RUNX transcription factors: orchestrators of development

Mével, Renaud; Draper, Julia; Lie-A-Ling, Michael; Kouskoff, Valérie; Lacaud, Georges

doi:10.1242/dev.148296

Cited by 168 publications

(180 citation statements)

References 297 publications

(429 reference statements)

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“…We demonstrate here that two important haematopoietic transcription factors, Gata3 and Runx1, both of which also perform important roles in adult haematopoietic lineages, are co‐expressed in the sub‐aortic mesenchyme of the AGM and that their interaction may regulate the timing of HSC emergence. Furthermore, using AGM‐derived stromal cell lines as a model, we demonstrate that Runx1 as well as other important haematopoietic factors such as Kit and Cxcl12 are direct targets of Gata3.…”

Section: Introductionmentioning

confidence: 80%

Gata3 targets Runx1 in the embryonic haematopoietic stem cell niche

et al. 2019

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Runx1 is an important haematopoietic transcription factor as stressed by its involvement in a number of haematological malignancies. Furthermore, it is a key regulator of the emergence of the first haematopoietic stem cells (HSCs) during development. The transcription factor Gata3 has also been linked to haematological disease and was shown to promote HSC production in the embryo by inducing the secretion of important niche factors. Both proteins are expressed in several different cell types within the aorta-gonads-mesonephros (AGM) region, in which the first HSCs are generated; however, a direct interaction between these two key transcription factors in the context of embryonic HSC production has not formally been demonstrated. In this current study, we have detected co-localisation of Runx1 and Gata3 in rare sub-aortic mesenchymal cells in the AGM. Furthermore, the expression of Runx1 is reduced in Gata3 −/− embryos, which also display a shift in HSC emergence. Using an AGMderived cell line as a model for the stromal microenvironment in the AGM and performing ChIP-Seq and ChIP-on-chip experiments, we demonstrate that Runx1, together with other key niche factors, is a direct target gene of Gata3. In addition, we can pinpoint Gata3 binding to the Runx1 locus at specific enhancer elements which are active in the microenvironment. These results reveal a direct interaction between Gata3 and Runx1 in the niche that supports embryonic HSCs and highlight a dual role for Runx1 in driving the transdifferentiation of haemogenic endothelial cells into HSCs as well as in the stromal cells that support this process. K E Y W O R D Saorta-gonads-mesonephros, Gata3, haematopoietic stem cells, niche, Runx1, stromal cells

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Section: Introductionmentioning

confidence: 80%

Gata3 targets Runx1 in the embryonic haematopoietic stem cell niche

et al. 2019

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“…RUNX1, an important transcription factor, is also involved in embryonic development, tumorigenesis, the immune response and, especially, the inflammatory response [30][31][32]. Some reports show that inhibition of RUNX1 activity with the small molecule resulted in a significant reduction in neovascular tufts in oxygen-induced retinopathy, supporting the feasibility of targeting RUNX1 in aberrant retinal angiogenesis [24].…”

Section: Discussionmentioning

confidence: 99%

p38 promoted retinal micro-angiogenesis through up-regulated RUNX1 expression in diabetic retinopathy

et al. 2020

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Diabetic retinopathy (DR) is the most common microvascular complication of diabetes and is characterized by visible microvascular alterations including retinal ischemia–reperfusion injury, inflammation, abnormal permeability, neovascularization and macular edema. Despite the available treatments, some patients present late in the course of the disease when treatment is more difficult. Hence, it is crucial that the new targets are found and utilized in the clinical therapy of DR. In the present study, we constructed a DR animal model and a model in HRMECs to investigate the relationship between p38 and RUNX1 in retinal micro-angiogenesis in diabetic retinopathy. We found that p38 could promote retinal micro-angiogenesis by up-regulating RUNX1 expression in diabetic retinopathy. This suggested that the p38/ RUNX1 pathway could become a new retinal micro-angiogenesis target in DR treatment.

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“…The transcription factor RUNX1 regulates the differentiation of multiple hematopoietic lineages, including megakaryocytes and lymphocytes, and is mutated in both sporadic and inherited forms of leukemia. [1][2][3][4] RUNX1 also regulates immunity and inflammation through its function in lineage determination or by modulating the activity of inflammatory signaling pathways. RUNX1's role in inflammation is best understood in T regulatory (Treg) cells, in which it controls Treg activity through regulating expression of the important Treg transcription factor, factor fork-head-box P3 (FoxP3), and cytokine genes, such as interleukin-2 (IL-2) and interferon-g (IFN-g).…”

Section: Introductionmentioning

confidence: 99%

Runx1 negatively regulates inflammatory cytokine production by neutrophils in response to Toll-like receptor signaling

et al. 2020

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RUNX1 is frequently mutated in myeloid and lymphoid malignancies. It has been shown to negatively regulate Toll-like receptor 4 (TLR4) signaling through nuclear factor κB (NF-κB) in lung epithelial cells. Here we show that RUNX1 regulates TLR1/2 and TLR4 signaling and inflammatory cytokine production by neutrophils. Hematopoietic-specific RUNX1 loss increased the production of proinflammatory mediators, including tumor necrosis factor-α (TNF-α), by bone marrow neutrophils in response to TLR1/2 and TLR4 agonists. Hematopoietic RUNX1 loss also resulted in profound damage to the lung parenchyma following inhalation of the TLR4 ligand lipopolysaccharide (LPS). However, neutrophils with neutrophil-specific RUNX1 loss lacked the inflammatory phenotype caused by pan-hematopoietic RUNX1 loss, indicating that dysregulated TLR4 signaling is not due to loss of RUNX1 in neutrophils per se. Rather, single-cell RNA sequencing indicates the dysregulation originates in a neutrophil precursor. Enhanced inflammatory cytokine production by neutrophils following pan-hematopoietic RUNX1 loss correlated with increased degradation of the inhibitor of NF-κB signaling, and RUNX1-deficient neutrophils displayed broad transcriptional upregulation of many of the core components of the TLR4 signaling pathway. Hence, early, pan-hematopoietic RUNX1 loss de-represses an innate immune signaling transcriptional program that is maintained in terminally differentiated neutrophils, resulting in their hyperinflammatory state. We hypothesize that inflammatory cytokine production by neutrophils may contribute to leukemia associated with inherited RUNX1 mutations.

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RUNX transcription factors: orchestrators of development

Cited by 168 publications

References 297 publications

Gata3 targets Runx1 in the embryonic haematopoietic stem cell niche

Gata3 targets Runx1 in the embryonic haematopoietic stem cell niche

p38 promoted retinal micro-angiogenesis through up-regulated RUNX1 expression in diabetic retinopathy

Runx1 negatively regulates inflammatory cytokine production by neutrophils in response to Toll-like receptor signaling

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