Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Sox17 dependence distinguishes the transcriptional regulation of fetal from adult hematopoietic stem cells.

ABSTRACT: Fetal stem cells differ phenotypically and functionally from adult stem cells in diverse tissues. However, little is known about how these differences are regulated. To address this we compared the gene expression profiles of fetal versus adult hematopoietic stem cells (HSCs) and discovered that the Sox17 transcriptional regulator is specifically expressed in fetal and neonatal but not adult HSCs. Germline deletion of Sox17 led to severe fetal hematopoietic defects, including a lack of detectable definitive HSCs. Conditional deletion of Sox17 from hematopoietic cells led to the loss of fetal and neonatal but not adult HSCs. HSCs stopped expressing Sox17 approximately 4 weeks after birth. During this transition, loss of Sox17 expression correlated with slower proliferation and the acquisition of an adult phenotype by individual HSCs. Sox17 is thus required for the maintenance of fetal and neonatal HSCs and distinguishes their transcriptional regulation from adult HSCs.

SUBMITTER: Kim I

PROVIDER: S-EPMC2577201 | biostudies-literature | 2007 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Sox17 dependence distinguishes the transcriptional regulation of fetal from adult hematopoietic stem cells.

Kim Injune I Saunders Thomas L TL Morrison Sean J SJ

Cell 20070726 3

Fetal stem cells differ phenotypically and functionally from adult stem cells in diverse tissues. However, little is known about how these differences are regulated. To address this we compared the gene expression profiles of fetal versus adult hematopoietic stem cells (HSCs) and discovered that the Sox17 transcriptional regulator is specifically expressed in fetal and neonatal but not adult HSCs. Germline deletion of Sox17 led to severe fetal hematopoietic defects, including a lack of detectabl ...[more]

PMID: 17655922

Similar Datasets

Sox17 expression confers self-renewal potential and fetal stem cell characteristics upon adult hematopoietic progenitors.

Project description:A key question concerns the mechanisms that determine temporal identity in stem cells. Fetal hematopoietic stem cells (HSCs) differ from adult HSCs in terms of gene expression profile, surface marker expression, differentiation, and self-renewal capacity. We previously showed that the transcription factor SOX17 is expressed by fetal, but not adult, HSCs and is required for the maintenance of fetal and neonatal, but not adult, HSCs. In the current study, we show that ectopic expression of Sox17 in adult HSCs and transiently reconstituting multipotent progenitors was sufficient to confer increased self-renewal potential and the expression of fetal HSC genes, including fetal HSC surface markers. Sox17 expression enabled transiently reconstituting adult progenitors to give long-term multilineage reconstitution that resembled fetal hematopoiesis, including increased erythropoiesis, increased myelopoiesis, and decreased lymphopoiesis. Long-term ectopic expression of Sox17 eventually led to leukemogenesis. These data demonstrate that SOX17 is sufficient to confer fetal HSC characteristics to adult hematopoietic progenitors and is therefore a key determinant of fetal HSC identity.

| S-EPMC3182027 | biostudies-literature

Hematopoietic stem cells temporally transition to thrombopoietin dependence in the fetal liver.

Project description:Tissue stem cells temporally change intrinsic mechanisms to meet physiological demands. However, little is known whether and how stem cells rely on distinct extrinsic maintenance mechanisms over time. Here, we found that hematopoietic stem cells (HSCs) temporally transition to depend on thrombopoietin (TPO), a key extrinsic factor, from E16.5 onward in the developing liver. Deletion of Tpo reduced mTOR activity, induced differentiation gene expression, and preferentially depleted metabolically active HSCs. Ectopic activation of the JAK2 or MAPK pathway did not rescue HSCs in Tpo-/- mice. Enforced activation of the mTOR pathway by conditionally deleting Tsc1 significantly rescued HSCs and their gene expression in Tpo-/- mice. Lin28b intrinsically promoted mTOR activation in HSCs, and its expression diminished over time. Conditional deletion of Lin28b further reduced mTOR activity and strongly exacerbated HSC depletion in Tpo-/- mice. Therefore, HSCs temporally transition from intrinsic LIN28B-dependent to extrinsic TPO-dependent maintenance in the developing liver.

| S-EPMC8926339 | biostudies-literature

Spatial Genome Re-organization between Fetal and Adult Hematopoietic Stem Cells.

Project description:Fetal hematopoietic stem cells (HSCs) undergo a developmental switch to become adult HSCs with distinct functional properties. To better understand the molecular mechanisms underlying the developmental switch, we have conducted deep sequencing of the 3D genome, epigenome, and transcriptome of fetal and adult HSCs in mouse. We find that chromosomal compartments and topologically associating domains (TADs) are largely conserved between fetal and adult HSCs. However, there is a global trend of increased compartmentalization and TAD boundary strength in adult HSCs. In contrast, intra-TAD chromatin interactions are much more dynamic and widespread, involving over a thousand gene promoters and distal enhancers. These developmental-stage-specific enhancer-promoter interactions are mediated by different sets of transcription factors, such as TCF3 and MAFB in fetal HSCs, versus NR4A1 and GATA3 in adult HSCs. Loss-of-function studies of TCF3 confirm the role of TCF3 in mediating condition-specific enhancer-promoter interactions and gene regulation in fetal HSCs.

| S-EPMC7262670 | biostudies-literature

Distinct Molecular Signature of Murine Fetal Liver and Adult Hematopoietic Stem Cells Identify Novel Regulators of Hematopoietic Stem Cell Function.

Project description:During ontogeny, fetal liver (FL) acts as a major site for hematopoietic stem cell (HSC) maturation and expansion, whereas HSCs in the adult bone marrow (ABM) are largely quiescent. HSCs in the FL possess faster repopulation capacity as compared with ABM HSCs. However, the molecular mechanism regulating the greater self-renewal potential of FL HSCs has not yet extensively been assessed. Recently, we published RNA sequencing-based gene expression analysis on FL HSCs from 14.5-day mouse embryo (E14.5) in comparison to the ABM HSCs. We reanalyzed these data to identify key transcriptional regulators that play important roles in the expansion of HSCs during development. The comparison of FL E14.5 with ABM HSCs identified more than 1,400 differentially expressed genes. More than 200 genes were shortlisted based on the gene ontology (GO) annotation term "transcription." By morpholino-based knockdown studies in zebrafish, we assessed the function of 18 of these regulators, previously not associated with HSC proliferation. Our studies identified a previously unknown role for tdg, uhrf1, uchl5, and ncoa1 in the emergence of definitive hematopoiesis in zebrafish. In conclusion, we demonstrate that identification of genes involved in transcriptional regulation differentially expressed between expanding FL HSCs and quiescent ABM HSCs, uncovers novel regulators of HSC function.

| S-EPMC5961932 | biostudies-literature

Regulation of adult hematopoietic stem cells fate for enhanced tissue-specific repair.

Project description:The ability to control the differentiation of adult hematopoietic stem cells (HSCs) would promote development of new cell-based therapies to treat multiple degenerative diseases. Systemic injection of NaIO(3) was used to ablate the retinal pigment epithelial (RPE) layer in C57Bl6 mice and initiate neural retinal degeneration. HSCs infected ex vivo with lentiviral vector expressing the RPE-specific gene RPE65 restored a functional RPE layer, with typical RPE phenotype including coexpression of another RPE-specific marker, CRALBP, and photoreceptor outer segment phagocytosis. Retinal degeneration was prevented and visual function, as measured by electroretinography (ERG), was restored to levels similar to that found in normal animals. None of the controls (no HSCs, HSCs alone and HSCs infected with lentiviral vector expressing LacZ) showed these effects. In vitro gene array studies demonstrated that infection of HSC with RPE65 increased adenylate cyclase mRNA. In vitro exposure of HSCs to a pharmacological agonist of adenylate cyclase also led to in vitro differentiation of HSCs to RPE-like cells expressing pigment granules and the RPE-specific marker, CRALBP. Our data confirm that expression of the cell-specific gene RPE65 promoted fate determination of HSCs toward RPE for targeted tissue repair, and did so in part by activation of adenylate cyclase signaling pathways. Expression by HSCs of single genes unique to a differentiated cell may represent a novel experimental paradigm to influence HSC plasticity, force selective differentiation, and ultimately lead to identification of pharmacological alternatives to viral gene delivery.

| S-EPMC2835259 | biostudies-literature

Fetal and adult hematopoietic stem cells give rise to distinct T cell lineages in humans.

Project description:Although the mammalian immune system is generally thought to develop in a linear fashion, findings in avian and murine species argue instead for the developmentally ordered appearance (or "layering") of distinct hematopoietic stem cells (HSCs) that give rise to distinct lymphocyte lineages at different stages of development. Here we provide evidence of an analogous layered immune system in humans. Our results suggest that fetal and adult T cells are distinct populations that arise from different populations of HSCs that are present at different stages of development. We also provide evidence that the fetal T cell lineage is biased toward immune tolerance. These observations offer a mechanistic explanation for the tolerogenic properties of the developing fetus and for variable degrees of immune responsiveness at birth.

| S-EPMC3276679 | biostudies-literature

Computational promoter modeling identifies the modes of transcriptional regulation in hematopoietic stem cells.

Project description:Extrinsic and intrinsic regulators are responsible for the tight control of hematopoietic stem cells (HSCs), which differentiate into all blood cell lineages. To understand the fundamental basis of HSC biology, we focused on differentially expressed genes (DEGs) in long-term and short-term HSCs, which are closely related in terms of cell development but substantially differ in their stem cell capacity. To analyze the transcriptional regulation of the DEGs identified in the novel transcriptome profiles obtained by our RNA-seq analysis, we developed a computational method to model the linear relationship between gene expression and the features of putative regulatory elements. The transcriptional regulation modes characterized here suggest the importance of transcription factors (TFs) that are expressed at steady state or at low levels. Remarkably, we found that 24 differentially expressed TFs targeting 21 putative TF-binding sites contributed significantly to transcriptional regulation. These TFs tended to be modulated by other nondifferentially expressed TFs, suggesting that HSCs can achieve flexible and rapid responses via the control of nondifferentially expressed TFs through a highly complex regulatory network. Our novel transcriptome profiles and new method are powerful tools for studying the mechanistic basis of cell fate decisions.

| S-EPMC3977923 | biostudies-literature

The transcriptional coactivator Cbp regulates self-renewal and differentiation in adult hematopoietic stem cells.

Project description:The transcriptional coactivator Cbp plays an important role in a wide range of cellular processes, including proliferation, differentiation, and apoptosis. Although studies have shown its requirement for hematopoietic stem cell (HSC) development, its role in adult HSC maintenance, as well as the cellular and molecular mechanisms underlying Cbp function, is not clear. Here, we demonstrate a gradual loss of phenotypic HSCs and differentiation defects following conditional ablation of Cbp during adult homeostasis. In addition, Cbp-deficient HSCs reconstituted hematopoiesis with lower efficiency than their wild-type counterparts, and this response was readily exhausted under replicative stress. This phenotype relates to an alteration in cellular fate decisions for HSCs, with Cbp loss leading to an increase in differentiation, quiescence, and apoptosis. Genome-wide analyses of Cbp occupancy and differential gene expression upon Cbp deletion identified HSC-specific genes regulated by Cbp, providing a molecular basis for the phenotype. Finally, Cbp binding significantly overlapped at genes combinatorially bound by 7 major hematopoietic transcriptional regulators, linking Cbp to a critical HSC transcriptional regulatory network. Our data demonstrate that Cbp plays a role in adult HSC homeostasis by maintaining the balance between different HSC fate decisions, and our findings identify a putative HSC-specific transcriptional network coordinated by Cbp.

| S-EPMC3233028 | biostudies-literature

Retroviral Sox17 over-expression adult hematopoietic stem/progenitor cells microarray

2011-07-15 | GSE30444 | GEO

Retroviral Sox17 over-expression adult hematopoietic stem/progenitor cells microarray

Project description:The transcription factor SOX17 is expressed by fetal, but not adult hematoipoietic stem cells (HSCs), and is required for the maintenance of fetal and neonatal, but not adult, HSCs. In the current study we show that ectopic expression of Sox17 in adult HSCs and transiently reconstituting multipotent progenitors was sufficient to confer increased self-renewal potential and the expression of fetal HSC genes including fetal HSC surface markers. To assess the mechanisms by which ectopic Sox17 expression in adult hematopoietic progenitors increased self-renewal potential and conferred fetal HSC properties, we compared the gene expression profiles of E16.5 fetal liver HSCs, young adult bone marrow HSCs, young adult bone marrow CD48+LSK cells, and Sox17-expressing CD48+LSK cells isolated from mice that had been transplanted with MSCV-Sox17-infected bone marrow cells 12 weeks earlier. Total RNA (~5ng) was isolated from 3 independent, freshly isolated aliquots of 10,000 E16.5 fetal liver HSCs, 10,000 fetal liver CD48+LSK cells, 10,000 adult bone marrow HSCs, 10,000 adult bone marrow CD48+LSK cells, 10,000 Sox17-expressing CD48+LSK cells isolated from primary recipients 12 weeks after transplantation of MSCV-Sox17-infected bone marrow cells. Purified RNA was reverse transcribed and amplified using the WT-Ovation™ Pico RNA Amplification system (NuGEN Technologies) following the manufacturer’s instructions. Sense strand cDNA was generated using WT-Ovation™ Exon Module (NuGEN), then fragmented and labeled using the FL-Ovation™ cDNA Biotin Module V2 (NuGEN). 2.5µg of labeled cDNA were hybridized to Affymetrix Mouse Gene ST 1.0 microarrays.

2011-07-14 | E-GEOD-30444 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

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