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<p>MicroRNA-mediated post-transcriptional regulation of lung alveolar type 2 (AT2) and AT1 cell differentiation remains understudied. Here, we demonstrate that the <i>let-7</i> 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 <i>let-7a1/let-7f1/let-7d</i> cluster (<i>let-7afd</i>) 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 <i>let-7</i> targets within an oncogene feed-forward regulatory network, including BACH1/EZH2/MYC, which drives an aberrant fibrotic cascade. Additional CUT&amp;RUN-sequencing analyses revealed that <i>let-7afd</i> loss disrupts histone acetylation and methylation, driving epigenetic reprogramming and altered gene transcription in profibrotic AT2 cells. This study identifies <i>let-7</i> as a central hub linking unchecked oncogenic signaling to impaired AT2 cell plasticity and fibrogenesis.</p>

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Let-7 restrains an epigenetic circuit in AT2 cells to prevent fibrogenic intermediates in pulmonary fibrosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月10日

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  • 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

摘要

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.