Global genome decompaction leads to stochastic activation of gene expression as a first step toward fate commitment in human hematopoietic cells.
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE156735 | GEO | 2020/08/25
REPOSITORIES: GEO
Similar Datasets
Project description:When human cord blood derived CD34+ cells are induced to differentiate, they undergo rapid and dynamic morphological and molecular transformations that are critical for fate commitment. In particular, the cells passe through a transitory phase known as “multilineage primed” state. These cells are characterized by a mixed gene expression profile, different in each cell, with the co-expression of many genes characteristic for concurrent cell lineages. The aim of our study is to understand the mechanisms of the establishment and the exit from this transitory state. We investigated this issue using single-cell RNA sequencing and ATAC-seq. Two phases were detected. The first phase is a rapid and global chromatin decompaction that makes most of the gene promoters in the genome accessible for transcription. It results 24h later in enhanced and pervasive transcription of the genome leading to the concomitant increase in the cell-to-cell variability of transcriptional profiles. The second phase is the exit from the multilineage-primed phase marked by a slow chromatin closure and a subsequent overall downregulation of gene transcription. This process is selective and results in the emergence of coherent expression profiles corresponding to distinct cell subpopulations. The typical time scale of these events spans 48 to 72 hours. These observations suggest that the non-specificity of genome decompaction is the condition for the generation of a highly variable multilineage expression profile. The non-specific phase is followed by specific regulatory actions that stabilize and maintain the activity of key genes, while the rest of the genome becomes repressed again by the chromatin re-compaction. Thus, the initiation of differentiation is reminiscent of a trial-and-error process that associates the spontaneous generation of gene expression diversity to subsequent regulatory actions that maintain the activity of some genes while the rest of the genome sinks back to the repressive closed chromatin state.
2022-05-26 | GSE203567 | GEO
Project description:When human cord blood derived CD34+ cells are induced to differentiate in vitro, they undergo rapid and dynamic morphological and molecular transformation that are critical for the fate commitment. Using ATAC-seq and single-cell RNA sequencing we detected two phases of this process. We show that a rapid and widespread chromatin opening - that makes most of the gene promoters in the genome accessible - precedes the high and unrestrained transcription of a large variety of genes. This phase results in a quasi-random gene expression profile unique to each cell. During the second phase, slow chromatin closing precedes the downregulation of transcription and the emergence of coherent expression profiles. Transcription factors may play a role in the maintenance of the transcription activity of their target genes rather than in their initial activation. These observations are consistent with a model based on the spontaneous probabilistic organization of the cellular process of fate commitment.
2020-08-25 | GSE156734 | GEO
Project description:When human cord blood derived CD34+ cells are induced to differentiate in vitro, they undergo rapid and dynamic morphological and molecular transformation that are critical for the fate commitment. Using ATAC-seq and single-cell RNA sequencing we detected two phases of this process. We show that a rapid and widespread chromatin opening - that makes most of the gene promoters in the genome accessible - precedes the high and unrestrained transcription of a large variety of genes. This phase results in a quasi-random gene expression profile unique to each cell. During the second phase, slow chromatin closing precedes the downregulation of transcription and the emergence of coherent expression profiles. Transcription factors may play a role in the maintenance of the transcription activity of their target genes rather than in their initial activation. These observations are consistent with a model based on the spontaneous probabilistic organization of the cellular process of fate commitment.
2020-08-25 | GSE156733 | GEO
Project description:Global genome decompaction leads to stochastic activation of gene expression as a first step toward fate commitment in human hematopoietic cells [scATAC-seq]
| PRJNA841459 | ENA
Project description:Molecular mechanisms employed by individual multipotent cells at the point of lineage commitment remain largely uncharacterized. Current paradigms span from instructive to noise-driven mechanisms. Of considerable interest is also whether commitment involves a limited set of genes or the entire transcriptional program, and to what extent gene expression configures multiple trajectories into commitment. Importantly, the transient nature of the commitment transition confounds the experimental capture of committing cells. We develop a computational framework that simulates stochastic commitment events, and affords mechanistic exploration of the fate transition. We use a combined modeling approach guided by gene expression classifier methods that infers a time-series of stochastic commitment events from experimental growth characteristics and gene expression profiling of individual hematopoietic cells captured immediately before and after commitment. We define putative regulators of commitment and probabilistic rules of transition through machine learning methods, and employ clustering and correlation analyses to interrogate gene regulatory interactions in multipotent cells. Against this background, we develop a Monte Carlo time-series stochastic model of transcription where the parameters governing promoter status, mRNA production and mRNA decay in multipotent cells are fitted to experimental static gene expression distributions. Monte Carlo time is converted to physical time using cell culture kinetic data. Probability of commitment in time is a function of gene expression as defined by a logistic regression model obtained from experimental single-cell expression data. Our approach should be applicable to similar differentiating systems where single cell data is available. Within our system, we identify robust model solutions for the multipotent population within physiologically reasonable values and explore model predictions with regard to molecular scenarios of entry into commitment. The model suggests distinct dependencies of different commitment-associated genes on mRNA dynamics and promoter activity, which globally influence the probability of lineage commitment.
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Project description:Hematopoietic stem cells possess lifelong self-renewal activity and generate multipotent progenitors that differentiate into lineage-committed and subsequently mature cells. We present a comparative transcriptome analysis of ex vivo isolated mouse multipotent hematopoietic stem/progenitor cells (Lin(neg)SCA-1(+)c-KIT(+)) and myeloid committed precursors (Lin(neg)SCA-1(neg)c-KIT(+)). Our data display dynamic transcriptional networks and identify a stem/progenitor gene expression pattern that is characterized by cell adhesion and immune response components including kallikrein-related proteases. We identify 498 expressed lncRNAs, which are potential regulators of multipotency or lineage commitment. By integrating these transcriptome with our recently reported proteome data, we found evidence for posttranscriptional regulation of processes including metabolism and response to oxidative stress. Finally, our study identifies a high number of genes with transcript isoform regulation upon lineage commitment. This in-depth molecular analysis outlines the enormous complexity of expressed coding and noncoding RNAs and posttranscriptional regulation during the early differentiation steps of hematopoietic stem cells toward the myeloid lineage.
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Project description:UV B (UVB) radiation induces clones of cells mutant for the p53 tumor suppressor gene in human and murine epidermis. Here we reanalyze large datasets that report the fate of clones in mice subjected to a course of UVB radiation, to uncover how p53 mutation affects epidermal progenitor cell behavior. We show that p53 mutation leads to exponential growth of clones in UV-irradiated epidermis; this finding is also consistent with the size distribution of p53 mutant clones in human epidermis. Analysis of the tail of the size distribution further reveals that the fate of individual mutant cells is stochastic. Finally, the data suggest that ending UVB exposure results in the p53 mutant cells adopting the balanced fate of wild-type cells: the loss of mutant cells is balanced by proliferation so that the population of preneoplastic cells remains constant. We conclude that preneoplastic clones do not derive from long-lived, self-renewing mutant stem cells but rather from mutant progenitors with random cell fate. It follows that ongoing, low-intensity UVB radiation will increase the number of precancerous cells dramatically compared with sporadic, higher-intensity exposure at the same cumulative dose, which may explain why nonmelanoma skin cancer incidence depends more strongly on age than on radiation dosage. Our approach may be applied to determine cell growth rates in clonally labeled material from a wide range of tissues including human samples.
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