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Interpretable machine learning uncovers epithelial transcriptional rewiring and a role for Gelsolin in COPD

ABSTRACT: Transcriptomic analyses have advanced the understanding of complex disease pathophysiology including chronic obstructive pulmonary disease (COPD). However, identifying relevant biologic causative factors has been limited by the integration of high dimensionality data. COPD is characterized by lung destruction and inflammation with smoke exposure being a major risk factor. To define previously unknown biological mechanisms in COPD, we utilized unsupervised and supervised interpretable machine learning analyses of single cell-RNA sequencing data from the gold standard mouse smoke exposure model to identify significant latent factors (context-specific co-expression modules) impacting pathophysiology. The machine learning transcriptomic signatures coupled to protein networks uncovered a reduction in network complexity and new biological alterations in actin-associated gelsolin (GSN), which was transcriptionally linked to disease state. GSN was altered in airway epithelial cells in the mouse model and in human COPD. GSN was increased in plasma from COPD patients, and smoke exposure resulted in enhanced GSN release from airway cells from COPD patients. This method provides insights into rewiring of transcriptional networks that are associated with COPD pathogenesis and provide a translational analytical platform for other diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE277533 | GEO | 2024/10/14

REPOSITORIES: GEO

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Interpretable machine learning uncovers epithelial transcriptional rewiring and a role for Gelsolin in COPD

Project description:Interpretable machine learning uncovers epithelial transcriptional rewiring and a role for Gelsolin in COPD

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2016-09-20 | GSE87098 | GEO

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2017-10-26 | E-MTAB-6004 | biostudies-arrayexpress

Project description:Along the trachea-bronchial tree, including the small airway region, cigarette smoke exposure induces inflammation, which can exacerbate the development of chronic obstructive pulmonary disease (COPD). The small airway region is known as the primary location of airway blockage in COPD and asthma. Therefore, evaluating exposure impact on the small airway is relevant for risk assessment. Using an in vitro human small airway culture model and a Systems Toxicology approach, this present study reports an assessment of the biological impact of an aerosol from a candidate modified-risk tobacco product, tobacco heating system (THS) 2.2, as compared with 3R4F smoke, at similar nicotine concentrating other functional measures (e.g., cytotoxicity, ciliary beating function, secretion of pro-inflammatory mediators) and histological assessment. The NPA methodology provides not only a qualitative measure of the exposure impact, but also a quantification of the exposure effect: the highest biological impact was observed in cultures 4 h post-exposure to 3R4F smoke at 0.15 mg nicotine/L (100% impact). In contrast, THS2.2 aerosol at similar nicotine concentration, only elicited 15% relative biological impact at 4 h post-exposure in the context of various biological processes modeled in the networks: Cell Fate, Cell Proliferation, Cell Stress, and Inflammatory Process Networks. Consistently, ciliary beating function and culture morphology were not remarkably altered in samples exposed to THS2.2 aerosol, even at nicotine concentration three times that of 3R4F smoke.

2017-10-26 | E-MTAB-6098 | biostudies-arrayexpress

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Project description:Chronic obstructive pulmonary disease (COPD) is the 3rd leading cause of death in the United States and is caused primarily by cigarette smoking. Increased numbers of mucus-producing secretory (“goblet”) cells defined as goblet cell metaplasia or hyperplasia (GCMH), contributes significantly to COPD pathophysiology. The objective of this study was to determine whether NOTCH signaling regulates goblet cell differentiation in response to cigarette smoke. To this end, primary human bronchial epithelial cells (HBECs) from nonsmokers and COPD smokers were differentiated in vitro on air-liquid interface and exposed to cigarette smoke extract (CSE) for 7 days. NOTCH signaling activity was modulated using (1) the NOTCH/γ-secretase inhibitor Dibenzazepine (DBZ), (2) lentiviral over-expression of the NOTCH3-intracellular domain (NICD3) or (3) NOTCH3-specific siRNA. Cell differentiation and response to CSE were evaluated by qPCR, Western blotting, immunostaining and RNA-Seq. Our data demonstrate that CSE exposure of nonsmoker airway epithelium induced goblet cell differentiation characteristic of GCMH. Treatment with DBZ suppressed CSE-dependent induction of goblet cell differentiation. Furthermore, CSE induced NOTCH3 activation, as revealed by increased NOTCH3 nuclear localization and elevated NICD3 protein levels. Over-expression of NICD3 increased expression of the goblet cell associated genes SPDEF and MUC5AC, whereas NOTCH3 knockdown suppressed CSE-mediated induction of SPDEF and MUC5AC. Finally, CSE exposure of COPD airway epithelium induced goblet cell differentiation in a NOTCH3-dependent manner. These results identify NOTCH3 activation as one of the important mechanisms by which cigarette smoke induces goblet cell differentiation, thus providing a potential strategy to control GCMH-related pathologies in smokers and patients with COPD.

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Project description:Chronic obstructive pulmonary disease (COPD) is a disease state characterized by poorly reversible, limited airflow that is usually both progressive and associated with an abnormal inflammatory response of the lung. One cause of COPD is chronic exposure to airborne materials such as cigarette smoke (CS), which leads to impaired respiratory function in damaged tissues. Damaged epithelial tissue initiates repair processes including proliferation and re-differentiation until there is complete regeneration of a pseudostratified epithelium. These repair processes in airway epithelial tissues are essential for maintaining normal airway function. However, impairment of epithelial repair leads to architectural changes through region-dependent remodeling processes that are associated with a fixed airflow limitation in COPD. To fully understand what factors mostly contribute to airway remodeling heterogeneity in COPD pathogenesis, we used two in vitro human airway epithelial 3D culture models, namely, MucilAir™ and SmallAir™ tissues, which are derived from large and small airway epithelial cells, respectively. To focus on regional heterogeneity of the respiratory tract, tissues from a single donor were used to eliminate potential donor-to-donor differences in responses to external stimuli. We exposed the tissues to different concentrations of whole CS (low, middle, and high), and examined the transcriptome at different post-exposure periods (4, 24, 48, and 72 h post-exposure).

2020-12-24 | E-MTAB-8680 | biostudies-arrayexpress

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