Journal article
Integrated multiomic analysis identifies TRIP13 as a mediator of alveolar epithelial type II cell dysfunction in idiopathic pulmonary fibrosis
Biochimica et biophysica acta. Molecular basis of disease, Vol.1871(3), 167572
03/2025
DOI: 10.1016/j.bbadis.2024.167572
PMCID: PMC11951472
PMID: 39547519
Abstract
Idiopathic pulmonary fibrosis (IPF) is a lethal progressive lung disease urgently needing new therapies. Current treatments only delay disease progression, leaving lung transplant as the sole remaining option. Recent studies support a model whereby IPF arises because alveolar epithelial type II (AT2) cells, which normally mediate distal lung regeneration, acquire airway and/or mesenchymal characteristics, preventing proper repair. Mechanisms driving this abnormal differentiation remain unclear. We performed integrated transcriptomic and epigenomic analysis of purified AT2 cells which revealed genome-wide alterations in IPF lungs. The most prominent epigenetic alteration was activation of an enhancer in thyroid receptor interactor 13 (TRIP13), although TRIP13 was not the most significantly transcriptionally upregulated gene. TRIP13 is broadly implicated in epithelial-mesenchymal plasticity. In cultured human AT2 cells and lung slices, small molecule TRIP13 inhibitor DCZ0415 prevented acquisition of the mesenchymal gene signature characteristic of IPF, suggesting TRIP13 inhibition as a potential therapeutic approach to fibrotic disease.
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•Genome-wide transcriptomic and epigenomic alterations in IPF AT2 cells•TRIP13 expression elevated in IPF distal lung epithelium.•TRIP13 inhibition prevents epithelial-mesenchymal transition in human AT2 cells.•TRIP13 modulates STAT3 and WNT/β-catenin pathways in AT2 cells.•TRIP13 may be a novel therapeutic target in IPF.
Details
- Title: Subtitle
- Integrated multiomic analysis identifies TRIP13 as a mediator of alveolar epithelial type II cell dysfunction in idiopathic pulmonary fibrosis
- Creators
- Laurence St. Pierre - University of Southern CaliforniaAsres Berhan - University of California San DiegoEun K. Sung - University of Southern CaliforniaJuan R. Alvarez - University of Southern CaliforniaHongjun Wang - University of Southern CaliforniaYanbin Ji - Hastings CenterYixin Liu - University of Southern CaliforniaHaoze Yu - University of Southern CaliforniaAngela Meier - University of California San DiegoKamyar Afshar - University of California San DiegoEugene M. Golts - University of California San DiegoGrace Y. Lin - University of California San DiegoAlessandra Castaldi - University of California San DiegoBen A Calvert - University of IowaAmy Ryan - University of IowaBeiyun Zhou - University of Southern CaliforniaIte A. Offringa - University of Southern CaliforniaCrystal N. Marconett - University of Southern CaliforniaZea Borok - University of California San Diego
- Resource Type
- Journal article
- Publication Details
- Biochimica et biophysica acta. Molecular basis of disease, Vol.1871(3), 167572
- DOI
- 10.1016/j.bbadis.2024.167572
- PMID
- 39547519
- PMCID
- PMC11951472
- NLM abbreviation
- Biochim Biophys Acta Mol Basis Dis
- ISSN
- 0925-4439
- eISSN
- 1879-260X
- Publisher
- Elsevier B.V
- Grant note
- National Heart, Lung, and Blood Institute (NHLBI): R35 HL135747, R01HL114959 Tobacco Related Disease Research Program: T31IP913 Hastings Center for Pulmonary ResearchPulmonary Fibrosis Foundation (AB)Cystic Fibrosis Foundation: P30CA014089
The authors thank the laboratory of Neil Siegel, PhD, for training and advice on ATAC methods. This study was funded by the National Heart, Lung, and Blood Institute (NHLBI) [R35 HL135747 (ZB) and R01HL114959 (BZ) ] , the Tobacco Related Disease Research Program [T31IP913 (IAO in support of LSP) ] , the Hastings Center for Pulmonary Research (HCPR) at USC (AB) , the Pulmonary Fibrosis Foundation (AB) , the Cystic Fibrosis Foundation, CFFT FIRTH21XX0 (ALR, BC, HY, ES and CNM) and the NIH/NCI Norris Comprehensive Cancer Center core grant P30CA014089.
- Language
- English
- Electronic publication date
- 11/13/2024
- Date published
- 03/2025
- Academic Unit
- Anatomy and Cell Biology
- Record Identifier
- 9984749559702771
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