Ezh2 is essential for the generation of functional yolk sac derived erythro-myeloid progenitors

Neo, Wen Hao; Meng, Yiran; Rodríguez-Meira, Alba; Fadlullah, Muhammad Zaki Hidayatullah; Booth, Christopher A.G.; Azzoni, Emanuele; Thongjuea, Supat; Bruijn, Marella F. T. R. de; Jacobsen, Sten Eirik W.; Mead, Adam J.; Lacaud, Georges

doi:10.1038/s41467-021-27140-8

Cited by 10 publications

(2 citation statements)

References 71 publications

(85 reference statements)

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“…Whole‐genome expression arrays in a previous study indicated the involvement of EZH2 target genes in the Wnt signaling pathway [45]. Another study pointed out that nearly half of Wnt signaling genes were EZH2 target genes and that deletion of EZH2 dysregulated Wnt signaling [46]. Thus, we assumed that the Wnt1/β‐catenin signaling pathway was one major component of the regulation of peritoneal angiogenesis by EZH2.…”

Section: Discussionmentioning

confidence: 91%

Inhibition of EZH2 suppresses peritoneal angiogenesis by targeting a VEGFR2/ERK1/2/HIF‐1α‐dependent signaling pathway

Shi

Chen

et al. 2022

The Journal of Pathology

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The catalytic subunit of polycomb repressive complex 2 (PRC2), enhancer of zeste homolog 2 (EZH2), has been reported to be involved in angiogenesis in some tumors and autoimmune diseases. However, the mechanisms by which EZH2 regulates peritoneal angiogenesis remain unclear. We detected the expression of EZH2 in clinical samples and the peritoneal tissue of a mouse peritoneal fibrosis model induced by chlorhexidine gluconate (CG). In addition, we further investigated the mechanisms by which inhibition of EZH2 by 3‐deazaneplanocin A (3‐DZNeP) alleviated the CG‐induced peritoneal fibrosis mouse model in vivo and 3‐DZNeP or EZH2 siRNA treatment in cultured human peritoneal mesothelial cells (HPMCs) and human umbilical vein endothelial cells (HUVECs). The expression of EZH2 in the peritoneum of long‐term peritoneal dialysis (PD) patients and the CG‐induced peritoneal fibrosis mouse model was remarkably increased and this was positively associated with higher expression of vascular markers (CD31, CD34, VEGF, p‐VEGFR2). Peritoneal injection of 3‐DZNeP attenuated angiogenesis in the peritoneum of CG‐injured mice; improved peritoneal membrane function; and decreased phosphorylation of STAT3, ERK1/2, and activation of Wnt1/β‐catenin. In in vitro experiments, we demonstrated that inhibition of EZH2 by 3‐DZNeP or EZH2 siRNA decreased tube formation and the migratory ability of HUVECs via two pathways: the Wnt1/β‐catenin pathway and the IL‐6/STAT3 pathway. Suppression of the Wnt1/β‐catenin pathway and the IL‐6/STAT3 pathway subsequently reduced VEGF production in HPMCs. Using specific inhibitors of VEGFR2, ERK1/2, and HIF‐1α, we found that a VEGFR2/ERK1/2/HIF‐1α axis existed and contributed to angiogenesis in vitro. Moreover, phosphorylation of VEGFR2 and activation of the ERK1/2 pathway and HIF‐1α in HUVECs could be suppressed by inhibition of EZH2. Taken together, the results of this study suggest that EZH2 may be a novel target for preventing peritoneal angiogenesis in PD patients. © 2022 The Pathological Society of Great Britain and Ireland.

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Section: Discussionmentioning

confidence: 91%

Inhibition of EZH2 suppresses peritoneal angiogenesis by targeting a VEGFR2/ERK1/2/HIF‐1α‐dependent signaling pathway

Shi

Chen

et al. 2022

The Journal of Pathology

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“…Similar to metabolic activity, epigenetic regulation of gene expression has also been explored in the transition switches accompanying developmental haematopoiesis and foetal to adult HSC transitions. Several epigenetic regulators have been shown to differentially affect the successive haematopoietic waves, as exemplified by EZH2 [ 133 ], LSD1 [ 134 ] and HDAC1/2 [ 135 ], whose developmental knockouts hinder EMP formation in the yolk sac, but not intra-aortic specification of progenitors and HSC.…”

Section: Pitfalls and Potential Opportunities For Haemogenic Gastrulo...mentioning

confidence: 99%

Haematopoietic development and HSC formation in vitro: promise and limitations of gastruloid models

Dijkhuis,

Johns,

Ragusa

et al. 2023

Emerging Topics in Life Sciences

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Haematopoietic stem cells (HSCs) are the most extensively studied adult stem cells. Yet, six decades after their first description, reproducible and translatable generation of HSC in vitro remains an unmet challenge. HSC production in vitro is confounded by the multi-stage nature of blood production during development. Specification of HSC is a late event in embryonic blood production and depends on physical and chemical cues which remain incompletely characterised. The precise molecular composition of the HSC themselves is incompletely understood, limiting approaches to track their origin in situ in the appropriate cellular, chemical and mechanical context. Embryonic material at the point of HSC emergence is limiting, highlighting the need for an in vitro model of embryonic haematopoietic development in which current knowledge gaps can be addressed and exploited to enable HSC production. Gastruloids are pluripotent stem cell-derived 3-dimensional (3D) cellular aggregates which recapitulate developmental events in gastrulation and early organogenesis with spatial and temporal precision. Gastruloids self-organise multi-tissue structures upon minimal and controlled external cues, and are amenable to live imaging, screening, scaling and physicochemical manipulation to understand and translate tissue formation. In this review, we consider the haematopoietic potential of gastruloids and review early strategies to enhance blood progenitor and HSC production. We highlight possible strategies to achieve HSC production from gastruloids, and discuss the potential of gastruloid systems in illuminating current knowledge gaps in HSC specification.

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Translational Comparison of the Human and Mouse Yolk Sac Development and Function

et al. 2022

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Ezh2 is essential for the generation of functional yolk sac derived erythro-myeloid progenitors

Cited by 10 publications

References 71 publications

Inhibition of EZH2 suppresses peritoneal angiogenesis by targeting a VEGFR2/ERK1/2/HIF‐1α‐dependent signaling pathway

Inhibition of EZH2 suppresses peritoneal angiogenesis by targeting a VEGFR2/ERK1/2/HIF‐1α‐dependent signaling pathway

Haematopoietic development and HSC formation in vitro: promise and limitations of gastruloid models

Translational Comparison of the Human and Mouse Yolk Sac Development and Function

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