Kirchhof, K. | bioRxiv Science

bioRxiv2026

Flow-Induced Yap/Taz Signaling Balances Endothelial and Hematopoietic Stem Cell Fates

Mechanical forces from blood flow are essential for production of hematopoietic stem and progenitor cells (HSPCs) during embryogenesis, but the molecular mechanisms by which hemodynamic cues are sensed and orchestrate endothelial-to-hematopoietic (EHT) transition remain incompletely defined. We previously identified YAP mechanotransduction as a key integrator of physical forces with EHT. Here we show that hemodynamic forces can activate YAP signaling via the mechanoresponsive ion channel Piezo1 in human iPSC-derived hemogenic endothelium (HE) and zebrafish embryos. Investigation of the Piezo1/YAP axis revealed shared and unique roles of YAP and its paralogue TAZ in EHT. Mechanistically, we find a requirement for the Tead DNA-binding co-factor in YAP/TAZ-dependent control of HSPC number, and note that TAZ uniquely augments transcriptional output of the hematopoietic master regulator Runx1 via direct protein-protein interactions. By comprehensive scRNA-sequencing of YAP/TAZ gain-of-function (GOF) and yap-deficient cells from zebrafish, we reveal that YAP/TAZ promotes HSC production by positively regulating gene programs for hematopoietic self-renewal, cell cycle, and glycolysis-to-oxidative phosphorylation switching, while preventing reversion to endothelial identity. Importantly, comparison of GOF transcriptomes and functional analyses suggest decoupling of metabolic/proliferative and endothelial gene regulatory modules between YAP and TAZ: while either can functionally compensate for loss of the other in EHT, indiscriminate overactivation of TAZ enhances an endothelial program over pro-hematopoietic fate, ultimately blunting progression of HSPC production. Given that hemodynamic cues are integrated simultaneously by arterial and HE cells in embryonic vessels in which EHT occurs, these findings have strong implications for strategies designed to introduce biomechanical cues to in vitro hematopoietic differentiation systems to drive HSC production.

Cell Biology↗

bioRxiv2024

SF3B1-mutant mis-splicing of UBA1 confers a targetable therapeutic vulnerability through UBA1 inhibition

SF3B1 mutation-driven myelodysplastic syndromes (MDS-SF3B1) arise due to somatic mutation in the splicing factor SF3B1 gene. SF3B1 mutations induce RNA mis-splicing and loss of expression of critical genes for erythropoiesis, leading to erythroid dysplasia and ultimately refractory anemia. The development of precision medicine approaches for MDS- SF3B1 is hampered by the complexity of the mis-splicing landscape and its evaluation in disease-accurate model systems. To identify novel RNA mis-splicing events, isogenic SF3B1K700E and SF3B1WT iPSC lines from an MDS-SF3B1 patient were differentiated into hematopoietic cells in vitro and subjected to unsupervised splicing event analysis using full-length RNA sequencing data. This revealed SF3B1K700E-specific mis-splicing of ubiquitin-like modifier activating enzyme 1 (UBA1) transcripts, which encode the essential E1 protein at the apex of the ubiquitination cascade. UBA1 mis-splicing (UBA1ms) preserved UBA1ms mRNA but not protein expression. Consequently, UBA1ms diminished the pool of functional UBA1, sensitizing SF3B1K700E cell lines to the small-molecule UBA1 inhibitor TAK-243. Finally, analysis of CD34+ RNA sequencing data from an MDS patient cohort confirmed unique and ubiquitous UBA1ms in MDS-SF3B1 patients, without detection in other splicing factor-mutated MDS patients, or in healthy individuals. TAK-243 selectively targeted MDS-SF3B1 primary CD34+ cells and reduced mutant cell number in colony-forming unit studies. In contrast, normal hematopoietic progenitor cells were unaffected. Altogether, we here define UBA1ms as a novel therapeutic vulnerability in SF3B1-mutant cells, introducing UBA1 inhibition as a potential avenue for future MDS-SF3B1 treatments.

cancer biology↗