Key result
Multiplexed enhancer repression silences ~79% of profibrotic genes and curbs cardiac fibrosis.
Why the study?
Fibroblast activation drives organ failure across human diseases, yet its regulatory basis remains largely undefined.
Does repression of disease-activated enhancers or fibroblast-specific deletion of Meox1 attenuate profibrotic fibroblast activation and improve cardiac function and fibrosis in experimental heart failure?
Does repression of disease-activated enhancers or fibroblast-specific deletion of Meox1 attenuate profibrotic fibroblast activation and improve cardiac function and fibrosis in experimental heart failure?
This study maps the cis-regulatory architecture of profibrotic fibroblasts, demonstrating that fibroblast-specific deletion of the central transcription factor MEOX1 or multiplexed repression of six enhancers collapses the profibrotic network and improves cardiac function and fibrosis in experimental heart failure.
Summary Fibroblast activation drives organ failure across human diseases, yet its regulatory basis remains largely undefined. Here, we repressed 280 conserved disease-activated enhancers using CRISPR droplet sequencing (CROP-seq) in ∼550,000 fibroblasts, constructing a regulome of 15 gene programs governing the profibrotic state. Systematic TF perturbation converged on MEOX1 as a central regulator, and fibroblast-specific Meox1 deletion in mice improved cardiac function, reduced fibrosis, and rewired profibrotic fibroblasts toward quiescence in heart failure. Effector gene perturbation in human cardiac fibroblasts revealed distinct regulators of contractility, migration, and inflammatory signaling, and these programs were conserved across profibrotic states in human lung, liver, and skin. Simultaneous repression of just six enhancers using a multiplexed dCas12a-KRAB system collapsed the profibrotic network, suppressed migration and contraction, and rewired fibroblast paracrine signaling to attenuate macrophage inflammation. These findings define the regulatory logic of fibroblast plasticity and establish a new framework for reprogramming profibrotic cell states in disease.
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Zhu et al. (2026) studied Cardiac fibrosis and heart failure (n=53). CRISPRi-mediated repression of 280 disease-activated enhancers (including multiplexed dCas12a-KRAB repression of 6 enhancers) and fibroblast-specific Meox1 deletion vs. Non-targeting guide RNA controls or control TAC mice (Meox1flox/flox TAC) was evaluated on Suppression of profibrotic gene programs, cardiac fibrosis (% area), left ventricular ejection fraction, and global longitudinal strain. Simultaneous dCas12a-KRAB repression of six disease-activated enhancers silenced 79% of the profibrotic gene signature, while fibroblast-specific Meox1 deletion in mice reduced cardiac fibrosis.
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