Transcriptional control of megakaryocyte development

Goldfarb, Adam N.

doi:10.1038/sj.onc.1210762

Cited by 50 publications

(51 citation statements)

References 62 publications

(85 reference statements)

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“…There is evidence that the competition between KLF1 and FLI1 on one hand 8,9,40 and the expression level of MYB 41,42 on the other hand regulate the MEP fate, and that several other transcription factors such as GATA1, GATA2, and NFE2 are necessary for both erythroid and MK differentiation. [5][6][7] Our study demonstrates that a distinct pattern of transcription factors and cytokine receptors is associated with the 3 cellular subsets that were analyzed. When the 3 global populations were considered, the progressive commitment was evidenced by a decrease in EPOR/KLF1 gene expression and an increase in AML1 and GABPA only in MK cells, whereas commitment to the erythroid lineage was associated with a decrease in MPL/FLI1/AML1/GABPA/GATA2 gene expression and an increase in EPOR/KLF1 gene expression.…”

Section: Discussionmentioning

confidence: 98%

“…They are homodimeric class I cytokine receptors, and both require JAK2 for signaling. 3,4 Numerous transcription factors, such as GATA2, GATA1, FOG1, TAL1/SCL, GFI1B, and NFE2, are critical for both erythroid and MK development, [5][6][7] whereas others are more dedicated for unilineage differentiation, such as the erythroid EKLF (KLF1) 8,9 and MYB 10 or the MK FLI1, 11 GABPA, 12 and AML1. 13 Studies of adult hematopoiesis, both in human and mice, have shown that the erythroid and MK lineages arise from a bipotential megakaryocyte-erythroid progenitor (MEP), [14][15][16] a separate entity with no lymphoid and granulomonocytic potential.…”

Section: Introductionmentioning

confidence: 99%

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A common bipotent progenitor generates the erythroid and megakaryocyte lineages in embryonic stem cell–derived primitive hematopoiesis

Klimchenko

Mori

DiStefano

et al. 2009

Blood

135

122

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The megakaryocytic (MK) and erythroid lineages are tightly associated during differentiation and are generated from a bipotent megakaryocyte-erythroid progenitor (MEP). In the mouse, a primitive MEP has been demonstrated in the yolk sac. In human, it is not known whether the primitive MK and erythroid lineages are generated from a common progenitor or independently. Using hematopoietic differentiation of human embryonic stem cells on the OP9 cell line, we identified a primitive MEP in a subset of cells coexpressing glycophorin A (GPA) and CD41 from day 9 to day 12 of coculturing. This MEP differentiates into primitive erythroid (GPA ؉ CD41 ؊ ) and MK (GPA ؊ CD41 ؉ ) lineages. In contrast to erythropoietin (EPO)-dependent definitive hematopoiesis, KIT was not detected during erythroid differentiation. A molecular signature for the commitment and differentiation toward both the erythroid and MK lineages was detected by assessing expression of transcription factors, thrombopoietin receptor (MPL) and erythropoietin receptor (EPOR). We showed an inverse correlation between FLI1 and both KLF1 and EPOR during primitive erythroid and MK differentiation, similar to definitive hematopoiesis. This novel MEP differentiation system may allow an in-depth exploration of the molecular bases of erythroid and MK commitment and differentiation.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

A common bipotent progenitor generates the erythroid and megakaryocyte lineages in embryonic stem cell–derived primitive hematopoiesis

Klimchenko

Mori

DiStefano

et al. 2009

Blood

135

122

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“…During development, the decision to leave the self-renewing state and selection of a differentiation pathway are regulated by transcription factors (TFs) [3-6]. Intense experimental studies during the past two decades have suggested that tight regulation of HSC differentiation is controlled by the interaction of a number of genetic and epigenetic regulators of gene transcription, including the two TFs PU.1 and GATA-1.…”

Section: Introductionmentioning

confidence: 99%

“…they repress the production of each other [7-9]. In the erythrocyte/megakaryocite lineage high expression levels of gene GATA-1 and low levels of PU.1 were detected [6,10]; conversely, in the granulocyte/macrophage lineage higher expression levels of PU.1 and low levels of GATA-1 were measured [5,11]. However, the initial progenitor cells stay in the third state that has low-level activation of both genes PU.1 and GATA-1 .…”

Section: Introductionmentioning

confidence: 99%

Mathematical modeling of GATA-switching for regulating the differentiation of hematopoietic stem cell

Tian

Smith‐Miles

2014

BMC Systems Biology

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BackgroundHematopoiesis is a highly orchestrated developmental process that comprises various developmental stages of the hematopoietic stem cells (HSCs). During development, the decision to leave the self-renewing state and selection of a differentiation pathway is regulated by a number of transcription factors. Among them, genes GATA-1 and PU.1 form a core negative feedback module to regulate the genetic switching between the cell fate choices of HSCs. Although extensive experimental studies have revealed the mechanisms to regulate the expression of these two genes, it is still unclear how this simple module regulates the genetic switching.MethodsIn this work we proposed a mathematical model to study the mechanisms of the GATA-PU.1 gene network in the determination of HSC differentiation pathways. We incorporated the mechanisms of GATA switch into the module, and developed a mathematical model that comprises three genes GATA-1, GATA-2 and PU.1. In addition, a novel multiple-objective optimization method was designed to infer unknown parameters in the proposed model by realizing different experimental observations. A stochastic model was also designed to describe the critical function of noise, due to the small copy numbers of molecular species, in determining the differentiation pathways.ResultsThe proposed deterministic model has successfully realized three stable steady states representing the priming and different progenitor cells as well as genetic switching between the genetic states under various experimental conditions. Using different values of GATA-1 synthesis rate for the GATA-1 protein availability in the chromatin sites during the time period of GATA switch, stochastic simulations for the first time have realized different proportions of cells leading to different developmental pathways under various experimental conditions.ConclusionsMathematical models provide testable predictions regarding the mechanisms and conditions for realizing different differentiation pathways of hematopoietic stem cells. This work represents the first attempt at using a discrete stochastic model to realize the decision of HSC differentiation pathways showing a multimodal distribution.

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“…9 The specific combination of transcription factors allowing erythrocytic or megakaryocytic lineages commitment remains poorly understood. 10,11 Indeed, both lineages are dependent on many common transcription factors including Gata1, Tal1, Nfe2, Gfi1b, Zbp89, as well as cofactors like Fog1, Lmo2, or Ldb1 acting in large multiprotein complexes such as Fog1/Gata1/Zbp89 12 or Gata1/Tal1/Lmo2/Ldb1. 13 No differential requirement of these factors for either lineage has been reported to date.…”

Section: Introductionmentioning

confidence: 99%

Inducible Fli-1 gene deletion in adult mice modifies several myeloid lineage commitment decisions and accelerates proliferation arrest and terminal erythrocytic differentiation

Starck

Weiss‐Gayet

Gonnet

et al. 2010

Blood

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This study investigated the role of the ETS transcription factor Fli-1 in adult myelopoiesis using new transgenic mice allowing inducible Fli-1 gene deletion. Fli-1 deletion in adult induced mild thrombocytopenia associated with a drastic decrease in large mature megakaryocytes number. Bone marrow bipotent megakaryocyticerythrocytic progenitors (MEPs) increased by 50% without increase in erythrocytic and megakaryocytic common myeloid progenitor progeny, suggesting increased production from upstream stem cells. These MEPs were almost unable to generate pure colonies containing large mature megakaryocytes, but generated the same total number of colonies mainly identifiable as erythroid colonies containing a reduced number of more differentiated cells. Cytological and fluorescenceactivated cell sorting analyses of MEP progeny in semisolid and liquid cultures confirmed the drastic decrease in large mature megakaryocytes but revealed a surprisingly modest (50%) reduction of CD41-positive cells indicating the persistence of a megakaryocytic commitment potential. Symmetrical increase and decrease of monocytic and granulocytic progenitors were also observed in the progeny of purified granulocytic-monocytic progenitors and common myeloid progenitors. In summary, this study indicates that Fli-1 controls several lineages commitment decisions at the stem cell, MEP, and granulocytic-monocytic progenitor levels, stimulates the proliferation of committed erythrocytic progenitors at the expense of their differentiation, and is a major regulator of late stages of megakaryocytic differentiation. (Blood. 2010;116(23):4795-4805) IntroductionMature blood cells in adults are permanently regenerated from a limited pool of pluripotent hematopoietic stem cells (HSCs) localized in the bone marrow. This process occurs through the hierarchical generation of intermediate progenitors with more and more restricted differentiation and proliferation potential that can be prospectively purified. According to current models, myeloid lineages are derived from a common myeloid progenitor (CMP) generating 2 distinct bipotent progenitors, the megakaryocyticerythrocytic progenitors (MEPs) and the granulocytic-monocytic progenitors (GMP). 1 MEPs generate in turn erythrocytic and megakaryocytic monopotent progenitors, whereas GMP generate granulocytic and monocytic monopotent progenitors. Increasing data also indicate an alternative pathway generating MEPs directly from HSCs. [2][3][4] All this process is controlled by permanent crosstalk between extracellular signals and intracellular regulatory networks of transcription factors. Although having no instructive role, erythropoietin (EPO) is the major cytokine controlling erythropoiesis through the stimulation of proliferation and survival of committed erythrocytic progenitors expressing the specific receptor EPOR. 5 Thrombopoietin (TPO) is the major cytokine controlling megakaryopoiesis through the stimulation of proliferation and differentiation of committed megakaryocytic progenitors expressing the sp...

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Transcriptional control of megakaryocyte development

Cited by 50 publications

References 62 publications

A common bipotent progenitor generates the erythroid and megakaryocyte lineages in embryonic stem cell–derived primitive hematopoiesis

A common bipotent progenitor generates the erythroid and megakaryocyte lineages in embryonic stem cell–derived primitive hematopoiesis

Mathematical modeling of GATA-switching for regulating the differentiation of hematopoietic stem cell

Inducible Fli-1 gene deletion in adult mice modifies several myeloid lineage commitment decisions and accelerates proliferation arrest and terminal erythrocytic differentiation

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