Coordinated Changes in Gene Expression Kinetics Underlie both Mouse and Human Erythroid Maturation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA704981 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13786506.fastq.gz | Fastqsanger.gz | |||
| SRR13786507.fastq.gz | Fastqsanger.gz | |||
| SRR13786508.fastq.gz | Fastqsanger.gz | |||
| SRR13786509.fastq.gz | Fastqsanger.gz | |||
| SRR13786510.fastq.gz | Fastqsanger.gz |
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Project description:Background: Single cell molecular profiling technologies are transforming biomedical research, including the recent demonstration that unspliced pre-mRNA present in single cell RNA-Seq permits prediction of future expression states. Here we applied this ‘so-called RNA velocity concept’ to an extended timecourse dataset covering mouse gastrulation and early organembryogenesis. Results: Intriguingly, RNA velocity correctly identified epiblast cells as the starting point, but several This analysis revealed major limitations of the current RNA velocity framework, whereby application to extended timecourse data resulted in trajectory predictions at later stages were inconsistentmpatible with both real time ordering and existing knowledge. The most striking discrepancy concerned red blood cell maturation, with velocity-inferred trajectories diametrically opposinged to the true differentiation path. Investigating the underlying causes revealed a group of genes with a coordinated step-changeboost in transcriptionexpression kinetics, thus violating the assumptions behindframework of current velocity analysis suites, which does not accommodate time-dependent kinetics changes in expression dynamicsover a lineage. Using scRNA-Seq analysis of chimaeric mouse embryos lacking the major erythroid master regulator Gata1, we show that genes with the step-changes in expression dynamics during erythroid differentiation fail to be up-regulated in the mutant cells, thus underscoring the coordination of modulating transcription rate along a differentiation trajectory. e expected block in erythroid maturation as well as induction of PU.1 and expansion of megakaryocyte progenitors. MoreoverIn addition to, the expected block in erythroid maturation, the Gata1- chimera dataset revealed induction of PU.1 and expansion of megakaryocyte progenitors. genes with complex expression kinetics in wild type cells fail to progress to the late erythroid boost in kinetics, thus underscoring the coordination in modulating expression kinetics. Finally, we show that erythropoiesiserythroid maturation in human fetal liver is similarly characterized by a coordinated step-changes in gene expression kinetics. Conclusions: By identifying a limitation of the current velocity framework coupled with in vivo analysis of mutant cells, we reveal that erythroid maturation is characterized by a coordinated step-change in gene expression kinetics during erythropoiesis, with likely implications for many other differentiation processes.
2021-06-15 | GSE167576 | GEO
Project description:BackgroundSingle-cell technologies are transforming biomedical research, including the recent demonstration that unspliced pre-mRNA present in single-cell RNA-Seq permits prediction of future expression states. Here we apply this RNA velocity concept to an extended timecourse dataset covering mouse gastrulation and early organogenesis.ResultsIntriguingly, RNA velocity correctly identifies epiblast cells as the starting point, but several trajectory predictions at later stages are inconsistent with both real-time ordering and existing knowledge. The most striking discrepancy concerns red blood cell maturation, with velocity-inferred trajectories opposing the true differentiation path. Investigating the underlying causes reveals a group of genes with a coordinated step-change in transcription, thus violating the assumptions behind current velocity analysis suites, which do not accommodate time-dependent changes in expression dynamics. Using scRNA-Seq analysis of chimeric mouse embryos lacking the major erythroid regulator Gata1, we show that genes with the step-changes in expression dynamics during erythroid differentiation fail to be upregulated in the mutant cells, thus underscoring the coordination of modulating transcription rate along a differentiation trajectory. In addition to the expected block in erythroid maturation, the Gata1-chimera dataset reveals induction of PU.1 and expansion of megakaryocyte progenitors. Finally, we show that erythropoiesis in human fetal liver is similarly characterized by a coordinated step-change in gene expression.ConclusionsBy identifying a limitation of the current velocity framework coupled with in vivo analysis of mutant cells, we reveal a coordinated step-change in gene expression kinetics during erythropoiesis, with likely implications for many other differentiation processes.
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Project description:Transcription and splicing kinetics are coordinated within both genes and higher-order chromatin domains
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Project description:Here, we set out to understand if and how splicing kinetics are coordinated beyond individual intron removal and if this potential coordination could regulate alternative splicing outcomes. By measuring rates of transcription and splicing genome-wide, we found that the rate of splicing is coordinated across introns within individual genes. Furthermore, we found that elongation rates and splicing rates are coordinated within TADs, as are alternative splicing changes that result from cell type differences, differentiation programs, and alterations in splicing factor levels. Overall, our work establishes that the kinetics of transcription and splicing are coordinated within the spatial organization of the genome, which could be a control point for alternative splicing regulation that can modulate the function of a cell.
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Project description:Transcription and splicing kinetics are coordinated within both genes and higher-order chromatin domains [dataset1]
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Project description:Transcription and splicing kinetics are coordinated within both genes and higher-order chromatin domains [dataset2]
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Project description:Preeclampsia (PE) has been associated with placental dysfunction, resulting in foetal hypoxia, accelerated erythropoiesis and increased erythroblast count in the umbilical cord blood (UCB). Although the detailed effects remain unknown, placental dysfunction can also cause inflammation, nutritional and oxidative stress in the fetus that can affect erythropoiesis. Here, we compared the expression of surface adhesion molecules and erythroid differentiation capacity of UCB hematopoietic stem/ progenitor cells (HSPCs), UCB erythroid profiles along with transcriptome and proteome of these cells between male and female foetuses from PE and normotensive pregnancies. While no significant differences were observed in UCB HSPC migration/ homing and in vitro erythroid colony differentiation, the UCB HSPC transcriptome and the proteomic profile of the in vitro differentiated erythroid cells differed between PE vs normotensive samples. Accordingly, despite absence of significant differences in the UCB erythroid populations in male or female foetuses from PE or normotensive pregnancies, transcriptional changes were observed during erythropoiesis, particularly affecting male foetuses. Pathway analysis suggested deregulation in mTORC1/AMPK signaling pathways controlling cell cycle, differentiation and protein synthesis. These results associate PE with transcriptional and proteomic changes in foetal HSPCs and erythroid cells that may underlie the higher erythroblast count in the UCB in PE.
2019-06-20 | PXD010364 | Pride
Project description:Adult hematopoiesis has been studied in terms of progenitor differentiation potentials, whereas its kinetics in vivo is poorly understood. We combined inducible lineage tracing of endogenous adult hematopoietic stem cells (HSC) with flow cytometry and single-cell RNA sequencing to characterize early steps of hematopoietic differentiation in the steady state. Labeled cells, comprising primarily long-term HSC and some short-term HSC, produced megakaryocytic lineage progeny within one week, in a process that required only 2-3 cell divisions. Erythroid and myeloid progeny emerged simultaneously by 2 weeks, and included a progenitor population with expression features of both lineages. Myeloid progenitors at this stage showed diversification into granulocytic, monocytic and dendritic cell types, and rare intermediate cell states could be detected. In contrast, lymphoid differentiation was virtually absent within the first 3 weeks of tracing. These results show that continuous differentiation of HSC rapidly produces major hematopoietic lineages and cell types, and reveal fundamental kinetic differences between megakaryocytic, erythroid, myeloid and lymphoid differentiation.
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Project description:Missense mutations in transcription factor GATA1 underlie several distinct forms of anemia and thrombocytopenia. Clinical severity depends on the site and type of substitution, and distinct substiutions of the same residue produce disparate phenotypes. To investigate the effect of GATA1 missense mutations on erythroid differentiation we expressed conditionally activated wild type or mutant versions of GATA1 in GATA1-null G1E cells. We used gene expression microarrays to explore how GATA1 missense mutations affect erythroid transcription programs.
2013-03-04 | GSE43356 | GEO
Project description:Missense mutations in transcription factor GATA1 underlie several distinct forms of anemia and thrombocytopenia. Clinical severity depends on the site and type of substitution, and distinct substiutions of the same residue produce disparate phenotypes. To investigate the effect of GATA1 missense mutations on erythroid differentiation we expressed conditionally activated wild type or mutant versions of GATA1 in GATA1-null G1E cells. We used gene expression microarrays to explore how GATA1 missense mutations affect erythroid transcription programs. GATA1-null G1E cells ectopically expressing conditionally activated versions of GATA1 (GATA1-ER, GATA1(R216Q)-ER, GATA1(R216W)-ER, GATA1(D218G)-ER, or GATA1(D218Y)-ER) were treated with estradiol for 24 hours to initiate erythroid differentiation. Total RNA from treated cells was extracted for Affymetrix microarray. All data were generated from three biological replicates. Transcript levels were compared in wild type vs. mutant lines.
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