@article{0ac90e80bc214b4582355366c646fb50,
title = "Dysfunctional ERG signaling drives pulmonary vascular aging and persistent fibrosis",
abstract = "Vascular dysfunction is a hallmark of chronic diseases in elderly. The contribution of the vasculature to lung repair and fibrosis is not fully understood. Here, we performed an epigenetic and transcriptional analysis of lung endothelial cells (ECs) from young and aged mice during the resolution or progression of bleomycin-induced lung fibrosis. We identified the transcription factor ETS-related gene (ERG) as putative orchestrator of lung capillary homeostasis and repair, and whose function is dysregulated in aging. ERG dysregulation is associated with reduced chromatin accessibility and maladaptive transcriptional responses to injury. Loss of endothelial ERG enhances paracrine fibroblast activation in vitro, and impairs lung fibrosis resolution in young mice in vivo. scRNA-seq of ERG deficient mouse lungs reveales transcriptional and fibrogenic abnormalities resembling those associated with aging and human lung fibrosis, including reduced number of general capillary (gCap) ECs. Our findings demonstrate that lung endothelial chromatin remodeling deteriorates with aging leading to abnormal transcription, vascular dysrepair, and persistent fibrosis following injury.",
author = "Nunzia Caporarello and Jisu Lee and Pham, {Tho X.} and Jones, {Dakota L.} and Jiazhen Guan and Link, {Patrick A.} and Meridew, {Jeffrey A.} and Grace Marden and Takashi Yamashita and Osborne, {Collin A.} and Bhagwate, {Aditya V.} and Huang, {Steven K.} and Nicosia, {Roberto F.} and Tschumperlin, {Daniel J.} and Maria Trojanowska and Giovanni Ligresti",
note = "Funding Information: We thank Dr. Derek Radisky (Mayo Clinic) for kindly providing Col1α1-GFP transgenic mice, Mrunal K. Dehankar (Mayo Clinic), and Tianmu Hu (Boston University) for supporting bioinformatics analysis, Dr. Tamas Ordog and Dr. Jeong-Heon Lee (Mayo Clinic) for thoughtful insights on processing samples for ATAC-seq, and Dr. Akhilesh Pandey, Dr. Cristine M. Charlesworth, and Benjamin C. Brown (Mayo Clinic) for supporting proteomic analysis. We gratefully acknowledge the support of this work by the National Institutes of Health (NIH) grants HL142596 (G.L.), HL158733 (G.L.), HL150638 (M.T.), AR060780 (M.T.), HL092961 (D.J.T.), HL105355 (P.A.L. and D.L.J.), HL007035 (T.X.P.), the American Lung Association Dalsemer Award (N.C.), and the Boehringer Ingelheim Discovery Award IPF/ILD (N.C.). Funding Information: We thank Dr. Derek Radisky (Mayo Clinic) for kindly providing Col1α1-GFP transgenic mice, Mrunal K. Dehankar (Mayo Clinic), and Tianmu Hu (Boston University) for supporting bioinformatics analysis, Dr. Tamas Ordog and Dr. Jeong-Heon Lee (Mayo Clinic) for thoughtful insights on processing samples for ATAC-seq, and Dr. Akhilesh Pandey, Dr. Cristine M. Charlesworth, and Benjamin C. Brown (Mayo Clinic) for supporting proteomic analysis. We gratefully acknowledge the support of this work by the National Institutes of Health (NIH) grants HL142596 (G.L.), HL158733 (G.L.), HL150638 (M.T.), AR060780 (M.T.), HL092961 (D.J.T.), HL105355 (P.A.L. and D.L.J.), HL007035 (T.X.P.), the American Lung Association Dalsemer Award (N.C.), and the Boehringer Ingelheim Discovery Award IPF/ILD (N.C.). Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
month = dec,
doi = "10.1038/s41467-022-31890-4",
language = "English (US)",
volume = "13",
journal = "Nature communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}