Gene regulation of murine hematopoietic specification
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ABSTRACT:
PROVIDER: PRJNA1022428 | ENA |
REPOSITORIES: ENA
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Project description:In vertebrates, lifelong supply of all the blood cell types in suitable numbers is maintained by the hematopoietic stem cells (HSCs). During development, these HSCs emerge in the aorta-gonad-mesonephros (AGM) from specialized vascular endothelium through a transdifferentiation process, called as endothelial-to-hematopoietic transition (EHT). During this process, select endothelial cells (CD31+c-kit- or CD31PCKITN) switch to a hematopoietic transcriptional program, undergo morphological changes and become hemogenic (CD31+c-kit+ or CD31PCKITP) and gives rise to hematopoietic cells (CD31-c-kit+ or CD31NCKITP). A complex interplay of key transcription factors and signaling pathways coordinates the whole process. Specific metabolic signature of a cell can precisely define its phenotype. Evidence has emerged that cellular phenotype and function can be driven according to the changes in cellular metabolism. Metabolic programs, which are stage specific, allow stem cells to adapt their function in different microenvironments. In the present study, we performed nano LC-MS/MS based proteomic analysis to understand the molecular program involved in the transdifferentiation of endothelial to hematopoietic cells.
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Project description:The realization of human embryonic stem cells (hESC) as a model for human developmental hematopoiesis and potential cell replacement strategies relies on an improved understanding of the extrinsic and intrinsic factors regulating hematopoietic-specific hESC differentiation. Mesenchymal stem cells (hMSCs) are multipotent cells of mesodermal origin that form part of hematopoietic stem cell niches and have an important role in the regulation of hematopoiesis through production of secreted factors and/or cell-to-cell interactions. We have previously shown that hESCs may be successfully maintained feeder-free using hMSC-conditioned media (MSC-CM). Here, we hypothesized that hESCs maintained in MSC-CM may be more prone to differentiation towards hematopoietic lineage than hESCs grown in standard human foreskin fibroblast (HFF)-conditioned media (HFF-CM). We report that specification into hemogenic progenitors and subsequent hematopoietic differentiation and clonogenic progenitor capacity is robustly enhanced in hESC lines maintained in MSC-CM. Interestingly, co-culture of hESCs on hMSCs fully abrogates hematopoietic specification of hESCs suggesting that the improved hematopoietic differentiation is mediated by MSC-secreted factors rather than by MSC-hESC physical interactions. To investigate the molecular mechanism involved in this process, we analyzed global (LINE-1) methylation and genome-wide promoter DNA methylation. Human ESCs grown in MSC-CM showed a decrease of 20% in global DNA methylation and a promoter DNA methylation signature consisting in 45 genes commonly hypomethylated and 102 genes frequently hypermethylated. Our data indicate that maintenance of hESCs in MSC-CM robustly augments hematopoietic specification and that the process seems mediated by MSC-secreted factors conferring a DNA methylation signature to undifferentiated hESCs which may influence further predisposition towards hematopoietic specification. Total DNA isolated by standard procedures from human embryonic stem cells (hESC) cultured in different conditioned media
2011-10-02 | E-GEOD-30456 | biostudies-arrayexpress
Project description:Gene regulation by PCGF1 in hematopoietic progenitor cells
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Project description:Analysis of hematopoietic stem/progenitors from GATA-1-GFP transgenic mouse bone marrow at gene expression level. Results provide changes in gene expression pattern accompanied with up-regulation of GATA-1 transcription factor at early stage of murine adult hematopoiesis. RNA samples obtained from isolated GATA1+LSK and other hemaopoietic stem/progenitor populations including GATA1-LSK, LMPP, CMP and LT-HSC were subjected to mRNA amplification and cDNA microarray analysis.
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Project description:MLL-AF4 is a hallmark genomic aberration which arises prenatally in high-risk infant acute lymphoblastic leukemia (ALL). In human embryonic stem cells (hESCs), MLL-AF4 skewed hemato-endothelial specification but was not sufficient for transformation. Additional cooperating genetic insults seem required for MLL-AF4-mediated leukemogenesis. FLT3 is highly expressed in MLL-AF4+ ALL through activating mutations (FLT3-TKD or FLT3-ITD) or increased transcriptional expression, being therefore considered a potential cooperating event in MLL-AF4+ ALL. Here, we explored the developmental impact of FLT3 activation on its own or in cooperation with MLL-AF4 in the hematopoietic fate of hESCs. FLT3 activation did not impact specification of CD45-CD31+ hemogenic precursors but significantly enhanced the formation of CD45+CD34+ and CD45+ blood cells and blood progenitors with clonogenic potential. Importantly, FLT3 activation through FLT3 mutations or FLT3-WT overexpression completely abrogated hematopoietic differentiation from MLL-AF4-expressing hESCs, indicating that FLT3 activation cooperates with MLL-AF4 to inhibit human embryonic hematopoiesis. Cell cycle/apoptosis analyses suggest that FLT3 activation directly impacts hESC specification rather than selective proliferation/survival of hESC-emerging hematopoietic derivatives. Transcriptional profiling supported the limited impact of FLT3 activation on hESC specification towards CD45-hemogenic precursors and the enhanced hematopoiesis upon FLT3 activation, and inhibited hematopoiesis upon MLL-AF4 expression in FLT3-activated hESCs which was associated to large transcriptional changes and regulation of master early hematopoietic genes. Also, although FLT3 activation and MLL-AF4 cooperate to inhibit embryonic hematopoiesis the underlying molecular/genetic mechanisms differ depending on how FLT3 activation is achieved. Finally, FLT3 activation did not cooperate with MLL-AF4 to immortalize/transform hESC-derived hematopoietic cells. 18 samples were analyzed. CD45- hemogenic precursors EV, 2 biological rep CD45- hemogenic precursors FLT3-TKD, 2 biological rep CD45- hemogenic precursors FLT3-WT, 2 biological rep CD45- hemogenic precursors FLT3-TKD/MLLAF4, 2 biological rep CD45- hemogenic precursors FLT3-WT/MLLAF4, 2 biological rep CD45+ blood cells EV, 1 biological rep CD45+ blood cells FLT3-TKD, 2 biological rep CD45+ blood cells FLT3-WT, 2 biological rep CD45+ blood cells FLT3-TKD/MLLAF4, 2 biological rep CD45+ blood cells FLT3-WT/MLLAF4, 1 biological rep
2013-06-04 | E-GEOD-40103 | biostudies-arrayexpress
Project description:Mammalian development is regulated by the interplay of tissue-specific and ubiquitously expressed transcription factors, such as Sp1. Sp1 knock-out mice die in utero with multiple phenotypic aberrations, but the underlying molecular mechanism of this differentiation failure has been elusive. Here we used conditional knock-out mice as well as the differentiation of mouse ES cells as a model to address this issue. To this end we examined differentiation potential, global gene expression patterns and Sp1 target regions in Sp1 wild-type and deficient cells representing different stages of hematopoiesis. Sp1-/- cells progress through most embryonic stages of blood cell development but cannot complete terminal differentiation. For most Sp1 target and non-target genes, gene expression is unaffected by Sp1 inactivation. However, Cdx and multiple Hox genes are stage-specific targets of Sp1 and are down-regulated at an early stage. As a consequence, expression of genes involved in hematopoietic specification are progressively deregulated, highlighting the regulatory hierarchy of hematopoietic specification. Our work demonstrates that the early absence of active Sp1 sets a cascade in motion that culminates in a failure of terminal hematopoietic differentiation and emphasizes the role of ubiquitously expressed transcription factors for tissue-specific gene regulation. Microarray expression data, 16 arrays with 2 independent biological replicates (8 arrays wildtype and 8 arrays knock out) obtained from differentiation of ES cells to study the transcription factor Sp1 activity at early stages of early hematopoietic specification.
2014-06-12 | E-GEOD-52497 | biostudies-arrayexpress
Project description:Chromatin priming elements direct tissue-specific gene activity prior to hematopoietic specification
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Project description:The realization of human embryonic stem cells (hESC) as a model for human developmental hematopoiesis and potential cell replacement strategies relies on an improved understanding of the extrinsic and intrinsic factors regulating hematopoietic-specific hESC differentiation. Mesenchymal stem cells (hMSCs) are multipotent cells of mesodermal origin that form part of hematopoietic stem cell niches and have an important role in the regulation of hematopoiesis through production of secreted factors and/or cell-to-cell interactions. We have previously shown that hESCs may be successfully maintained feeder-free using hMSC-conditioned media (MSC-CM). Here, we hypothesized that hESCs maintained in MSC-CM may be more prone to differentiation towards hematopoietic lineage than hESCs grown in standard human foreskin fibroblast (HFF)-conditioned media (HFF-CM). We report that specification into hemogenic progenitors and subsequent hematopoietic differentiation and clonogenic progenitor capacity is robustly enhanced in hESC lines maintained in MSC-CM. Interestingly, co-culture of hESCs on hMSCs fully abrogates hematopoietic specification of hESCs suggesting that the improved hematopoietic differentiation is mediated by MSC-secreted factors rather than by MSC-hESC physical interactions. To investigate the molecular mechanism involved in this process, we analyzed global (LINE-1) methylation and genome-wide promoter DNA methylation. Human ESCs grown in MSC-CM showed a decrease of 20% in global DNA methylation and a promoter DNA methylation signature consisting in 45 genes commonly hypomethylated and 102 genes frequently hypermethylated. Our data indicate that maintenance of hESCs in MSC-CM robustly augments hematopoietic specification and that the process seems mediated by MSC-secreted factors conferring a DNA methylation signature to undifferentiated hESCs which may influence further predisposition towards hematopoietic specification.
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