Let-7 Restrains an Epigenetic Circuit in AT2 Cells to Prevent Fibrogenic Intermediates in Pulmonary Fibrosis

Authors

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 C Wenlock
Scott A Ochsner
Anton Enright
Alex F Carisey
Freddy Romero
Ivan O Rosas
Katherine Y King
Neil J McKenna
Cristian Coarfa
Antony Rodriguez

Language

English

Publication Date

5-10-2025

Journal

Nature Communications

DOI

10.1038/s41467-025-59641-1

PMID

40348760

PMCID

PMC12065893

PubMedCentral® Posted Date

5-10-2025

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Animals, MicroRNAs, Pulmonary Fibrosis, Epigenesis, Genetic, Mice, Cell Differentiation, Alveolar Epithelial Cells, Enhancer of Zeste Homolog 2 Protein, Histones, Basic-Leucine Zipper Transcription Factors, Proto-Oncogene Proteins c-myc, Mice, Inbred C57BL, Organoids, Acetylation, Humans, Lung, Male

Published Open-Access

yes

Recommended Citation

Seasock, Matthew J; Shafiquzzaman, Md; Ruiz-Echartea, Maria E; et al., "Let-7 Restrains an Epigenetic Circuit in AT2 Cells to Prevent Fibrogenic Intermediates in Pulmonary Fibrosis" (2025). Faculty and Staff Publications. 4748.
https://digitalcommons.library.tmc.edu/baylor_docs/4748