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

Autor:	St Pierre L; Department of Surgery, University of Southern California, Los Angeles, CA 90089, USA; Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA., Berhan A; Department of Medicine, University of California San Diego, CA 92037, USA., Sung EK; Department of 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., Alvarez JR; 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., Wang H; 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., Ji Y; 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., Liu Y; 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., Yu H; Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA., Meier A; Department of Anesthesiology, University of California, San Diego, La Jolla, CA 92037, USA., Afshar K; Department of Medicine, University of California San Diego, CA 92037, USA., Golts EM; Department of Surgery, University of California, San Diego, La Jolla, CA 92037, USA., Lin GY; Department of Pathology, University of California, San Diego, La Jolla, CA 92037, USA., Castaldi A; Department of Medicine, University of California San Diego, CA 92037, USA., Calvert BA; Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA., Ryan A; Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA., Zhou B; 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., Offringa IA; Department of Surgery, University of Southern California, Los Angeles, CA 90089, USA; Department of Biochemistry and Molecular Medicine, 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. Electronic address: offringa@usc.edu., Marconett CN; Department of Surgery, University of Southern California, Los Angeles, CA 90089, USA; Department of 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., Borok Z; Department of Medicine, University of California San Diego, CA 92037, USA. Electronic address: zborok@health.ucsd.edu.
Jazyk:	angličtina
Zdroj:	Biochimica et biophysica acta. Molecular basis of disease [Biochim Biophys Acta Mol Basis Dis] 2024 Nov 13; Vol. 1871 (3), pp. 167572. Date of Electronic Publication: 2024 Nov 13.
DOI:	10.1016/j.bbadis.2024.167572
Abstrakt:	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. Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2024. Published by Elsevier B.V.)
Databáze:	MEDLINE
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