RACK1 maintains mouse hematopoietic stem cells by directly binding to and stabilizing LDB1

Rbm5 sustains leukemia stem cells through a Myc-driven transcriptional circuitry.

It is reported that an unappreciated RNA-binding protein, Rbm5, selectively promotes murine leukemogenesis, maintains LSC self-renewal in vivo, and is dispensable for normal hematopoiesis.

Prdm15 deficiency perturbs hematopoietic stem and progenitor cell homeostasis.

It is reported that Prdm15 deficiency in HSPCs induces the accumulation of immature hematopoietic stem cells in mice, establishing PRDM15 as a critical epigenetic regulator of HSPCs, offering valuable insights into the molecular mechanisms underlying hematopoietic homeostasis.

TAL1 is indispensable in ETV2-primed human endothelial cell fate determination

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.

Locus-specific transposable element expression drives human hematopoietic stem cell disease pathophysiology

This study provides direct evidence that VEXAS-specific TE govern HSC clonal dominance, thereby uncovering a regulatory axis underlying HSC biology and disease mechanisms, opening a therapeutic strategy directed towards the repetitive genome.

can modulate TAL1 transcriptional activity through interaction with LMO2

Targeting the NuRD Component, CHD4, Impairs Foxp3+ Treg Cell Production and Function and Promotes Anti-Tumor Immunity

Little is known about why Foxp3⁺ regulatory T (Treg) cells require at least three HDAC1/HDAC2-containing chromatin-remodeling complexes (NuRD, Sin3 and CoREST), or whether selective disruption of these complexes can be exploited to enhance antitumor immunity. Here, we investigated the role of chromodomain helicase DNA- binding protein 4 (CHD4), the ATP-dependent remodeling subunit of the NuRD complex, in Treg biology. Conditional deletion of Chd4 in Foxp3⁺ Tregs resulted in severe systemic autoimmunity and early lethality, accompanied by reduced Foxp3 expression, impaired Treg suppressive function, and loss of Treg lineage stability. Transcriptomic analyses demonstrated that CHD4 deficiency closely phenocopied Hdac2 deletion, whereas quantitative proteomic analyses revealed that CHD4 assembles into highly conserved NuRD complexes in both Treg and conventional CD4⁺ T cells. These findings indicate that the selective dependence of Tregs on CHD4 does not arise from the formation of lineage-specific protein complexes but rather from the unique epigenetic program maintained by CHD4-containing chromatin-remodeling complexes that is required for Treg differentiation and stability. Using a novel cellular target-engagement platform, we identified CH41, a potent small-molecule inhibitor of CHD4 that recapitulated the effects of genetic CHD4 ablation on Treg function. Pharmacological inhibition of CHD4 impaired intratumoral Treg accumulation and function and significantly inhibited the growth of lung and hepatocellular carcinomas in immunocompetent, but not immunodeficient, mice, without inducing systemic autoimmunity. Collectively, our findings identify CHD4 as a critical epigenetic regulator of Treg lineage stability and establish pharmacological targeting of the CHD4/NuRD axis as a promising strategy to selectively disrupt tumor-associated Tregs and enhance antitumor immunity.