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Integrative omics analysis identifies biomarkers of idiopathic pulmonary fibrosis

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Abstract

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by chronic progressive pulmonary fibrosis and a poor prognosis. Genetic studies, including transcriptomic and proteomics, have provided new insight into revealing mechanisms of IPF. Herein we provided a novel strategy to identify biomarkers by integrative analysis of transcriptomic and proteomic profiles of IPF patients. We examined the landscape of IPF patients' gene expression in the transcription and translation phases and investigated the expression and functions of two new potential biomarkers. Differentially expressed (DE) mRNAs were mainly enriched in pathways associated with immune system activities and inflammatory responses, while DE proteins are related to extracellular matrix production and wound repair. The upregulated genes in both phases are associated with wound repair and cell differentiation, while the downregulated genes in both phases are associated with reduced immune activities and the damage of the alveolar tissues. On this basis, we identified thirteen potential marker genes. Among them, we validated the expression changes of butyrophilin-like 9 (BTNL9) and plasmolipin (PLLP) and investigated their functional pathways in the IPF mechanism. Both genes are downregulated in the tissues of IPF patients and Bleomycin-induced mice, and co-expression analysis indicates that they have a protective effect by inhibiting extracellular matrix production and promoting wound repair in alveolar epithelial cells.

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Data availability

The authors declare that all data supporting the findings of this study are available from the corresponding authors on reasonable request.

Code availability

The authors declare that code for data analysis in this study are available from the corresponding authors on reasonable request.

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Funding

This work was supported by the National Natural Science Foundation of China (Project No. 81871736), Bureau of traditional Chinese Medicine Scientific Research Project of Guangdong (Project No. 20192048), The First Affiliated Hospital Of Guangzhou Medical University (ZH201915) (funds from GMU), Guangzhou Institute of Respiratory Health Open Project (Funds provided by China Evergrande Group, Project No. 2020GIRHHMS04), the Zhongnanshan Medical Foundation of Guangdong Province (Project No: ZNSA-2021005 and Project No: ZNSA-2020001), the University of Macau (grant numbers: FHS-CRDA-029-002-2017, and MYRG2018-00071-FHS), the Science and Technology Development Fund, Macau SAR (File No. 0004/2019/AFJ and 0011/2019/AKP), and Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (Project No. 2018PT31048). Funding for open access charge: National Natural Science Foundation of China.

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Author notes

  1. Shixue Sun

    Present address: Department of Allergy and Clinical Immunology, State Key Laboratory of Respiratory Disease, National Clinical Research Centre for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China

  2. Peiyan Zheng, Shixue Sun, Jingxian Wang, Xiaohua Douglas Zhang and Baoqing Sun should be regarded as joint first and joint correspondence authors, respectively.

Authors and Affiliations

  1. Department of Allergy and Clinical Immunology, State Key Laboratory of Respiratory Disease, National Clinical Research Centre for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China

    Peiyan Zheng, Zhangkai Jason Cheng, Mingshan Xue, Huimin Huang & Baoqing Sun

  2. Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China

    Shixue Sun, Kuan Cheok Lei, Teng Zhang & Xiaohua Douglas Zhang

  3. National Joint Local Engineering Laboratory for Cell Engineering and Biomedicine Technique, Guizhou Province Key Laboratory of Regenerative Medicine, Key Laboratory of Adult Stem Cell Translational Research (Chinese Academy of Medical Sciences), Guizhou Medical University, Guizhou, 550025, China

    Jingxian Wang

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Contributions

All authors participated in the study design, the interpretation of the results, and the drafting and revision of the manuscript. PZ and SS conceived the idea and conducted the experiments, JW collected the specimens and conducted the experiments, SS analyzed the data and drafted the first version of the manuscript, XDZ and BS supervised the research. All authors reviewed and commented on the manuscript and approved the final draft. The authors would like to express their sincere thanks to Prof. Yingying Gu and Dr. Zhucheng Chen from The First Affiliated Hospital of Guangzhou Medical University for her support in determining the HRCT and histological patterns of the patients and confirming the IPF diagnosis. Besides, we would like to thank all members of Professor Sun’s lab and Professor Zhang’s lab for their kind help in conducting the experiments and preparing this manuscript.

Corresponding authors

Correspondence to Xiaohua Douglas Zhang or Baoqing Sun.

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Conflict of interest

The authors declare no competing interests.

Ethical approval

All procedures in this study involving human participants and animals were performed with the approval and according to the guidelines of the ethics committee of The First Affiliated Hospital of Guangzhou Medical University. All procedures were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all individuals for being included in the study.

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Supplementary Information

Below is the link to the electronic supplementary material.

18_2021_4094_MOESM1_ESM.pdf

Supplementary file1 Quality control results of RNA sequencing. A, B, and C are QC plots for raw sequences, and D, E, and F are QC plots for filtered sequences. A and D: Percentage of base content along position in reads. The fluctuations around 150th of the read position are caused by the read length limitation. B and E: error rates of bases along the position in the reads. C and F: the quality score of bases along the position in the reads. The quality score was calculated as -10×log10 (error P) (PDF 468 KB)

18_2021_4094_MOESM2_ESM.pdf

Supplementary file2 Distribution of mapped reads. A. Saturation map of all samples. It displays the increase of mapped genes along with the percentage of mapped reads. “Con” stands for control samples, and “Exp” stands for IPF samples. B. Mapped reads distribution. C. Reads density of a sample in the chromosomes. Red stands for forward strands, blue stands for reverse strands (PDF 842 KB)

18_2021_4094_MOESM3_ESM.pdf

Supplementary file3 Quality control of proteome. A. Density distribution of precursors. CV: coefficient of variation. “C” stands for control group and “D” stands for IPF group. B. Cumulative recovery plot for identified proteins. C. Completeness plot of the identified proteins. D. Identified proteins in each sample. C.1–C.5 represent the five control samples, D.1–D.6 represent the six IPF samples. E. Heatmap of the intensity of all quantified proteins (PDF 560 KB)

18_2021_4094_MOESM4_ESM.png

Supplementary file4 IHC results in human lung tissues. This figure displays the IHC staining of BTNL9 and PLLP in healthy and IPF lung tissues. The hematoxylin-stained nucleus is blue, and the DAB-positive area is brownish yellow. “×100” represents images captured through a 100 times lens, while “×400” represents images captured through a 400 times lens. BTNL9 stained nuclei were observed in AEC I cells of healthy lung tissue, while not observed in those of IPF lung tissues. PLLP staining was observed in AEC I cell membrane of healthy lung tissue, while not observed in those of IPF lung tissues (PNG 7897 KB)

18_2021_4094_MOESM5_ESM.png

Supplementary file5 IHC results in mouse lung tissues. This figure displays the IHC staining of BTNL9 and PLLP in lung tissues from BLM-induced mice and healthy ones. The hematoxylin-stained nucleus is blue, and the DAB-positive area is brownish yellow. “×100” represents images captured through a 100 times lens, while “×400” represents images captured through a 400 times lens. The comparison displays the destruction of the lung tissues in BLM-induced mice; both BTNL9 and PLLP showed decreased expression in the cytosol of lung bronchioles epithelial cells, and they increased expressed in alveoli cells (PNG 8832 KB)

Supplementary file6 (XLS 32 KB)

Supplementary file7 (XLSX 20 KB)

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Zheng, P., Sun, S., Wang, J. et al. Integrative omics analysis identifies biomarkers of idiopathic pulmonary fibrosis. Cell. Mol. Life Sci. 79, 66 (2022). https://doi.org/10.1007/s00018-021-04094-0

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