58 / 2026-04-02 13:37:52

Integrative Epigenomic Profiling Reveals Distal Enhancer-Promoter Networks Regulating AT2 Cell Fate and Pulmonary Fibrosis

Long-range interactions,PLAC-seq/HiChIP,Alveolar type II cell (AT2),Pulmonary fibrosis,Fate transformation

Pulmonary fibrosis, characterized by aberrant tissue remodeling and destruction of alveolar structures, remains a life-threatening disease with limited therapeutic options. The trans-differentiation of alveolar type II (AT2) epithelial cells into type I (AT1) cells is essential for alveolar regeneration and homeostasis, yet this process is dysregulated in fibrosis. Although AT2 cell fate transition is critical for injury repair, its underlying epigenetic regulatory mechanisms remain poorly understood. Here, we applied an integrative epigenomic and transcriptomic approach to delineate the regulatory landscape of AT2 cells following bleomycin-induced injury. We generated a temporal multi-omics map combining chromatin state profiling and high-resolution promoter-centered chromatin interaction data using H3K4me3 MNase PLAC-seq. This integrative framework revealed that bleomycin treatment activates specific distal enhancers that prime AT2 cells for fate transition. By systematically linking active enhancers to their downstream genes through chromatin interactions, we constructed a cis-regulatory element-gene (cCRE-gene) interaction atlas in AT2 cells. This cCRE-gene network not only captured dynamic transcriptional reprogramming during the early stages of alveolar repair but also identified distal regulatory elements associated with key pulmonary fibrosis-related genes such as F3 and Krt7. Enhancer activity changes at these loci paralleled transcriptional alterations, uncovering upstream regulatory logic that connects injury response to fibrotic remodeling. Collectively, our study establishes a high-resolution, integrative epigenomic framework for decoding enhancer-gene regulation in AT2 cells. This work provides novel insights into the epigenetic control of alveolar repair and fibrosis, demonstrating the potential of advanced chromatin interaction-based technologies in dissecting complex disease-associated regulatory networks.