Aug 2026· Science Advances· Vol 12· 0 citations· 82 references
Medicine
TL;DR
It is demonstrated that ETV2 drives the rapid forward programming of human pluripotent stem cells (hPSCs) into endothelial cells (ECs) by direct remodeling of endothelial-specific enhancers and is established as a master gatekeeper of human EC specification.
Abstract
ETS variant transcription factor 2 (ETV2) serves as a foundational transcription factor for endothelial lineage specification. However, the lineage-specific cofactors that orchestrate with ETV2 during endothelial fate commitment remain elusive. Here, we demonstrate that ETV2 drives the rapid forward programming of human pluripotent stem cells (hPSCs) into endothelial cells (ECs) by direct remodeling of endothelial-specific enhancers. Crucially, we identify T cell acute lymphocytic leukemia protein 1 (TAL1), which is traditionally characterized as a hematopoietic regulator, as an indispensable cofactor for ETV2-mediated endothelial commitment. Distinct from its role in murine development, TAL1 deficiency in hPSCs not only aborts the endothelial program by impairing H3K27ac deposition at key enhancers but also triggers a profound lineage redirection toward a mesenchymal fate. Mechanistically, TAL1 physically interacts with ETV2 to recruit the p300, thereby facilitating a permissive chromatin environment for endothelial identity. By leveraging an hPSC-based differentiation model, our findings establish TAL1 as a master gatekeeper of human EC specification and provide a molecular blueprint for how ETV2-centric complexes synergistically govern human cell fate.
Hematopoietic stem and progenitor cells (HSPCs) arise from hemogenic endothelial cells (HECs) via the endothelial-to-hematopoietic transition (EHT). As a signature gene of hematopoietic stem cell-primed HECs, Mycn is highly expressed in these cells alongside its paralog, Myc. However, their roles and underlying mechanisms in EHT remain unclear. Here, we demonstrate that endothelial-specific deletion of Mycn, but not Myc, impairs HSPC formation in mouse embryos. Single-cell transcriptomics and functional assays reveal that Mycn deficiency specifically attenuates the HEC-to-HSPC transition but not thereafter. We also establish a mosaic analysis strategy to distinguish Mycn deletion states in mutant embryos, enabling precise characterization. Unlike control HECs that downregulate adhesion signatures during their specification, Mycn-deficient HECs aberrantly upregulate adhesion pathways. Inhibiting focal adhesion kinase, a critical modulator of cell adhesion, rescues HSPC production in Mycn-deficient explant cultures. These findings uncover a regulatory mechanism whereby Mycn promotes HSPC generation from endothelial cells by suppressing adhesion signaling.
Chi Wang, Zhe Chen, Mei-Lin Jiang et al.· Cell Reports· 0 citations
Hematopoietic stem and progenitor cells (HSPCs) arise from a specialized subset of arterial endothelial cells, the hemogenic endothelium (HE), during embryonic development and sustain blood production throughout life. Notch signalling is a key regulator of this process: its ligand Jag1 promotes HSPC formation, whereas Dll4 promotes arterial identity. However, how the activities of these ligands are temporally coordinated during HSPC emergence remains unresolved. Here we demonstrate that Dll4 is required prior to circulation onset, acting by dampening MAPK signalling to drive the transition from pre-HE to HE fate and enabling HE differentiation towards HSPCs. Subsequently, after circulation starts, Jag1a acts to maintain gene expression in HE and support transition to HSPC fate. Jag1a activity depends on blood flow-induced shear stress and rescues HSPC loss caused by impaired flow. Thus, rather than playing opposing roles, Dll4 and Jag1a act sequentially and coordinately to drive the endothelial-to-hematopoietic transition and promote HSPC emergence.
Dashuai Wu, B. Edginton-White, Dorothee Bornhorst et al.· bioRxiv· 0 citations
Single-cell RNA sequencing indicates that adulthood Rack1 deletion in type I interferon-I-responsive cells leads to aberrant lineage-geneset-scores of transcriptional HSCs and the emergence of stressed HSCs, and Mechanistically, RACK1 prevents HSC loss through maintaining the protein level of LDB1.
L. Deng, Jun-Jie Du, Zhe Xu et al.· Cell Death & Disease· 0 citations
It is demonstrated that TUG1, which is highly expressed in tumors, regulates early embryonic development in mice and is transformed from a cancer-specific effector to a critical regulator of the ZGA, raising the possibility that related regulatory principles may operate in other biological contexts.
Jian-Wu Wang, Guang Yang, Qingbo Yang et al.· Cellular and Molecular Life...· 0 citations
Gfi1 dynamics define EHT onset and functionally distinct HSC stemness, and a subset of adult bone marrow HSCs retained expression and exhibited superior repopulating and self-renewal capacity.
A novel function for VEZF1 is identified in coordinating pluripotency exit with expression of pro- differentiation signaling genes and a functional interplay between VEZF1 and CTCF during cell state transitions is revealed.
Isaiah K. Mensah, Minghao He, Mudasir Zahoor et al.· bioRxiv· 0 citations
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