Integrated multiomic analysis identifies TRIP13 as a mediator of alveolar epithelial type II cell dysfunction in idiopathic pulmonary fibrosis

Laurence St Pierre; Asres Berhan; Eun K Sung; Juan R Alvarez; Hongjun Wang; Yanbin Ji; Yixin Liu; Haoze Yu; Angela Meier; Kamyar Afshar; Eugene M Golts; Grace Y Lin; Alessandra Castaldi; Ben A Calvert; Amy Ryan; Beiyun Zhou; Ite A Offringa; Crystal N Marconett; Zea Borok

doi:10.1016/j.bbadis.2024.167572

Integrated multiomic analysis identifies TRIP13 as a mediator of alveolar epithelial type II cell dysfunction in idiopathic pulmonary fibrosis

Biochim Biophys Acta Mol Basis Dis. 2024 Nov 13:167572. doi: 10.1016/j.bbadis.2024.167572. Online ahead of print.

Authors

Laurence St Pierre¹, Asres Berhan², Eun K Sung³, Juan R Alvarez⁴, Hongjun Wang⁴, Yanbin Ji⁴, Yixin Liu⁴, Haoze Yu⁵, Angela Meier⁶, Kamyar Afshar², Eugene M Golts⁷, Grace Y Lin⁸, Alessandra Castaldi², Ben A Calvert⁹, Amy Ryan⁹, Beiyun Zhou¹⁰, Ite A Offringa¹¹, Crystal N Marconett¹², Zea Borok¹³

Affiliations

¹ Departments of Surgery, University of Southern California, Los Angeles, CA 90089, USA; Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
² Department of Medicine, University of California, San Diego, CA 92037, USA.
³ Translational Genomics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; Department of Integrative Translational Sciences, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
⁴ Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; Hastings Center for Pulmonary Research, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
⁵ Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
⁶ Anesthesiology, University of California, San Diego, La Jolla, CA 92037, USA.
⁷ Surgery, University of California, San Diego, La Jolla, CA 92037, USA.
⁸ Pathology, University of California, San Diego, La Jolla, CA 92037, USA.
⁹ Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
¹⁰ Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; Hastings Center for Pulmonary Research, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
¹¹ Departments of Surgery, University of Southern California, Los Angeles, CA 90089, USA; Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA. Electronic address: offringa@usc.edu.
¹² Departments of Surgery, University of Southern California, Los Angeles, CA 90089, USA; Translational Genomics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; Department of Integrative Translational Sciences, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA. Electronic address: cmarconett@coh.org.
¹³ Department of Medicine, University of California, San Diego, CA 92037, USA. Electronic address: zborok@health.ucsd.edu.

PMID: 39547519
DOI: 10.1016/j.bbadis.2024.167572

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.

Keywords: ATAC-seq; Epigenomic analysis; Epithelial-mesenchymal plasticity; Idiopathic pulmonary fibrosis (IPF); RNA-seq; TRIP13.