Robust regulatory interplay of enhancers, facilitators, and promoters in a native chromatin context.

July 17, 2026| Source: Cell

Enhancers are abundant and critical gene-distal cis-regulatory elements with distinct architectural features; however, a mechanistic understanding of their interactions within endogenous chromatin contexts remains challenging. Here, we developed a recombinase-mediated genome-rewriting platform to explore how a long-range human enhancer, eNMU, confers a remarkable 10,000-fold activation of its target gene, Neuromedin U (NMU), at its native locus. Our systematic dissection reveals two functionally distinct sub-elements of eNMU: the canonical autonomous enhancer e1 and the intrinsically inactive facilitator e2, which dramatically augments e1's activity. The autonomous enhancer e1 is functionally hierarchical to e2, additional facilitators, and the NMU promoter across the ∼100-kb NMU-eNMU region, and it orchestrates the formation of a 3D regulatory hub. e1 also harbors a bipartite structure: a divergently transcribed retroviral long terminal repeat (LTR) enhancer and an adjacent LTR promoter that dampens NMU expression. We explore and discuss the broader implications of our focused study for understanding enhancer regulatory mechanisms genome-wide.

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An innervated and vascularized HNSCC-on-a-chip model built on defined and tunable engineered extracellular matrices.

Understanding the tumor microenvironment requires experimental platforms that faithfully recapitulate its key components. Here, we present an innervated and vascularized head and neck squamous cell carcinoma (HNSCC)-on-a-chip platform built with fully defined and tunable engineered extracellular matrices (eECMs). In a stepwise increase of complexity, we first cocultured patient-derived HNSCC cells, cancer-associated fibroblasts, and endothelial cells within tailored eECMs, revealing extracellula

Health & MedicineNovember 3, 2026

Septin binding restricts Shigella growth and triggers intracellular tolerance.

Pathogen survival relies on their ability to adapt to changing environments, yet how intracellular bacteria tolerate cell-autonomous immunity remains unclear. Septins assemble into cage-like structures around cytoplasmic Shigella targeted by autophagy, but their antibacterial activity was unknown. Using advanced microscopy and cell-free reconstitution, we show that septins polymerize into circumferentially oriented filaments that inhibit bacterial growth. RNA-sequencing reveals that septin bindi

Health & MedicineNovember 3, 2026

DCAF6 reprograms TGF-β responses through TRIM33 destruction.

TGF-β signaling plays a pivotal role in regulating numerous cellular processes, primarily through the Smad-dependent pathway. Disruptions of the pathway are associated with developmental disorders and life-threatening diseases, such as cancer. It has been reported that TRIM33 inactivates Smad4 signaling and also drives its own signaling responses. However, the mechanism controlling TRIM33 activity has remained unclear. In this study, we identify DCAF6 as a previously unrecognized ubiquitin

Health & MedicineOctober 29, 2026

Stimulated protein degradation to promote mitochondrial function and neuronal survival.

Targeted protein degradation is a promising modality to treat cancer or inflammation, but whether it can provide a similar benefit for disorders caused by pervasive protein dysregulation is unclear. We describe stimulated protein degradation (SPD) as a strategy that leverages agonists of stress-responsive E3 ubiquitin ligases to simultaneously eliminate multiple pathogenic factors. Specifically, we show that activators of the reductive stress response E3 CUL2 FEM1B boost degradation of multiple