Biology subjects

Tompkins, A.

Publications and source records attributed to Tompkins, A..

2 recordsLinked to original sources

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↗

bioRxiv2025

Heterochromatin fidelity is a therapeutic vulnerability in lymphoma and other human cancers

Genes involved in the regulation of chromatin structure are frequently disrupted in cancer, contributing to an aberrant transcriptome and phenotypic plasticity. Yet, therapeutics targeting mutant forms of chromatin-modifying enzymes have yielded only modest clinical utility, underscoring the difficulty of targeting the epigenomic underpinnings of aberrant gene regulatory networks. Here, we sought to identify novel epigenetic vulnerabilities in diffuse large B-cell lymphoma (DLBCL). Through phenotypic screens and biochemical analysis, we demonstrated that inhibition of the H3K9 demethylases KDM4A and KDM4C elicits potent, subtype-agnostic cytotoxicity by antagonizing transcriptional networks associated with B-cell identity and epigenetically rewiring heterochromatin. KDM4 demethylases associated with the KRAB zinc finger ZNF587, and their enzymatic inhibition led to DNA replication stress and DNA damage-induced cGAS-STING activation. Broad surveys of transcriptional data from patients also revealed KDM4 family dysregulation in several other cancer types. To explore this potential therapeutic avenue, we performed high-throughput small molecule screens with H3K9me3 nucleosome substrates and identified novel KDM4 demethylase inhibitors. AI-guided protein-ligand binding predictions suggested diverse modes of action for various small molecule hits. Our findings underscore the relevance of targeting fundamental transcriptional and epigenetic mechanisms for anti-cancer therapy. HIGHLIGHTSO_LIPhenotypic screens identified JIB-04 as a potent anti-cancer agent for multiple subtypes of diffuse large B-cell lymphoma C_LIO_LIJIB-04 binds and inhibits KDM4 demethylases resulting in epigenomic rewiring of heterochromatin C_LIO_LIKDM4 demethylases cooperate with KRAB zinc fingers to limit DNA replication stress, and KDM4 inhibition instigates DNA-damage and cGAS-STING activation in several human cancers C_LIO_LIHigh-throughput small molecule screens with semi-synthetic nucleosome substrates and AI-guided molecular docking simulations identify novel KDM4 inhibitors C_LI

genomics↗