Let-7 restrains an epigenetic circuit in AT2 cells to prevent fibrogenic intermediates in pulmonary fibrosis
Matthew J. Seasock, Md Shafiquzzaman, Maria E. Ruiz-Echartea, Rupa S. Kanchi, Brandon T. Tran, Lukas M. Simon, Matthew D. Meyer, Phillip A. Erice, Shivani L. Lotlikar, Stephanie Wenlock, Scott A. Ochsner, Anton J. Enright, Alexandre F. Carisey, Freddy Romero, Iván O. Rosas, Katherine Y. King, Neil J. McKenna, Cristian Coarfa, Antony Rodriguez
Abstract
MicroRNA-mediated post-transcriptional regulation of lung alveolar type 2 (AT2) and AT1 cell differentiation remains understudied. Here, we demonstrate that the let-7 miRNA family plays a homeostatic role in AT2 quiescence by preventing the uncontrolled accumulation of AT2 transitional cells and promoting AT1 differentiation. Using mouse and organoid models, we show that genetic ablation of let-7a1/let-7f1/let-7d cluster (let-7afd) in AT2 cells prevents AT1 differentiation and leads to KRT8 transitional cell accumulation in progressive pulmonary fibrosis. Integration of AGO2-eCLIP with RNA-sequencing identified direct let-7 targets within an oncogene feed-forward regulatory network, including BACH1/EZH2/MYC, which drives an aberrant fibrotic cascade. Additional CUT&RUN-sequencing analyses revealed that let-7afd loss disrupts histone acetylation and methylation, driving epigenetic reprogramming and altered gene transcription in profibrotic AT2 cells. This study identifies let-7 as a central hub linking unchecked oncogenic signaling to impaired AT2 cell plasticity and fibrogenesis. Loss of let-7, a key microRNA, causes lung alveolar stem cells to grow abnormally and dieprematurely, leading to scarring and lung damage. Here the study links let-7 loss to cancer-like signals and epigenomic gene changes, revealing new treatment paths for lung fibrosis.