HOXA9 promotes hematopoietic commitment of human embryonic stem cells

Ramos-Mejía, Verónica; Navarro-Montero, Óscar; Ayllón, Verónica; Bueno, Clara; Romero, Tamara; Real, Pedro J.; Menéndez, Pablo

doi:10.1182/blood-2014-03-558825

Cited by 94 publications

(90 citation statements)

References 53 publications

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“…Importantly, the variability in GATA motif accessibility is not influenced by the cell cycle variation [19]. Interestingly, in addition to epigenomic variability associated with GATA binding, we also find high epigenomic variability within transcription factors that are expressed in hematopoietic progenitors, like ERG, HOXA9, SPI1 (PU.1), and RUNX1 [21–24]. We also observe variability associated with STAT1 and STAT2 binding, further reflecting hematopoietic differentiation, as the JAK-STAT pathway is an important regulator enabling cells to respond to interferons and cytokines.…”

Section: Resultsmentioning

confidence: 99%

Single-cell epigenomic variability reveals functional cancer heterogeneity

Litzenburger

Buenrostro

et al. 2017

Genome Biol

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BackgroundCell-to-cell heterogeneity is a major driver of cancer evolution, progression, and emergence of drug resistance. Epigenomic variation at the single-cell level can rapidly create cancer heterogeneity but is difficult to detect and assess functionally.ResultsWe develop a strategy to bridge the gap between measurement and function in single-cell epigenomics. Using single-cell chromatin accessibility and RNA-seq data in K562 leukemic cells, we identify the cell surface marker CD24 as co-varying with chromatin accessibility changes linked to GATA transcription factors in single cells. Fluorescence-activated cell sorting of CD24 high versus low cells prospectively isolated GATA1 and GATA2 high versus low cells. GATA high versus low cells express differential gene regulatory networks, differential sensitivity to the drug imatinib mesylate, and differential self-renewal capacity. Lineage tracing experiments show that GATA/CD24hi cells have the capability to rapidly reconstitute the heterogeneity within the entire starting population, suggesting that GATA expression levels drive a phenotypically relevant source of epigenomic plasticity.ConclusionSingle-cell chromatin accessibility can guide prospective characterization of cancer heterogeneity. Epigenomic subpopulations in cancer impact drug sensitivity and the clonal dynamics of cancer evolution.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-016-1133-7) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Single-cell epigenomic variability reveals functional cancer heterogeneity

Litzenburger

Buenrostro

et al. 2017

Genome Biol

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“…In addition, it was recently shown that HOXA9 promotes the hematopoietic differentiation of hESCs [24]. Thus, it is likely that these molecules are involved in the efficient induction of HEPs from hiPSCs by the transient GSKi treatment.…”

Section: Resultsmentioning

confidence: 99%

GSK3β inhibition activates the CDX/HOX pathway and promotes hemogenic endothelial progenitor differentiation from human pluripotent stem cells

Kitajima

Nakajima

Kanokoda

et al. 2016

Experimental Hematology

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WNT/β-CATENIN signaling promotes the hematopoietic/endothelial differentiation of human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs). The transient addition of a GSK3β inhibitor (GSKi) has been shown to facilitate in vitro endothelial cell differentiation from hESCs/hiPSCs. Since hematopoietic and endothelial cells are derived from common progenitors (hemogenic endothelial progenitors [HEPs]), we examined the effect of transient GSKi treatment on hematopoietic cell differentiation from hiPSCs. We found that transient GSKi treatment at the start of hiPSC differentiation induction altered the gene expression profile of the cells. Multiple CDX/HOX genes, which are expressed in the posterior mesoderm of developing embryos, were significantly upregulated by GSKi treatment. Further, inclusion of the GSKi in a serum- and stroma-free culture with chemically defined medium efficiently induced HEPs, and the HEPs gave rise to various lineages of hematopoietic and endothelial cells. Therefore, transient WNT/β-CATENIN signaling triggers the activation of the CDX/HOX pathway, which in turn confers hemogenic posterior mesoderm identity to differentiating hiPSCs. These data enhance our understanding of human embryonic hematopoietic/endothelial cell development and provide a novel in vitro system for inducing the differentiation of hematopoietic cells from hiPSCs.

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“…Indeed, many other factors such as HOXA9 ERG, RORA, SOX4, and MYB have been tested for promoting engraftment of HS/PCs generated in vitro. However, none of these factors were able to mediate long-term engraftment of these in vitro generated human HS/PCs (Doulatov et al., 2013, Ramos-Mejia et al., 2014, Vanhee et al., 2015). Another approach to generate HS/PCs in vitro is through direct specification of functional HECs into HS/PCs.…”

Section: Introductionmentioning

confidence: 99%

Generation and Analysis of GATA2 w/eGFP Human ESCs Reveal ITGB3/CD61 as a Reliable Marker for Defining Hemogenic Endothelial Cells during Hematopoiesis

Huang

Gao

et al. 2016

Stem Cell Reports

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SummaryThe transition from hemogenic endothelial cells (HECs) to hematopoietic stem/progenitor cells (HS/PCs), or endothelial to hematopoietic transition (EHT), is a critical step during hematopoiesis. However, little is known about the molecular determinants of HECs due to the challenge in defining HECs. We report here the generation of GATA2w/eGFP reporter in human embryonic stem cells (hESCs) to mark cells expressing GATA2, a critical gene for EHT. We show that during differentiation, functional HECs are almost exclusively GATA2/eGFP+. We then constructed a regulatory network for HEC determination and also identified a panel of positive or negative surface markers for discriminating HECs from non-hemogenic ECs. Among them, ITGB3 (CD61) precisely labeled HECs both in hESC differentiation and embryonic day 10 mouse embryos. These results not only identify a reliable marker for defining HECs, but also establish a robust platform for dissecting hematopoiesis in vitro, which might lead to the generation of HSCs in vitro.

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HOXA9 promotes hematopoietic commitment of human embryonic stem cells

Abstract: Key Points HOXA9 parallels blood development, but is restricted to HEP, and diminishes as they differentiate into blood cells. Functional assays reveal how HOXA9 enhances blood formation by promoting commitment of HEP to CD45+ cells with higher clonogenic potential.

Cited by 94 publications

References 53 publications

Single-cell epigenomic variability reveals functional cancer heterogeneity

Single-cell epigenomic variability reveals functional cancer heterogeneity

GSK3β inhibition activates the CDX/HOX pathway and promotes hemogenic endothelial progenitor differentiation from human pluripotent stem cells

Generation and Analysis of GATA2 w/eGFP Human ESCs Reveal ITGB3/CD61 as a Reliable Marker for Defining Hemogenic Endothelial Cells during Hematopoiesis

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