetic mutations, chronic lymphocytic leukemia (CLL) undergoes diversification through stochastic DNA methylation changes – epimutations. To measure the epimutation rate at single-cell resolution, we applied multiplexed reduced representation bisulfite sequencing (MscRRBS) to healthy donors B cells and CLL patient samples. We observed that the common clonal CLL origin results in consistently elevated epimutation rate (i.e., low cell-to-cell epimutation rate variability). In contrast, variable epimutation rates across normal B cells reflect diverse evolutionary ages across the B cell differentiation trajectory, consistent with epimutations serving as a molecular clock. Heritable epimutation information allowed high-resolution lineage reconstruction with single-cell data, applicable directly to patient sample. CLL lineage tree shape revealed earlier branching and longer branch lengths than normal B cells, reflecting rapid drift after the initial malignant transformation and a greater proliferative history. To validate the inferred tree topology, we integrated MscRRBS with single-cell transcriptomes and genotyping, which confirmed that genetic subclones map to distinct clades inferred solely based on epimutation information. Lastly, to examine potential lineage biases during therapy, we profiled serial CLL samples prior to and during ibrutinib-associated lymphocytosis. Lineage trees revealed divergent clades of cells preferentially expelled from the lymph node with ibrutinib therapy, marked by distinct transcriptional profiles. These data offer direct single-cell integration of genetic, epigenetic and transcriptional information in the study of leukemia evolution, providing deeper insight into its lineage topology and enabling the charting of its evolution with therapy.
2019-05-02 | GSE109085 | GEO
Project description:Genetic mosaicism and somatic mutation rate in tropical trees
| PRJDB15012 | ENA
Project description:Genetic mosaicism and somatic mutation rate in tropical trees
| PRJDB14538 | ENA
Project description:Stochastic changes in cytosine methylation are a source of heritable epigenetic and phenotypic diversity in plants. Using the model plant Arabidopsis thaliana, we derive robust estimates of the rate at which methylation is spontaneously gained (forward epimutation) or lost (backward epimutation) at individual cytosines and construct a comprehensive picture of the epimutation landscape in this species. We demonstrate that the dynamic interplay between forward and backward epimutations is modulated by genomic context and show that subtle contextual differences have profoundly shaped patterns of methylation diversity in A. thaliana natural populations over evolutionary timescales. Theoretical arguments indicate that the epimutation rates reported here are high enough to rapidly uncouple genetic from epigenetic variation, but low enough for new epialleles to sustain long-term selection responses. Our results provide new insights into methylome evolution and its population-level consequences. MethylC-seq of Arabidopsis thaliana
2015-05-13 | E-GEOD-64463 | biostudies-arrayexpress
Project description:Constitutional epimutations of tumor suppressor genes manifest as promoter methylation and transcriptional silencing of a single allele in normal somatic tissues, thereby predisposing to cancer. Constitutional MLH1 epimutations occur in individuals with young-onset cancer and demonstrate non-Mendelian inheritance through their reversal in the germline. We report a cancer-affected family showing dominant transmission of soma-wide highly mosaic MLH1 methylation and transcriptional repression linked to a particular genetic haplotype. The epimutation was erased in spermatozoa but reinstated in the somatic cells of the next generation. The affected haplotype harbored two single nucleotide substitutions in tandem: c.-27C>A located near the transcription initiation site and c.85G>T. The c.-27C>A variant significantly reduced transcriptional activity in reporter assays and is the probable cause of this epimutation.
2011-07-01 | GSE30348 | GEO
Project description:Mistakes in the maintenance of CG methylation is a source of heritable epimutations in plants. Multigenerational surveys indicate that the rate of these stochastic events varies substantially across the genome, with some regions harboring localized “epimutation hotspots”. Using Arabidopsis as a model, we show that epimutation hotspots are indexed by a specific set of chromatin states (CS) that map to sub-regions of gene body methylation genes. Although these regions comprise only ~12% of all CGs in the genome, they account for ~63% of all epimutation events per unit time. Molecular profiling revealed that these regions contain unique sequence features, harbor steady-state intermediate methylation levels, and act as putative targets of antagonistic DNA methylation pathways. We further demonstrate that experimentally-induced shifts in steady-state methylation in these hotspot regions are sufficient to significantly alter local epimutation intensities. Our work thus lays foundation for dissecting the molecular mechanisms of epimutation hotspots in plants.
2021-12-02 | GSE178684 | GEO
Project description:Molecular clocks are the basis for dating the divergence between lineages over macro-evolutionary timescales (~104-108 years). However, classical DNA-based clocks tick too slowly to inform us about the recent past. Here, we demonstrate that stochastic DNA methylation changes at a subset of cytosines in plant genomes possess a clock-like behavior. This ‘epimutation-clock’ is orders of magnitude faster than DNA-based clocks and enables phylogenetic explorations on a scale of years to centuries. We show experimentally that epimutation-clocks recapitulate known topologies and branching times of intra-species phylogenetic trees in the selfing plant A. thaliana and the clonal seagrass Z. marina, which represent the two primary modes of plant reproduction. This discovery will open new possibilities for high-resolution temporal studies of plant biodiversity.
2024-01-11 | GSE223810 | GEO
Project description:Molecular clocks are the basis for dating the divergence between lineages over macro-evolutionary timescales (~104-108 years). However, classical DNA-based clocks tick too slowly to inform us about the recent past. Here, we demonstrate that stochastic DNA methylation changes at a subset of cytosines in plant genomes possess a clock-like behavior. This ‘epimutation-clock’ is orders of magnitude faster than DNA-based clocks and enables phylogenetic explorations on a scale of years to centuries. We show experimentally that epimutation-clocks recapitulate known topologies and branching times of intra-species phylogenetic trees in the selfing plant A. thaliana and the clonal seagrass Z. marina, which represent the two primary modes of plant reproduction. This discovery will open new possibilities for high-resolution temporal studies of plant biodiversity.
2024-01-11 | GSE223861 | GEO
Project description:Stochastic changes in cytosine methylation are a source of heritable epigenetic and phenotypic diversity in plants. Using the model plant Arabidopsis thaliana, we derive robust estimates of the rate at which methylation is spontaneously gained (forward epimutation) or lost (backward epimutation) at individual cytosines and construct a comprehensive picture of the epimutation landscape in this species. We demonstrate that the dynamic interplay between forward and backward epimutations is modulated by genomic context and show that subtle contextual differences have profoundly shaped patterns of methylation diversity in A. thaliana natural populations over evolutionary timescales. Theoretical arguments indicate that the epimutation rates reported here are high enough to rapidly uncouple genetic from epigenetic variation, but low enough for new epialleles to sustain long-term selection responses. Our results provide new insights into methylome evolution and its population-level consequences.
2015-05-13 | GSE64463 | GEO
Project description:A revised mineral nutrient supplement increases biomass and growth rate in Chlamydomonas reinhardtii
| PRJNA133971 | ENA