E2A proteins maintain the hematopoietic stem cell pool and promote the maturation of myelolymphoid and myeloerythroid progenitors. Proceedings of the National Academy of Sciences of the United States of America

Division of Biological Sciences, 0377, University of California at San Diego, La Jolla, CA 92093, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 02/2009; 106(6):1930-5. DOI: 10.1073/pnas.0808866106
Source: PubMed


Hematopoiesis is a tightly controlled process maintained by a small pool of hematopoietic stem cells (HSCs). Here, we demonstrate that the LT-HSC, MPP, premegakaryocytic/erythroid, Pre CFU-E, Pre GM, MkP, and granulocyte-macrophage compartments were all significantly reduced in E2A-deficient bone marrow. Despite a severe depletion of erythroid progenitors, the erythrocyte and megakaryocyte compartments were equivalent in E2A-deficient bone marrow as compared with wild-type mice. E2A-deficient HSCs also failed to efficiently maintain the HSC pool on serial transplantation, and we demonstrate that the E2A proteins regulate cell cycle progression of HSCs by regulating the expression of p21(Cip1), p27(Kip1), and the thrombopoietin receptor, known regulators of HSC self-renewal activity. Based on these observations, we propose that the E2A proteins promote the developmental progression of the entire spectrum of early hematopoietic progenitors and to suppress an erythroid specific program of gene expression in alternative cell lineages. Last, the data mechanistically link E2A, cell cycle regulators, and the maintenance of the HSC pool in a common pathway.

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Available from: Cornelis Murre, Dec 24, 2013
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    • "E2A deficient mice showed an arrest at the pro-B cell stage during B cell development [3] and transgenic expression of either E12 or E47 could partially rescue the B lymphopoiesis initiation; similarly, E2A deficiency led to a block at the earliest stage of T cell development [4] and disturbed thymocyte positive selection [5]. Moreover, E2A has been found to be involved in some cellular activities including cell differentiation [6], proliferation [7], apoptosis [8], cell cycle [9] and epithelial-mesenchymal transition (EMT) [10]. "
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    ABSTRACT: Transcriptional factor E2A is crucial for the normal development and differentiation of B and T lymphocytes. Dysregulation of E2A leads to leukemia and tumorigenesis of some solid tumors. The expression and clinical significance of E2A as well as its role in colorectal cancer (CRC) are still unknown. This study aims to assess E2A expression in CRC tissues, evaluate its prognosis value, and investigate its role in colon cancer cell growth. E2A expression in CRC tissues and normal mucosa was detected by immunohistochemical staining; Kaplan-Meier survival curve and Cox regression model were used to evaluate the prognostic value of E2A. Lentivirus was used to construct E2A stably knocked-down cells. MTT assay was employed to detect cell proliferation change; cell cycle was analyzed by flow cytometry; and chromatin immunoprecipitation (ChIP) assay was used to validate the predicted binding target of E2A. Expression of E2A was lower in CRC tissues than normal mucosa; low E2A expression correlated with advanced TNM stage and larger tumor size, and predicted poor prognosis of CRC patients. E2A knockdown resulted in increased cell proliferation rate and cell cycle acceleration. ChIP assay showed miR-320a was a direct target of E2A and upregulation of miR-320a in E2A downregulated cells could reverse cell proliferation and cell cycle changes caused by E2A deficiency. E2A is an independent prognostic factor for CRC patients and targets miR-320a to regulate cell proliferation of colon cancer cells.
    Full-text · Article · Jan 2014 · PLoS ONE
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    • "Genetic ablation of one of the E proteins, E47, or the entire E2A gene resulted in a significant reduction in the number of short-term HSC or multipotent progenitors, suggesting a critical role for E proteins in the differentiation of HSCs. [17], [18] E2A deficiency also impaired long-term repopulating activity of stem cells in serial transplant assays [18], [23]. The function of E proteins can be hampered by inhibitory HLH proteins including Id (Id1–4), which diminish the DNA binding activities of E proteins [24]–[26]. "
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    ABSTRACT: Hematopoietic stem cells (HSCs) maintain life-long blood supply but are inevitably exposed to various inflammatory stimuli, which have been shown to be harmful for HSC integrity but the mediators of the deleterious effects have not been fully identified. Here, we show that daily injection of mice with 1 µg of LPS for 30 days triggers a storm of inflammatory cytokines. LPS injection also stimulated the transcription of the Id1 gene in HSCs in vivo but not in vitro, suggesting an indirect effect. To determine the effects of LPS treatment on HSC function and to evaluate the significance of Id1 expression, we assess the repopulating potential of wild type and Id1 deficient mice, which were subjected to a 30 day regimen of LPS treatment. We found that LPS caused dramatic reduction in the long-term but not short-term repopulating activity of wild type but not Id1 deficient HSC. This treatment also led to increases in HSC counts, decreases in BrdU-label retention and disturbance of quiescence detected by Ki67 staining in wild type but not Id1 deficient mice. Together, it appears that Id1, at least in part, plays a role in LPS-induced damage of HSC integrity.
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    • "The likely relevance of additional MK-specific transcription factors is further emphasized by our observation that the five factors studied here may only account for 30% of MK-specific expression. Additional important players within MK transcriptional programs are likely to include NF-E2, MEIS1, and E2A (Shivdasani, 1996; Hisa et al., 2004; Semerad et al., 2009). Our demonstration that PDZK1IP1 shares transcriptional regulatory elements with the blood stem cell regulator SCL has implications reaching beyond a better understanding of this particular gene locus. "
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    ABSTRACT: Hematopoietic differentiation critically depends on combinations of transcriptional regulators controlling the development of individual lineages. Here, we report the genome-wide binding sites for the five key hematopoietic transcription factors--GATA1, GATA2, RUNX1, FLI1, and TAL1/SCL--in primary human megakaryocytes. Statistical analysis of the 17,263 regions bound by at least one factor demonstrated that simultaneous binding by all five factors was the most enriched pattern and often occurred near known hematopoietic regulators. Eight genes not previously appreciated to function in hematopoiesis that were bound by all five factors were shown to be essential for thrombocyte and/or erythroid development in zebrafish. Moreover, one of these genes encoding the PDZK1IP1 protein shared transcriptional enhancer elements with the blood stem cell regulator TAL1/SCL. Multifactor ChIP-Seq analysis in primary human cells coupled with a high-throughput in vivo perturbation screen therefore offers a powerful strategy to identify essential regulators of complex mammalian differentiation processes.
    Full-text · Article · May 2011 · Developmental Cell
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