Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
Transcriptional regulatory model of fibrosis progression in the human lung
John E. McDonough, … , Wim A. Wuyts, Naftali Kaminski
John E. McDonough, … , Wim A. Wuyts, Naftali Kaminski
Published October 10, 2019
Citation Information: JCI Insight. 2019;4(22):e131597. https://doi.org/10.1172/jci.insight.131597.
View: Text | PDF
Research Article Pulmonology

Transcriptional regulatory model of fibrosis progression in the human lung

  • Text
  • PDF
Abstract

To develop a systems biology model of fibrosis progression within the human lung we performed RNA sequencing and microRNA analysis on 95 samples obtained from 10 idiopathic pulmonary fibrosis (IPF) and 6 control lungs. Extent of fibrosis in each sample was assessed by microCT-measured alveolar surface density (ASD) and confirmed by histology. Regulatory gene expression networks were identified using linear mixed-effect models and dynamic regulatory events miner (DREM). Differential gene expression analysis identified a core set of genes increased or decreased before fibrosis was histologically evident that continued to change with advanced fibrosis. DREM generated a systems biology model (www.sb.cs.cmu.edu/IPFReg) that identified progressively divergent gene expression tracks with microRNAs and transcription factors that specifically regulate mild or advanced fibrosis. We confirmed model predictions by demonstrating that expression of POU2AF1, previously unassociated with lung fibrosis but proposed by the model as regulator, is increased in B lymphocytes in IPF lungs and that POU2AF1-knockout mice were protected from bleomycin-induced lung fibrosis. Our results reveal distinct regulation of gene expression changes in IPF tissue that remained structurally normal compared with moderate or advanced fibrosis and suggest distinct regulatory mechanisms for each stage.

Authors

John E. McDonough, Farida Ahangari, Qin Li, Siddhartha Jain, Stijn E. Verleden, Jose Herazo-Maya, Milica Vukmirovic, Giuseppe DeIuliis, Argyrios Tzouvelekis, Naoya Tanabe, Fanny Chu, Xiting Yan, Johny Verschakelen, Robert J. Homer, Dimitris V. Manatakis, Junke Zhang, Jun Ding, Karen Maes, Laurens De Sadeleer, Robin Vos, Arne Neyrinck, Panayiotis V. Benos, Ziv Bar-Joseph, Dean Tantin, James C. Hogg, Bart M. Vanaudenaerde, Wim A. Wuyts, Naftali Kaminski

×

Figure 2

Expression of genes and regulators.

Options: View larger image (or click on image) Download as PowerPoint
Expression of genes and regulators.
(A) Euler diagrams showing the numbe...
(A) Euler diagrams showing the number of upregulated or downregulated genes or microRNAs at each stage of IPF. (B) Heatmap of the 100 genes with the greatest increased or decreased expression in all stages of IPF. (C) Box plots for expression of key genes and regulators showing median and interquartile ranges for each group compared using linear mixed-effects models. *P < 0.05, **P < 0.001, ***P < 0.0001 versus control.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts