Integrating molecular interactions and gene expression to identify biomarkers and network modules of chronic obstructive pulmonary disease

Huang, Haihui; Liang, Yong

doi:10.3233/thc-228013

Cited by 2 publications

(1 citation statement)

References 34 publications

(38 reference statements)

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“…Both FoxO and TGF-β have been linked to cancer pathogenesis, with the former being a positive mediator of cell growth (77) and vascular remodeling (41) and the latter having both tumor suppressing and promoting functions (78). Studies have shown decreased levels of the FoxO protein in COPD (41,(79)(80)(81). Di Stefano et al found that, compared to controls, COPD peripheral airway samples have decreased TGF-β1 + and TGF-β3 + bronchial epithelial cells (82).…”

Section: Discussionmentioning

confidence: 99%

Lung transcriptomics of radiologic emphysema reveal barrier function impairment and macrophage M1-M2 imbalance

Gregory

Suryadevara

et al. 2022

Preprint

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RationaleWhile many studies have examined gene expression in lung tissue, the gene regulatory processes underlying emphysema are still not well understood. Finding efficient non-imaging screening methods and disease-modifying therapies has been challenging, but knowledge of the transcriptomic features of emphysema may help in this effort.ObjectivesOur goals were to identify emphysema-associated biological pathways through transcriptomic analysis of bulk lung tissue, to determine the lung cell types in which these emphysema-associated pathways are altered, and to detect unique and overlapping transcriptomic signatures in blood and lung.MethodsUsing RNA-sequencing data from 456 samples in the Lung Tissue Research Consortium and 2,370 blood samples from the COPDGene study, we examined the transcriptomic features of computed tomography quantified emphysema. We also queried lung single-cell RNA-sequencing data to identify cell types showing COPD-associated differential expression of the emphysema pathways found in the bulk analyses.Measurements and Main ResultsIn the lung, 1,055 differentially expressed genes and 29 dysregulated pathways were significantly associated with emphysema. We observed alternative splicing of genes regulating NF-κB and cell adhesion and increased activity in the TGF-β and FoxO signaling pathways. Multiple lung cell types displayed dysregulation of epithelial barrier function pathways, and an imbalance between pro-inflammatory M1 and anti-inflammatory M2 macrophages was detected. Lung tissue and blood samples shared 251 differentially expressed genes and two pathways (oxidative phosphorylation and ribosomal function).ConclusionsThis study identified emphysema-related changes in gene expression and alternative splicing, cell-type specific dysregulated pathways, and instances of shared pathway dysregulation between blood and lung.AT A GLANCE COMMENTARYScientific Knowledge on the SubjectPrior studies have investigated the transcriptomic characteristics of emphysema and its associated biological pathways. However, less is known about alternative splicing mechanisms and cell-type specific transcriptional patterns in emphysema. Additionally, a comparison between dysregulated genes and pathways in blood and lung tissues is needed to better understand the utility of non-invasive diagnostic and prognostic tools for emphysema.What This Study Adds to the FieldUsing lung samples from the Lung Tissue Research Consortium (LTRC) and blood samples from the COPDGene study, we performed differential gene and alternative splicing association analyses for CT-quantified emphysema. We then queried a previously published lung tissue single-cell RNA-sequencing atlas of COPD patients and controls to determine lung cell-type specific expression patterns of the biological pathways identified from the bulk analyses. We demonstrated that multiple pathways, including oxidative phosphorylation and ribosomal function processes, were enriched in both blood and lung tissues. We also observed that in COPD, oxidative phosphorylation was downregulated in pro-inflammatory (M1) macrophages and upregulated in anti-inflammatory (M2) macrophages. Additionally, other immunity-related cell types, including plasma cells, natural killer cells, and T lymphocytes, were linked to epithelial barrier function, such as the Rap1, adherens junction, and TGF-β signaling pathways.

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