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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.

ORGANISM(S): Mus musculus

PROVIDER: GSE43007 | GEO | 2013/12/01

SECONDARY ACCESSION(S): PRJNA184266

REPOSITORIES: GEO

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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. C/EBPaplha binding was assesed in heamatopoietic stem- and progenitor cells (LSK) and in myeloid progenitor cells (GMP) using ChIP-seq

2013-12-01 | E-GEOD-43007 | biostudies-arrayexpress

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

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

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C/EBPa gene signature

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C/EBPa gene signature

Project description:We defined the C/EBPa signature characterized by a set of genes which are upregulated upon C/EBPa activation. In order to identify the C/EBPa signature, we performed microarray gene expression analysis of K562 cells stably expressing p42-C/EBPa-ER after activating the C/EBPa construct to translocate to the nucleus for 6 hours with beta-estradiol. The gene expression profile was performed in K562 p42-C/EBPa-ER expressing cells treated with beta-estradiol (n=4) or EtOH vehicle control (n-4) for 6 hours. Induction of nuclear localization of C/EBPa-ER fusion protein was achieved by addition of 1 uM beta-estradiol as indicated into the culture medium.

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Sox4 is a key oncogenic target in C/EBPa mutant Acute Myeloid Leukemia

Project description:Mutation or epigenetic silencing of the transcription factor C/EBPa is observed in ~10% of patients with acute myeloid leukemia (AML). In both cases, a common global gene expression profile is observed, but down-stream targets relevant for leukemogenesis are not known. Here we identify Sox4 as a direct target of C/EBPa whereby its expression is inversely correlated with C/EBPa activity. Downregulation of Sox4 abrogated increased self-renewal of leukemic cells and restored their differentiation. Gene expression profiles of leukemia initiating cells (LICs) from both Sox4 overexpression and murine mutant C/EBPa AML models clustered together, but differed from other types of AML. Our data demonstrate that Sox4 overexpression resulting from C/EBPa inactivation contributes to the development of leukemias with a distinct LIC phenotype.

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C/EBPa Regulates Protease/anti-protease Balance and Mediates Bronchiolar Cell Recovery After Injury

Project description:In the present study, we hypothesized that C/EBPa (CCAAT/enhancer-binding protein alpha) plays a role in cell regeneration in response to bronchiolar epithelial cell injury. C/EBPa mediated ciliated cell regeneration after naphthalene bronchiolar epithelial cell injury in vivo. Furthermore, we demonstrated that C/EBPa regulates protease/anti-protease balance after lung injury, and intratracheal treatment with anti-protease (BPTI) restored ciliated cell regeneration after naphthalene injury in CebpaD/D mice.

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Mitochondrial respiratory chain is essential for hematopoietic stem cell function

Project description:Adult and fetal hematopoietic stem cells (HSCs) display a glycolytic phenotype, which is required for maintenance of stemness; however, whether mitochondrial respiration is required to maintain HSC function is not known. Here we report that loss of the mitochondrial complex III subunit Rieske iron sulfur protein (RISP) in fetal mouse HSCs allows them to proliferate but impairs their differentiation, resulting in anemia and prenatal death. RISP null fetal HSCs displayed impaired respiration resulting in a decreased NAD+/NADH ratio. RISP null fetal HSCs and progenitors exhibited an increase in both DNA and histone methylation concomitant with increases in 2-hydroxyglutarate (2-HG), a metabolite known to inhibit DNA and histone demethylases. RISP inactivation in adult HSCs also impaired respiration resulting in loss of quiescence resulting in severe pancytopenia and lethality. Thus, respiration is dispensable for adult or fetal HSC proliferation, but essential for fetal HSC differentiation and maintenance of adult HSC quiescence.

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Sox4 is a key oncogenic target in C/EBPa mutant Acute Myeloid Leukemia

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Project description:The transcription factors OCT4 and SOX2 are required for generating induced pluripotent stem cells (iPSCs) and for maintaining embryonic stem cells (ESCs). To this end, OCT4 and SOX2 associate and bind to DNA in different configurations depending on the composite DNA element present in their target genes. Here, we have investigated the role of the different OCT4-SOX2 conformational arrangements in regulating and inducing pluripotency. To this end, we have generated SOX2 mutants that interfere with specific OCT4-SOX2 heterodimer configurations and we have assessed their abilities to generate iPSCs and to rescue ESC self-renewal. Our results demonstrate that the OCT4-SOX2 configuration that dimerizes on a Hoxb1-like composite, a canonical element with juxtaposed individual binding sites, plays a more critical role in the induction and maintenance of pluripotency than other OCT4-SOX2 configurations. Overall, the results of this study provide a new insight into the protein interactions required to establish a de novo pluripotent network and to maintain a true pluripotent cell fate.

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