Let-7 restrains an oncogenic epigenetic circuit in AT2 cells to prevent ectopic formation of fibrogenic transitional cell intermediates and pulmonary fibrosis.

Autor:	Seasock MJ; Immunology & Microbiology Graduate Program, Baylor College of Medicine, Houston, TX, 77030.; Department of Medicine, Immunology & Allergy Rheumatology, Baylor College of Medicine Houston TX, 77030., Shafiquzzaman M; Department of Medicine, Immunology & Allergy Rheumatology, Baylor College of Medicine Houston TX, 77030., Ruiz-Echartea ME; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030., Kanchi RS; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030.; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine Houston, TX, 77030., Tran BT; Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, 77030.; Department of Pediatrics, Division of Infectious Diseases, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, 77030., Simon LM; Therapeutic Innovation Center, Baylor College of Medicine, Houston, TX, 77030., Meyer MD; Shared Equipment Authority, Rice University, Houston, TX 77005., Erice PA; Immunology & Microbiology Graduate Program, Baylor College of Medicine, Houston, TX, 77030.; Department of Medicine, Immunology & Allergy Rheumatology, Baylor College of Medicine Houston TX, 77030., Lotlikar SL; Department of Medicine, Immunology & Allergy Rheumatology, Baylor College of Medicine Houston TX, 77030., Wenlock SC; Department of Pathology, University of Cambridge, Cambridge, CB2 1TN, UK., Ochsner SA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030., Enright A; Department of Pathology, University of Cambridge, Cambridge, CB2 1TN, UK., Carisey AF; William T. Shearer Center for Immunobiology, Texas Children's Hospital, Houston, TX, 77030.; Current Address: Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN., Romero F; Department of Medicine, Section of Pulmonary and Critical Care, Baylor College of Medicine. Houston, TX, 77030.; Current Address: Vertex Pharmaceuticals, 3215 Merryfield Row, San Diego, CA, 92121., Rosas IO; Department of Medicine, Section of Pulmonary and Critical Care, Baylor College of Medicine. Houston, TX, 77030., King KY; Department of Pediatrics, Division of Infectious Diseases, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, 77030., McKenna NJ; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030., Coarfa C; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030.; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine Houston, TX, 77030., Rodriguez A; Department of Medicine, Immunology & Allergy Rheumatology, Baylor College of Medicine Houston TX, 77030.; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine Houston, TX, 77030.; Center for Translational Research on Inflammatory Diseases, Michael E. Debakey, Baylor College of Medicine, Houston, TX, 77030.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 May 27. Date of Electronic Publication: 2024 May 27.
DOI:	10.1101/2024.05.22.595205
Abstrakt:	Analysis of lung alveolar type 2 (AT2) progenitor stem cells has highlighted fundamental mechanisms that direct their differentiation into alveolar type 1 cells (AT1s) in lung repair and disease. However, microRNA (miRNA) mediated post-transcriptional mechanisms which govern this nexus remain understudied. We show here that the let-7 miRNA family serves a homeostatic role in governance of AT2 quiescence, specifically by preventing the uncontrolled accumulation of AT2 transitional cells and by promoting AT1 differentiation to safeguard the lung from spontaneous alveolar destruction and fibrosis. Using mice and organoid models with genetic ablation of let-7a1/let-7f1/let-7d cluster ( let-7afd ) in AT2 cells, we demonstrate prevents AT1 differentiation and results in aberrant accumulation of AT2 transitional cells in progressive pulmonary fibrosis. Integration of enhanced AGO2 UV-crosslinking and immunoprecipitation sequencing (AGO2-eCLIP) with RNA-sequencing from AT2 cells uncovered the induction of direct targets of let-7 in an oncogene feed-forward regulatory network including BACH1/EZH2 which drives an aberrant fibrotic cascade. Additional analyses by CUT&RUN-sequencing revealed loss of let-7afd hampers AT1 differentiation by eliciting aberrant histone EZH2 methylation which prevents the exit of AT2 transitional cells into terminal AT1s. This study identifies let-7 as a key gatekeeper of post-transcriptional and epigenetic chromatin signals to prevent AT2-driven pulmonary fibrosis. Competing Interests: COMPETING INTEREST STATEMENT The authors declare no competing interests.
Databáze:	MEDLINE
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