Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Resolving fate and transcriptome of hematopoietic stem cell clones [multiple cell types]

ABSTRACT: Hematopoietic stem cell (HSC) differentiation into mature lineages has been studied under physiological conditions in vivo by genetic barcoding-driven lineage tracing. HSC clones differ in output (differentiation-inactive versus differentiation-active), and in fates (multilineage versus lineage-restricted). Single-cell sequencing data revealed transcriptome diversity of HSC and progenitors, and suggested differentiation pathways. However, molecular hallmarks of functionally distinct HSC clones have not been resolved because existing lineage tracing experiments did not provide transcriptomes, and single cell RNA sequencing lacked information on precursor-product relationships, and hence fate. To close this gap, here we introduce PolyloxExpress, a Cre recombinase-dependent DNA substrate for in situ barcoding in mice that is expressed as mRNA. PolyloxExpress barcoding allows parallel readout of clonal HSC fates (via comparison of barcodes in HSC and mature lineages), and transcriptomes (via single-cell RNA sequencing and barcode matching). Analysing a total of 91 individual HSC clones, we show that differentiation-inactive versus differentiation-active HSC clones reside in different regions of the transcriptional landscape. Inactive HSC clones are closer to the origin of the transcriptional trajectory, yet are proliferatively not more quiescent than active clones. Multilineage versus myelo-erythroid fate-restricted HSC clones show very few transcriptional differences at the HSC stage, yet pronounced fate-specific profiles at the multipotent progenitor stage. Projecting HSC clones with defined fates onto transcriptional landscapes provides a basis for future studies into the molecular determinants for stem cell fate.

ORGANISM(S): Mus musculus

PROVIDER: GSE144273 | GEO | 2020/08/11

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Resolving fate and transcriptome of hematopoietic stem cell clones [LT_ST_HSC]

Project description:Hematopoietic stem cell (HSC) differentiation into mature lineages has been studied under physiological conditions in vivo by genetic barcoding-driven lineage tracing. HSC clones differ in output (differentiation-inactive versus differentiation-active), and in fates (multilineage versus lineage-restricted). Single-cell sequencing data revealed transcriptome diversity of HSC and progenitors, and suggested differentiation pathways. However, molecular hallmarks of functionally distinct HSC clones have not been resolved because existing lineage tracing experiments did not provide transcriptomes, and single cell RNA sequencing lacked information on precursor-product relationships, and hence fate. To close this gap, here we introduce PolyloxExpress, a Cre recombinase-dependent DNA substrate for in situ barcoding in mice that is expressed as mRNA. PolyloxExpress barcoding allows parallel readout of clonal HSC fates (via comparison of barcodes in HSC and mature lineages), and transcriptomes (via single-cell RNA sequencing and barcode matching). Analysing a total of 91 individual HSC clones, we show that differentiation-inactive versus differentiation-active HSC clones reside in different regions of the transcriptional landscape. Inactive HSC clones are closer to the origin of the transcriptional trajectory, yet are proliferatively not more quiescent than active clones. Multilineage versus myelo-erythroid fate-restricted HSC clones show very few transcriptional differences at the HSC stage, yet pronounced fate-specific profiles at the multipotent progenitor stage. Projecting HSC clones with defined fates onto transcriptional landscapes provides a basis for future studies into the molecular determinants for stem cell fate.

2020-08-11 | GSE152555 | GEO

Dynamics of Chromatin Accessibility during Hematopoietic Stem Cell Differentiation into Lineage-Committed Progeny

Project description:Epigenetic mechanisms regulate the multilineage differentiation capacity of hematopoietic stem cells (HSCs) into a variety of blood and immune cells. Our recent work revealed evidence of multilineage gene priming in HSCs, where open cis-regulatory elements (CREs) exclusively shared between HSCs and unipotent lineage cells were enriched for DNA binding motifs of known lineage-specific transcription factors. To test the hypothesis that HSC-primed lineage-specific CREs remain accessible throughout differentiation, we used ATAC-seq to map the temporal dynamics of chromatin remodeling during blood cell differentiation. We observed epigenetic-driven clustering of oligopotent and unipotent progenitors into distinct erythromyeloid and lymphoid branches, with multipotent HSCs and MPPs associating with the erythromyeloid lineage. We mapped the dynamics of lineage-primed CREs throughout hematopoiesis and identified both unique and shared CREs as potential lineage reinforcement mechanisms at fate branch points in hematopoiesis. These findings provide insight into the regulation of stem cell multipotency and lineage commitment throughout hematopoiesis and serve as a resource to test functional drivers of hematopoietic lineage fate.

2023-03-30 | GSE184851 | GEO

Cell of origin epigenetic priming determines susceptibility to Tet2 mutation

Project description:Hematopoietic stem cell (HSC) mutations can result in clonal hematopoiesis (CH) with heterogeneous clinical outcomes. Here, we investigated how the cell state preceding Tet2 mutation impacts the pre-malignant phenotype. Using an inducible system for clonal analysis of myeloid progenitors, we found that the epigenetic features of clones at similar differentiation status were highly heterogeneous and functionally responded differently to Tet2 mutation. Cell differentiation stage also influenced Tet2 mutation response indicating that the cell of origin's epigenome modulates clone-specific behaviors in CH. Molecular features associated with higher risk outcomes include Sox4 that sensitized cells to Tet2 inactivation, inducing dedifferentiation, altered metabolism and increasing the in vivo clonal output of mutant cells, as confirmed in primary GMP and HSC models. Our findings validate the hypothesis that epigenetic features can predispose specific clones for dominance, explaining why identical genetic mutations can result in different phenotypes.

1970-01-01 | MTBLS9914 | MetaboLights

HSCs contribute actively to native multilineage hematopoiesis but with reduced differentiation capacity upon aging

Project description:A hallmark of adult hematopoiesis is the continuous replacement of blood cells with limited lifespans. While active hematopoietic stem cell (HSC) contribution to multilineage hematopoiesis is the foundation of clinical HSC transplantation, recent reports have questioned the physiological contribution of HSCs to normal/steady-state adult hematopoiesis. Here, we use inducible lineage tracing from genetically marked adult HSCs and reveal robust HSC-derived multilineage hematopoiesis. This commences via defined progenitor cells, but varies substantially in between different hematopoietic lineages. By contrast, adult HSC contribution to hematopoietic cells with proposed fetal origins is neglible. Finally, we establish that the HSC contribution to multilineage hematopoiesis declines with increasing age. Therefore, while HSCs are active contributors to native adult hematopoiesis, it appears that the numerical increase of HSCs is a physiologically relevant compensatory mechanism to account for their reduced differentiation capacity with age

2018-12-18 | GSE122473 | GEO

Mapping of clonal lineages across developmental stages in human neural differentiation (Biological Replicates #2 and #3)

Project description:The cell lineages across developmental stages remains to be elucidated. We developed single-cell split barcoding (SISBAR) to allow clonally tracking single-cell transcriptomes across stages in an in vitro model of human ventral midbrain-hindbrain differentiation. We developed “potential-spective” and “origin-spective” analysis to interrogate the cross-stage lineage relationships, and mapped a multi-level clonal lineage landscape depicting the whole differentiation process. We uncovered many previously uncharacterized converging and diverging trajectories. We demonstrated that a transcriptome-defined cell type can arise from distinct lineages that leave molecular imprints on their progenies, and the multi-lineage fates of a progenitor cell type represent the collective results of distinct rather than similar clonal fates of individual progenitors, each with distinct molecular signatures. Specifically, we uncovered a ventral midbrain progenitor cluster as the common clonal origin of midbrain dopaminergic (mDA) neurons, midbrain glutamatergic neurons, and vascular and leptomeningeal cells, and identified surface markers that can predict its lineage fate after transplantation and improve graft outcomes.

2022-12-27 | GSE221592 | GEO

Mapping of clonal lineages across developmental stages in human neural differentiation

2022-07-12 | GSE207921 | GEO

Transcription profiles of fate-restricted HSCs [Bulk RNAseq HSC]

Project description:HSC subtypes with distintic lineage restriction have been previously reported. Here we examine the transcriptome profiles of HSC subtypes with P-restricted, PEM-restricted or multilineage in vivo output.

2023-02-22 | GSE188113 | GEO

Epigenetic profiles of fate-restricted HSCs [Bulk_ATACseq_HSC]

Project description:HSC subtypes with distintic lineage restrictions have been previously reported. Here we examine the chromatin landscapes of HSC subtypes with P-restricted, PEM-restricted or multilineage in vivo output.

2023-02-22 | GSE188106 | GEO

Single cell transcriptomics of fate-restricted HSCs [scRNAseq HSC]

Project description:HSC subtypes with distintic lineage restriction have been previously reported. Here we examine the single cell transcriptomics of HSC subtypes with P-restricted, PEM-restricted or multilineage in vivo output.

2023-02-22 | GSE188118 | GEO

Clonal Tracking Uncovers Barriers and Validate New Strategies to Enhance Gene Editing in Human Hematopoietic Stem Cells [RNA-seq]

Project description:By applying a barcoding strategy to clonal tracking of edited cells (BAR-seq), we show that p53 activation triggered by HDR editing significantly shrink the HSPC clonal repertoire in hematochimeric mice, despite engrafted edited clones preserved multilineage and self-renewing capacity. Transient inhibition of p53 restored polyclonal graft composition. We then overcame HSC constraints to HDR by forcing cell cycle progression and upregulating components of the HDR machinery through transient expression of Adenovirus 5 E4orf6/7 protein, which operates the major cell cycle controller E2F. Combined E4orf6/7 expression and p53 inhibition resulted in high and stable HDR editing efficiencies in the human graft, without perturbing repopulation and self-renewing properties of edited HSCs.

2020-04-22 | GSE143995 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data