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C/EBPa is required for self-renewal, lineage priming and maintenance of epigenetic configurations in hematopoietic stem cells

ABSTRACT: Transcription factors are key regulators of hematopoieticstem cells (HSCs) and act through their ability to bind DNA andimpact on gene transcription. Their functions are interpreted inthe complex landscape of chromatin but current knowledge on howthis is achieved is very limited. C/EBPa is an importanttranscriptional regulator of hematopoiesis, but its potentialfunctions in HSCs have remained elusive. Here we report that C/EBPaserves to protect adult HSCs from apoptosis and to maintain theirquiescent state. Consequently, deletion of Cebpa is associatedwith loss of self-renewal and HSC exhaustion. By combining geneexpression analysis with genome-wide assessment of C/EBPa bindingand epigenetic configurations, we show that C/EBPa acts tomodulate the epigenetic states of genes belonging to molecularpathways important for HSC function. Moreover, we demonstrate thatC/EBPa acts as a priming factor at the HSC level to activelypromote myeloid differentiation and counteract lymphoid lineagechoice. Taken together our results show that C/EBPa is a keyregulator of HSC biology, which influences the epigeneticlandscape of HSCs in order to balance different cell fate options. C/EBPaplha binding was assesed in heamatopoietic stem- and progenitor cells (LSK) and in myeloid progenitor cells (GMP) using ChIP-seq

ORGANISM(S): Mus musculus

SUBMITTER: Bo Porse

PROVIDER: E-GEOD-43007 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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C/EBPa is required for self-renewal, lineage priming and maintenance of epigenetic configurations in hematopoietic stem cells

Project description:Transcription factors are key regulators of hematopoieticstem cells (HSCs) and act through their ability to bind DNA andimpact on gene transcription. Their functions are interpreted inthe complex landscape of chromatin but current knowledge on howthis is achieved is very limited. C/EBPa is an importanttranscriptional regulator of hematopoiesis, but its potentialfunctions in HSCs have remained elusive. Here we report that C/EBPaserves to protect adult HSCs from apoptosis and to maintain theirquiescent state. Consequently, deletion of Cebpa is associatedwith loss of self-renewal and HSC exhaustion. By combining geneexpression analysis with genome-wide assessment of C/EBPa bindingand epigenetic configurations, we show that C/EBPa acts tomodulate the epigenetic states of genes belonging to molecularpathways important for HSC function. Moreover, we demonstrate thatC/EBPa acts as a priming factor at the HSC level to activelypromote myeloid differentiation and counteract lymphoid lineagechoice. Taken together our results show that C/EBPa is a keyregulator of HSC biology, which influences the epigeneticlandscape of HSCs in order to balance different cell fate options.

2013-12-01 | GSE43007 | GEO

C/EBPa controls acquisition and maintenance of adult hematopoietic stem cell quiescence

Project description:In blood, the transcription factor C/EBPa is essential for myeloid differentiation and has been implicated in regulating self-renewal of fetal liver hematopoietic stem cells (HSCs). However, its function in adult HSCs is unknown. Here, using an inducible knockout model, we found that C/EBPa deficient adult HSCs underwent a pronounced expansion with enhanced proliferation, characteristics resembling fetal liver HSCs. Consistently, transcription profiling of C/EBPa deficient HSCs revealed a gene expression program similar to fetal liver HSCs. Moreover we observed that age-specific C/EBPa expression correlated with its inhibitory effect on the HSC cell cycle. Mechanistically, we identified N-Myc as a C/EBPa downstream target. C/EBPa upregulation during HSC transition from an active fetal state to a quiescent adult state was accompanied by down-regulation of N-Myc, and loss of C/EBPa resulted in de-repression of NMyc. Our data establish that C/EBPa acts as a molecular switch between fetal and adult states of HSC in part via transcriptional repression of the proto-oncogene N-Myc. HSCs of Pu.1 knock-in (PU.1ki/ki) mice were used for RNA extraction and hybridization on Affymetrix microarrays. We compared these microarray samples with the corresponding wild type.

2012-11-14 | E-GEOD-42234 | biostudies-arrayexpress

C/EBPa controls acquisition and maintenance of adult hematopoietic stem cell quiescence

2012-11-14 | GSE42234 | GEO

Expression data 550cGy vs 0cGy KSL

Project description:Precise study of HSCs during regeneration has been impeded by the rarity of the HSC population and depletion of phenotypic HSCs early following genotoxic stresses, such as total body irradiation (TBI). We isolated bone marrow (BM) ckit+sca-1+lin- (KSL) cells, which are enriched for HSCs, from adult C57Bl6 mice before and at several time points following TBI, as a means to map the dynamic molecular response of HSC regeneration. We isolated BM KSL cells and myeloid progenitor cells (c-kit+sca-1-lin- cells) at day +14 after irradiation and compared the gene expression profile of regenerating HSCs versus steady state HSCs (non-irradiated) and committed progenitor cells.

2016-04-05 | E-GEOD-79744 | biostudies-arrayexpress

Dicer1 deletion in myeloid-committed progenitors causes neutrophil dysplasia and blocks macrophage/dendritic cell development in mice

Project description:MiRNAs have the potential to regulate cellular differentiation programs. However, miRNA-deficiency in primary hematopoietic stem cells (HSCs) results in HSC depletion in mice, leaving the question of whether miRNAs play a role in early-lineage decisions unanswered. To address this issue, we deleted Dicer1, which encodes an essential RNaseIII enzyme for miRNA biogenesis, in murine CCAAT/enhancer-binding protein alpha (C/EBPA)-positive myeloid-committed progenitors in vivo. In contrast to the results in HSCs, we found that miRNA depletion affected neither the number of myeloid progenitors nor the percentage of C/EBPA-positive progenitor cells. Analysis of gene-expression profiles from wild type and Dicer1-deficient granulocyte-macrophage progenitors (GMPs) revealed that 20 miRNA families were active in GMPs. Of the derepressed miRNA targets in Dicer1-null GMPs, 27% are normally exclusively expressed in HSCs or are specific for multi-potent progenitors and erythropoiesis, indicating an altered gene-expression landscape. Dicer1-deficient GMPs were defective in myeloid development in vitro and exhibited an increased replating capacity, indicating a regained self-renewal potential of these cells. In mice, Dicer1 deletion blocked monocytic differentiation, depleted macrophages and caused myeloid dysplasia with morphological features of Pelger-Huët anomaly. These results provide evidence for a miRNA-controlled switch for a cellular program of self-renewal and expansion towards myeloid differentiation in GMPs.

2012-06-18 | GSE35844 | GEO

Gene expression analyses of hematopoietic stem cell (HSC) subsets in wildtype or CD41-KO mice

Project description:The hematopoietic stem cell (HSC) compartment is heterogeneous, yet our understanding of the identities of different HSC subtypes is limited. Here we show that platelet integrin CD41 (M-NM-1IIb), currently thought to only transiently mark fetal HSCs, is expressed on an adult HSC subtype that accumulates with age. CD41+ HSCs were largely quiescent and exhibited myeloerythroid and megakaryocyte gene priming, governed by Gata1, whereas CD41- HSCs were more proliferative and exhibited lymphoid gene priming. When isolated without the use of blocking antibodies, CD41+ HSCs possessed long-term repopulation capacity upon serial transplantations and showed a marked myeloid-bias compared to CD41-HSCs, which yielded a more lymphoid-biased progeny. CD41-knockout mice displayed multilineage hematopoietic defects coupled with decreased quiescence and survival of HSCs, suggesting that CD41 is functionally relevant for HSC maintenance and hematopoietic homeostasis. Transplantation experiments indicated that CD41-KO associated defects are long-term transplantable and HSC-derived, and in part mediated through the loss of platelet mass leading to decreases in HSC exposure to important platelet released cytokines, such as TGFM-NM-21. In summary, our data provide a novel marker to identify a myeloid-biased HSC subtype that becomes prevalent with age, and highlights the dogma of HSC regulation by their progeny. For microarray analysis, 1000 HSCs were FACS sorted from pools of 4-5 mice directly into lysis buffer, RNA extracted and whole transcript amplification was performed as previously described (Gonzalez-Roca E, Garcia-Albeniz X, Rodriguez-Mulero S, Gomis RR, Kornacker K, Auer H. Accurate expression profiling of very small cell populations. PLoS One. 2010;5:e14418.)

2013-04-11 | E-GEOD-45561 | biostudies-arrayexpress

Hematopoietic cell differentiation is required for initiation of acute myeloid leukemia [Microarray expression]

Project description:Leukemia initiating cells (LICs) of acute myeloid leukemia (AML) may arise from self-renewing hematopoietic stem cells (HSCs) and from committed progenitors. However, it remains unclear how leukemia-associated oncogenes instruct LIC formation from cells of different origins and if differentiation along the normal hematopoietic hierarchy is involved. Here, using murine models with the driver mutations MLL-AF9 or MOZ-TIF2, we found that regardless of the transformed cell types, myelomonocytic differentiation to the granulocyte macrophage progenitor (GMP) stage is critical for LIC generation. Blocking myeloid differentiation through disrupting the lineage-restricted transcription factor C/EBPa eliminates GMPs, blocks normal granulopoiesis, and prevents AML development. In contrast, restoring myeloid differentiation through inflammatory cytokines “rescues” AML transformation. Our findings identify myeloid differentiation as a critical step in LIC formation and AML development, thus guiding new therapeutic approaches. Primary KSL, CMP, and GMP cells from wildtype controls and C/Ebpa knockouts were used for RNA extraction and hybridization on Affymetrix microarrays. We also compared the microarray samples of leukemic granulocyte macrophage progenitor compartments (L-GMPs) from MLL-AF9 transformed control or cytokine rescued C/EBPa KO leukemic mouse bone marrow and their secondary recipients with those non-Leukemia KSLs and CMPs from MLL-AF9 transduecd KO recipients with no leukemia development.

2015-08-04 | E-GEOD-71687 | biostudies-arrayexpress

Hematopoietic cell differentiation is required for initiation of acute myeloid leukemia

2014-09-17 | E-GEOD-61468 | biostudies-arrayexpress

B-myb is Essential Regulator of Hematopoietic Stem Cell and Myeloid Progenitor Cell Development

Project description:The B-myb (MYBL2) gene is a member of the MYB family of transcription factors and is involved in cell cycle regulation, DNA replication and maintenance of genomic integrity. However, its function during adult development and hematopoiesis is unknown. We show here that conditional inactivation of B-myb in vivo results in depletion of the HSC pool, leading to profound reductions in mature lymphoid, erythroid and myeloid cells. This defect is autonomous to the bone marrow and is first evident in the HSCs, which accumulate in the S and G2/M phases. B-myb inactivation also causes defects in the myeloid progenitor compartment and results in an accumulation of GMPs. Microarray studies indicate that B-myb null LKS+ cells differentially express genes that direct myeloid lineage development and commitment, suggesting that B-myb is a key player in controlling cell fate. Collectively, these studies demonstrate that B-myb is essential for HSC and progenitor maintenance and survival during hematopoiesis. Total RNA was isolated from FACS purified LKS+ cells isolated from pIpC-treated control and B-myb floxed-MxCre mice. Each sample is derived from a pool of 3-5 mice. 2 samples were analyzed for each genotype.

2014-02-12 | E-GEOD-53875 | biostudies-arrayexpress

Igf2bp2 deletion reduces energy metabolism, gIgf2bp2 deletion reduces energy metabolism, growth signaling, and aging of hematopoietic stem cells in micerowth signaling, and aging of hematopoietic stem cells in mice

Project description:Increasing evidence links metabolic activity and cell growth to decline in hematopoietic stem cell (HSC) function during aging. The Lin28b/Hmga2 pathway controls tissue development and in the hematopoietic system the postnatal downregulation of this pathway causes a decrease in self renewal of adult HSCs compared to fetal HSCs. Igf2bp2 is an RNA binding protein and a mediator of the Lin28b/Hmga2 pathway, which regulates metabolism and growth signaling by influencing RNA stability and translation of its target genes. It is currently unknown whether Lin28/Hmga2/Igf2bp2 signaling impacts on aging-associated impairments in HSC function and hematopoiesis. Here, we analyzed homozygous Igf2bp2 germline knockout mice and wildtype control animals to address this question. The study shows that Igf2bp2 deletion rescues aging phenotypes of the hematopoietic system, such as the expansion of HSC numbers in bone marrow and the biased increase of myeloid cells in peripheral blood. This rescue of hematopoietic aging coincides with reduced mitochondrial metabolism and glycolysis in Igf2bp2-/- HSCs compared to Igf2bp2+/+ HSCs. Conversely, Igf2bp2 overexpression activates protein synthesis pathways in HSCs and leads to a rapid loss of self renewal by enhancing myeloid skewed differentiation in an mTOR/PI3K-dependent manner. Together, these results show that Igf2bp2 regulates energy metabolism and growth signaling in HSCs and that the activity of this pathways influences self renewal, differentiation, and aging of HSCs.

2024-05-21 | PXD018535 | Pride

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