A Compact Regulatory Logic Governs Fibroblast Cell State Plasticity in Fibrosis
- 1Gladstone Institutes; San Francisco, CA, USA
Abstract
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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BibTeX
@misc{zhu2026compact,
title = {{A Compact Regulatory Logic Governs Fibroblast Cell State Plasticity in Fibrosis}},
author = {A. M. Zhu and Y. Li and H. Zhang and B. Rathinasabapathi and B. Cimarosti and R. Nadadur and V. Xu and Y. Huang and Y. An and K. Auclair and A. Mahr and M. U. Sheth and C. Y. Lee and C. Wang and T. Yamawaki and A. Pelonero and A. Padmanabhan and S. S. Ranade and J. M. Engreitz and B. Ason and C.-M. Li and S. Jackson and J. M. Amrute and P. F. Przytycki and M. Alexanian},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.09.757677},
url = {https://www.biorxiv.org/content/10.64898/2026.10.09.757677v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - A Compact Regulatory Logic Governs Fibroblast Cell State Plasticity in Fibrosis
AU - A. M. Zhu
AU - Y. Li
AU - H. Zhang
AU - B. Rathinasabapathi
AU - B. Cimarosti
AU - R. Nadadur
AU - V. Xu
AU - Y. Huang
AU - Y. An
AU - K. Auclair
AU - A. Mahr
AU - M. U. Sheth
AU - C. Y. Lee
AU - C. Wang
AU - T. Yamawaki
AU - A. Pelonero
AU - A. Padmanabhan
AU - S. S. Ranade
AU - J. M. Engreitz
AU - B. Ason
AU - C.-M. Li
AU - S. Jackson
AU - J. M. Amrute
AU - P. F. Przytycki
AU - M. Alexanian
PY - 2026
DA - 2026/10/09
PB - bioRxiv
DO - 10.64898/2026.10.09.757677
UR - https://www.biorxiv.org/content/10.64898/2026.10.09.757677v1
AB - 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.
ER -