Let-7 restrains an epigenetic circuit in AT2 cells to prevent fibrogenic intermediates in pulmonary fibrosis
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.
Authors
- Matthew J. Seasock (ORCID: https://orcid.org/0000-0002-5940-5913)
- Phillip A. Erice (ORCID: https://orcid.org/0000-0001-6349-4480)
- Katherine Y. King (ORCID: https://orcid.org/0000-0002-5093-6005)
- Stephanie Wenlock
- Matthew D. Meyer (ORCID: https://orcid.org/0000-0002-0680-6123)
- Brandon T. Tran (ORCID: https://orcid.org/0000-0002-9800-8953)
- Rupa S. Kanchi
- Iván O. Rosas (ORCID: https://orcid.org/0000-0003-4622-618X)
- Maria E. Ruiz-Echartea
- Md Shafiquzzaman (ORCID: https://orcid.org/0000-0002-4668-0983)
- Anton James Enright (ORCID: https://orcid.org/0000-0002-6090-3100)
- Cristian Coarfa (ORCID: https://orcid.org/0000-0002-4183-4939)
- Scott A. Ochsner (ORCID: https://orcid.org/0000-0003-1099-7863)
- Alexandre F. Carisey (ORCID: https://orcid.org/0000-0003-1326-2205)
- Neil J. McKenna (ORCID: https://orcid.org/0000-0001-6689-0104)
- Lukas M. Simon (ORCID: https://orcid.org/0000-0001-6148-8861)
- Shivani L. Lotlikar
- Freddy Romero (ORCID: https://orcid.org/0000-0002-0389-9010)
- Antony Rodriguez (ORCID: https://orcid.org/0000-0002-6649-1856)
Institutions
- Michael E. DeBakey VA Medical Center (US)
- St. Jude Children's Research Hospital (US)
- Baylor College of Medicine (US)
- University of Cambridge (GB)
- Texas Children's Hospital (US)
- Children's Cancer Center (US)
- Vertex Pharmaceuticals (United States) (US)
- Rice University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-10
- DOI
- https://doi.org/10.1038/s41467-025-59641-1
- Citations
- 9
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 7.25
Funders
- Cancer Prevention and Research Institute of Texas
- Texas Children's Hospital
- National Institutes of Health
- National Heart, Lung, and Blood Institute
- National Institute of General Medical Sciences
- National Institute of Environmental Health Sciences