Integrated multiomic analysis identifies TRIP13 as a mediator of alveolar epithelial type II cell dysfunction in idiopathic pulmonary fibrosis
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.
Authors
- Asres Berhan (ORCID: https://orcid.org/0000-0001-7406-0856)
- Angela Meier (ORCID: https://orcid.org/0000-0002-6766-531X)
- Kamyar Afshar (ORCID: https://orcid.org/0000-0002-7574-0738)
- Amy L. Ryan (ORCID: https://orcid.org/0000-0003-1363-905X)
- Ite A. Laird‐Offringa (ORCID: https://orcid.org/0000-0001-5729-6488)
- Haoze Yu (ORCID: https://orcid.org/0000-0002-3831-2291)
- Zea Borok (ORCID: https://orcid.org/0000-0001-8673-8177)
- Alessandra Castaldi (ORCID: https://orcid.org/0000-0002-6616-6519)
- Eugene Golts (ORCID: https://orcid.org/0000-0002-6289-5773)
- Crystal N. Marconett (ORCID: https://orcid.org/0000-0002-8463-7126)
- Grace Lin (ORCID: https://orcid.org/0000-0001-8018-5604)
- Laurence St. Pierre (ORCID: https://orcid.org/0000-0002-3019-186X)
- Hongjun Wang (ORCID: https://orcid.org/0000-0001-7421-1917)
- Yixin Liu (ORCID: https://orcid.org/0000-0001-9043-3691)
- Beiyun Zhou (ORCID: https://orcid.org/0000-0002-9084-5933)
- Juan R. Alvarez
- Eun Kyu Sung
- Yanbin Ji
- Ben A. Calvert
Institutions
- University of Southern California (US)
- University of Iowa (US)
- University of California San Diego (US)
- Southern California Clinical and Translational Science Institute (US)
Publication Details
- Journal
- Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
- Published
- 2024-11-13
- DOI
- https://doi.org/10.1016/j.bbadis.2024.167572
- Citations
- 2
- Primary Topic
- Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Type
- article
- Field-Weighted Citation Impact
- 0.84
Funders
- Pulmonary Fibrosis Foundation
- Tobacco-Related Disease Research Program
- Cystic Fibrosis Foundation Therapeutics
- National Institutes of Health
- National Heart, Lung, and Blood Institute
- National Cancer Institute