New insights into the regulation by RUNX1 and GFI1(s) proteins of the endothelial to hematopoietic transition generating primordial hematopoietic cells

RUNX transcription factors orchestrate many different aspects of biology, including basic cellular and developmental processes, stem cell biology and tumorigenesis. In this Primer, we introduce the molecular hallmarks of the three mammalian RUNX genes, RUNX1, RUNX2 and RUNX3, and discuss the regulation of their activities and their mechanisms of action. We then review their crucial roles in the specification and maintenance of a wide array of tissues during embryonic development and adult homeostasis.

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“…in hematopoiesis (de Bruijn and Dzierzak, 2017; Ebihara et al, 2017;Gao et al, 2018;Thambyrajah et al, 2016b;Tober et al, 2016;Voon et al, 2015).…”

Section: Runx1 Ckomentioning

confidence: 99%

RUNX transcription factors: orchestrators of development

et al. 2019

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“…This generates the first hematopoietic stem cells (HSCs) in the intraembryonic aorta–gonad–mesonephros region, silencing the endothelial program. Interestingly, the expression pattern of both genes is different: Gfi1 is specifically expressed within the dorsal aorta in endothelial cells and cells within emerging intra-aortic hematopoietic clusters, whereas Gfi1b expression is more associated with the fully formed intra-aortic hematopoietic clusters (12). This suggests that although both proteins can apparently compensate for the loss of one gene by the other, they play unique differential roles in vivo .…”

Section: Gfi1 and Gfi1b Structure And Functionmentioning

confidence: 99%

Transcription Factor GFI1B in Health and Disease

et al. 2017

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Many human diseases arise through dysregulation of genes that control key cell fate pathways. Transcription factors (TFs) are major cell fate regulators frequently involved in cancer, particularly in leukemia. The GFI1B gene, coding a TF, was identified by sequence homology with the oncogene growth factor independence 1 (GFI1). Both GFI1 and GFI1B have six C-terminal C2H2 zinc fingers and an N-terminal SNAG (SNAIL/GFI1) transcriptional repression domain. Gfi1 is essential for neutrophil differentiation in mice. In humans, GFI1 mutations are associated with severe congenital neutropenia. Gfi1 is also required for B and T lymphopoiesis. However, knockout mice have demonstrated that Gfi1b is required for development of both erythroid and megakaryocytic lineages. Consistent with this, human mutations of GFI1B produce bleeding disorders with low platelet count and abnormal function. Loss of Gfi1b in adult mice increases the absolute numbers of hematopoietic stem cells (HSCs) that are less quiescent than wild-type HSCs. In keeping with this key role in cell fate, GFI1B is emerging as a gene involved in cancer, which also includes solid tumors. In fact, abnormal activation of GFI1B and GFI1 has been related to human medulloblastoma and is also likely to be relevant in blood malignancies. Several pieces of evidence supporting this statement will be detailed in this mini review.

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“…Two of its downstream effectors are the transcriptional repressors GFI1 and GFI1B ( Lancrin et al., 2012 ). While loss of either Gfi1 paralog has no apparent impact on EHT, Gfi1/1b double knockout (KO) HE cells cannot undergo EHT ( Thambyrajah et al., 2016a , Thambyrajah et al., 2016b ). Gfi1 s regulate EHT by recruiting the CoREST epigenetic remodeling complex in order to induce the silencing of the endothelial identity of the HE ( Thambyrajah et al., 2016a ).…”

Section: Introductionmentioning

confidence: 99%

HDAC1 and HDAC2 Modulate TGF-β Signaling during Endothelial-to-Hematopoietic Transition

et al. 2018

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SummaryThe first hematopoietic stem and progenitor cells are generated during development from hemogenic endothelium (HE) through trans-differentiation. The molecular mechanisms underlying this endothelial-to-hematopoietic transition (EHT) remain poorly understood. Here, we explored the role of the epigenetic regulators HDAC1 and HDAC2 in the emergence of these first blood cells in vitro and in vivo. Loss of either of these epigenetic silencers through conditional genetic deletion reduced hematopoietic transition from HE, while combined deletion was incompatible with blood generation. We investigated the molecular basis of HDAC1 and HDAC2 requirement and identified TGF-β signaling as one of the pathways controlled by HDAC1 and HDAC2. Accordingly, we experimentally demonstrated that activation of this pathway in HE cells reinforces hematopoietic development. Altogether, our results establish that HDAC1 and HDAC2 modulate TGF-β signaling and suggest that stimulation of this pathway in HE cells would be beneficial for production of hematopoietic cells for regenerative therapies.

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New insights into the regulation by RUNX1 and GFI1(s) proteins of the endothelial to hematopoietic transition generating primordial hematopoietic cells

Cited by 18 publications

References 104 publications

RUNX transcription factors: orchestrators of development

RUNX transcription factors: orchestrators of development

Transcription Factor GFI1B in Health and Disease

HDAC1 and HDAC2 Modulate TGF-β Signaling during Endothelial-to-Hematopoietic Transition

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