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EVI2B is a C/EBP? target gene required for granulocytic differentiation and functionality of hematopoietic progenitors.

ABSTRACT: Development of hematopoietic populations through the process of differentiation is critical for proper hematopoiesis. The transcription factor CCAAT/enhancer binding protein alpha (C/EBP?) is a master regulator of myeloid differentiation, and the identification of C/EBP? target genes is key to understand this process. Here we identified the Ecotropic Viral Integration Site 2B (EVI2B) gene as a direct target of C/EBP?. We showed that the product of the gene, the transmembrane glycoprotein EVI2B (CD361), is abundantly expressed on the surface of primary hematopoietic cells, the highest levels of expression being reached in mature granulocytes. Using shRNA-mediated downregulation of EVI2B in human and murine cell lines and in primary hematopoietic stem and progenitor cells, we demonstrated impaired myeloid lineage development and altered progenitor functions in EVI2B-silenced cells. We showed that the compromised progenitor functionality in Evi2b-depleted cells can be in part explained by deregulation of cell proliferation and apoptosis. In addition, we generated an Evi2b knockout murine model and demonstrated altered properties of hematopoietic progenitors, as well as impaired G-CSF dependent myeloid colony formation in the knockout cells. Remarkably, we found that EVI2B is significantly downregulated in human acute myeloid leukemia samples characterized by defects in CEBPA. Altogether, our data demonstrate that EVI2B is a downstream target of C/EBP?, which regulates myeloid differentiation and functionality of hematopoietic progenitors.

SUBMITTER: Zjablovskaja P

PROVIDER: S-EPMC5384033 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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EVI2B is a C/EBPα target gene required for granulocytic differentiation and functionality of hematopoietic progenitors.

Zjablovskaja Polina P Kardosova Miroslava M Danek Petr P Angelisova Pavla P Benoukraf Touati T Wurm Alexander A AA Kalina Tomas T Sian Stephanie S Balastik Martin M Delwel Ruud R Brdicka Tomas T Tenen Daniel G DG Behre Gerhard G Fiore Fréderic F Malissen Bernard B Horejsi Vaclav V Alberich-Jorda Meritxell M

Cell death and differentiation 20170210 4

Development of hematopoietic populations through the process of differentiation is critical for proper hematopoiesis. The transcription factor CCAAT/enhancer binding protein alpha (C/EBPα) is a master regulator of myeloid differentiation, and the identification of C/EBPα target genes is key to understand this process. Here we identified the Ecotropic Viral Integration Site 2B (EVI2B) gene as a direct target of C/EBPα. We showed that the product of the gene, the transmembrane glycoprotein EVI2B ( ...[more]

PMID: 28186500

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Project description:Cellular differentiation during hematopoiesis is guided by gene regulatory networks (GRNs) comprising transcription factors (TFs) and the effectors of cytokine signaling. Based largely on analyses conducted at steady state, these GRNs are thought to be organized as a hierarchy of bistable switches, with antagonism between Gata1 and PU.1 driving red- and white-blood cell differentiation. Here, we utilize transient gene expression patterns to infer the genetic architecture-the type and strength of regulatory interconnections-and dynamics of a twelve-gene GRN including key TFs and cytokine receptors. We trained gene circuits, dynamical models that learn genetic architecture, on high temporal-resolution gene-expression data from the differentiation of an inducible cell line into erythrocytes and neutrophils. The model is able to predict the consequences of gene knockout, knockdown, and overexpression experiments and the inferred interconnections are largely consistent with prior empirical evidence. The inferred genetic architecture is densely interconnected rather than hierarchical, featuring extensive cross-antagonism between genes from alternative lineages and positive feedback from cytokine receptors. The analysis of the dynamics of gene regulation in the model reveals that PU.1 is one of the last genes to be upregulated in neutrophil conditions and that the upregulation of PU.1 and other neutrophil genes is driven by Cebpa and Gfi1 instead. This model inference is confirmed in an independent single-cell RNA-Seq dataset from mouse bone marrow in which Cebpa and Gfi1 expression precedes the neutrophil-specific upregulation of PU.1 during differentiation. These results demonstrate that full PU.1 upregulation during neutrophil development involves regulatory influences extrinsic to the Gata1-PU.1 bistable switch. Furthermore, although there is extensive cross-antagonism between erythroid and neutrophil genes, it does not have a hierarchical structure. More generally, we show that the combination of high-resolution time series data and data-driven dynamical modeling can uncover the dynamics and causality of developmental events that might otherwise be obscured.

Dataset Information

EVI2B is a C/EBP? target gene required for granulocytic differentiation and functionality of hematopoietic progenitors.

Publications

EVI2B is a C/EBPα target gene required for granulocytic differentiation and functionality of hematopoietic progenitors.

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