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Gene expression analysis of Cbp deficient LSK cells

ABSTRACT: The transcriptional coactivator Cbp is critical for hematopoietic stem cell (HSC) development. However, its role in adult HSC and the mechanistic detail of Cbp control of HSC function remains unknown. Using conditional deletion of Cbp in the adult HSC compartment, we demonstrate an altered balance between differentiation and self-renewal with gradual loss of phenotypic HSC, differentiation defects in lower compartments and the development of myeloid malignancies. In addition, we demonstrate that Cbp -/- HSCs reconstitute hematopoiesis with lower efficiency than their wild type counterparts and readily exhaust over time when placed under the replicative stress of serial transplantation. Furthermore, we demonstrate abnormal cell cycle (re)entry and apoptosis in HSC which, with preferential differentiation, also contribute to stem cell exhaustion. Finally we demonstrate global transcriptional abnormalities predicted to alter cell cycle control, balanced differentiation and HSC function upon Cbp deletion and link Cbp to a critical HSC transcriptional regulatory network through genome-wide analysis of Cbp binding. Genome-wide gene expression analysis of LSK population after Cbp deletion. The LSK population of bone marrow is enriched for hematopoietic stem cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE25268 | GEO | 2011/12/15

SECONDARY ACCESSION(S): PRJNA142573

REPOSITORIES: GEO

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Gene expression analysis of Cbp deficient LSK cells

Project description:The transcriptional coactivator Cbp is critical for hematopoietic stem cell (HSC) development. However, its role in adult HSC and the mechanistic detail of Cbp control of HSC function remains unknown. Using conditional deletion of Cbp in the adult HSC compartment, we demonstrate an altered balance between differentiation and self-renewal with gradual loss of phenotypic HSC, differentiation defects in lower compartments and the development of myeloid malignancies. In addition, we demonstrate that Cbp -/- HSCs reconstitute hematopoiesis with lower efficiency than their wild type counterparts and readily exhaust over time when placed under the replicative stress of serial transplantation. Furthermore, we demonstrate abnormal cell cycle (re)entry and apoptosis in HSC which, with preferential differentiation, also contribute to stem cell exhaustion. Finally we demonstrate global transcriptional abnormalities predicted to alter cell cycle control, balanced differentiation and HSC function upon Cbp deletion and link Cbp to a critical HSC transcriptional regulatory network through genome-wide analysis of Cbp binding. Genome-wide gene expression analysis of LSK population after Cbp deletion. The LSK population of bone marrow is enriched for hematopoietic stem cells. Total RNA was extracted from flow-sorted LSK population of bone marrow, 4 weeks after pIpC induced deletion of Cbp. 2 replicates for Cbp wt control, 2 replicates for Cbp Mx.

2011-12-15 | E-GEOD-25268 | biostudies-arrayexpress

Genome-wide analysis of the binding pattern of the transcriptional co-activator Cbp.

Project description:The transcriptional coactivator Cbp is critical for hematopoietic stem cell (HSC) development. However, its role in adult HSC and the mechanistic detail of Cbp control of HSC function remain unknown. Using conditional deletion of Cbp in the adult HSC compartment, we demonstrate an altered balance between differentiation and self-renewal with gradual loss of phenotypic HSC, differentiation defects in lower compartments and the development of myeloid malignancies. In addition, we demonstrate that Cbp -/- HSCs reconstitute hematopoiesis with lower efficiency than their wild type counterparts and readily exhaust over time when placed under the replicative stress of serial transplantation. Furthermore, we demonstrate abnormal cell cycle (re)entry and apoptosis in HSC which, with preferential differentiation, also contribute to stem cell exhaustion. Finally we demonstrate global transcriptional abnormalities predicted to alter cell cycle control, balanced differentiation and HSC function upon Cbp deletion and link Cbp to a critical HSC transcriptional regulatory network through genome-wide analysis of Cbp binding. 1 sample (Cbp) and 1 control, all prepared from a hematopoietic progenitor/stem cell line (BM-HPC)

2011-12-15 | E-GEOD-25265 | biostudies-arrayexpress

Genome-wide analysis of the binding pattern of the transcriptional co-activator Cbp.

Project description:The transcriptional coactivator Cbp is critical for hematopoietic stem cell (HSC) development. However, its role in adult HSC and the mechanistic detail of Cbp control of HSC function remain unknown. Using conditional deletion of Cbp in the adult HSC compartment, we demonstrate an altered balance between differentiation and self-renewal with gradual loss of phenotypic HSC, differentiation defects in lower compartments and the development of myeloid malignancies. In addition, we demonstrate that Cbp -/- HSCs reconstitute hematopoiesis with lower efficiency than their wild type counterparts and readily exhaust over time when placed under the replicative stress of serial transplantation. Furthermore, we demonstrate abnormal cell cycle (re)entry and apoptosis in HSC which, with preferential differentiation, also contribute to stem cell exhaustion. Finally we demonstrate global transcriptional abnormalities predicted to alter cell cycle control, balanced differentiation and HSC function upon Cbp deletion and link Cbp to a critical HSC transcriptional regulatory network through genome-wide analysis of Cbp binding.

2011-12-15 | GSE25265 | GEO

Transcription profiling of mouse gain- and loss-of-function Hedgehod (Hh) genetic models reveals Hedgehog signaling is dispensable for adult hematopoietic stem cell function

Project description:The Hedgehog (Hh) signaling pathway is a developmentally conserved regulator of stem cell function. Several reports suggested that Hh signaling is an important regulator of hematopoietic stem cell (HSC) maintenance and differentiation. Here we test this hypothesis in vivo using both gain- and loss-of-function Hh genetic models. Surprisingly, our studies demonstrate that conditional Smoothened (Smo) deletion or over-activation has no significant effects on adult HSC self-renewal and function. Moreover, they indicate a lack of synergism between the Notch and Hh pathways in HSC function, as RBPJ- and Smo-deficiency do not affect hematopoiesis. In agreement with this notion, detailed genome-wide transcriptome analysis reveals that silencing of Hh signaling does not significantly alter the HSC-specific gene expression âsignatureâ. Our studies demonstrate that the Hh signaling pathway is dispensable for adult HSC function and suggest that the Hh pathway can be targeted in future clinical trials addressing the effect of Hh inhibition on leukemia-initiating cell maintenance. Transcriptional consequences of inactivating Smo (hh loss-of-function) in LKS cells. Experiment Overall Design: Four samples were analyzed: wild-type (WT) control and Smo-deficient (SMO) Lin-ckit+Sca1+ (LSK) cells, as well as Lin-ckit+Sca1- myeloid progenitor (MP) cells, which served as a control for LSK-enriched/specific genes. Total bone marrow cells were pooled from four WT and four SMO mice before sorting LSK and MP populations.

2009-03-21 | E-GEOD-15194 | biostudies-arrayexpress

Chromatin accessibility promotes hematopoietic and leukemia stem cell activity

Project description:Chromatin organization is a highly orchestrated process that influences gene expression, in part by modulating access of regulatory factors to DNA and nucleosomes. We found that the chromatin accessibility regulator HMGN1, a target of recurrent DNA copy gains in leukemia, controls myeloid differentiation. HMGN1 amplification was associated with increased accessibility, expression, and histone H3K27 acetylation of loci important for hematopoietic stem cell (HSC) function and AML, such as HoxA cluster genes. In vivo, HMGN1 overexpression was linked to decreased quiescence and increased HSC activity in bone marrow transplantation. HMGN1 overexpression also cooperated with the AML-ETO9a fusion oncoprotein to impair myeloid differentiation and enhance leukemia stem cell (LSC) activity. Inhibition of histone acetyltransferases CBP/p300 relieved the HMGN1-associated differentiation block. These data nominate factors that modulate chromatin accessibility as regulators of HSCs and LSCs and suggest that targeting HMGN1 or its downstream effects on histone acetylation could be therapeutically active in AML.

2020-02-25 | PXD017054 | Pride

Transcription profiling of mouse Fbw7-/-/hematopoietic stem cells

Project description:Ubiquitination is a post-translational mechanism of control of diverse cellular processes. We focus here on the ubiquitin ligase Fbw7, a recently identified hematopoietic tumor suppressor that can target for degradation several important oncogenes including Notch1, c-Myc and cyclin E. We have generated conditional Fbw7 knock-out animals and inactivated the gene in hematopoietic stem cells (HSC) and their differentiated progeny. Deletion of Fbw7 specifically and rapidly affects the HSC compartment in a cell-autonomous manner. Fbw7-/- HSCs show defective maintenance of quiescence, leading to impaired self-renewal and a severe loss of competitive repopulating capacity. Furthermore, Fbw7-/- HSC are unable to colonize the thymus leading to a profound depletion of T cell progenitors. Deletion of Fbw7 in bone marrow stem cells and progenitors leads to the stabilization of c-Myc, a transcription factor previously implicated in HSC self-renewal. On the other hand, neither Notch1 nor cyclin E are stabilized in the bone marrow of Fbw7 deficient mice. Genome-wide transcriptome studies of Fbw7-/- HSC and hematopoietic progenitors indicate that Fbw7 controls, through the regulation of HSC cell cycle entry, the global transcriptional âsignatureâ that is associated with the quiescent, self-renewing HSC phenotype. Transcriptional consequences of inactivating Fbw7 in LKS cells. Experiment Overall Design: Four samples were analyzed: wild-type (WT) control and Fbw7-deficient (FBW7) Lin-ckit+Sca1+ (LSK) cells, as well as Lin-ckit+Sca1- myeloid progenitor (MP) cells, which served as a control for LSK-enriched/specific genes. Total bone marrow cells were pooled from three WT and three FBW7 mice before sorting LSK and MP populations.

2008-06-11 | E-GEOD-11178 | biostudies-arrayexpress

The E3 ubiquitin ligase DDB1 controls homeostasis of hematopoietic stem and progenitor cells

Project description:Hematopoietic stem cells (HSC) are regulated to keep the balance between self-renewal and differentiation. However, little is known about post-translational regulations in HSCs. In this study, we characterize the role of DDB1, a component of the Cul4A-DDB1 E3 ubiquitin ligase complex, in HSCs and progenitors by using conditional DDB1 knockout models. We show that the maintenance and differentiation of both adult and fetal HSCs and progenitor cells is dependent on DDB1 function. Deletion of DDB1 alters cell cycle progression and induces apoptosis. Furthermore, deletion of DDB1 in developing thymocytes had no effects on T cell differentiation, whereas DDB1-deficient peripheral T cells were not able to enter cell cycle when stimulated in vitro. In addition, DDB1 is essential for T cell leukemia initiation. Our results reveal that DDB1 is required for adult and fetal hematopoiesis as it controls progenitor and stem cell homeostasis. Transcriptional consequences of inactivating DDB1 in fetal LSK cells. Four samples were analyzed: wild-type (WT) control and DDB1-deficient (DDB1) Lin-ckit+Sca1+ (LSK) cells sorted from fetal livers E16.5 of DDB1 flox/flox, VavCre+ and control mice.

2015-07-10 | E-GEOD-70658 | biostudies-arrayexpress

Low-C on Human CB-derived LT-HSC and ST-HSC

Project description:Low-C was performed upon human cord-blood long-term hematopoietic stem cells (LT-HSC) and short-term hematopoietic stem cells (ST-HSC). This was used to demonstrate that chromatin conformation changes associated with LT-HSC activation are enriched in ST-HSC.

| EGAS00001004744 | EGA

DNA hypomethylation leads to derepression of myeloerythroid genes in hematopoietic stem cells (HSC)

Project description:Analysis of hematopoietic stem cells (HSC, LSK Flt3-) and myeloid progenitors (MP, LK CD34+) sorted from wildtype and Dnmt1 hypomorph mice

2009-10-06 | GSE17765 | GEO

Microarray expression analysis of wild type and Erg knockdown bone marrow hematopoietic stem and progenitor cells

Project description:Erg is an ETS family transcription factor frequently overexpressed in human leukemias and has been implicated as a key regulator of hematopoietic stem cells (HSCs). However how Erg controls normal hematopoiesis, particularly at the stem cell level, remains poorly understood. Using homologous recombination, we generated an Erg knockdown allele (Ergkd) in which Erg expression can be restored upon Cre-mediated excision of a Stopper cassette. In Ergkd/+ mice, ~40% reduction in Erg dosage perturbed both fetal liver and bone marrow hematopoiesis by reducing the numbers of Lin-Sca-1+c-Kit+ (LSK) hematopoietic stem and progenitor cells (HSPCs) and megakaryocytic progenitors. By genetic mosaic analysis, we found Erg-restored HSPCs outcompeted Ergkd/+ HSPCs for contributing to adult hematopoiesis in vivo. Intriguingly, HSC differentiation also appeared attenuated, leading to accumulation of long-term HSCs in the mutant LSK population. Accordingly, microarray analysis of Erg-restored and Ergkd/+ HSPCs from the same animal revealed enrichment of stem cell-related pathways in Ergkd/+ HSPCs. Overall, reduced Erg dosage perturbs hematopoiesis by reducing HSC numbers and impairing HSC differentiation, possibly via two Erg targets, Jun and Myc.

2017-06-20 | GSE48600 | GEO

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