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Comparative Transcriptome Analyses Reveal a Transcriptional Landscape of Human Silicosis Lungs and Provide Potential Strategies for Silicosis Treatment.

ABSTRACT: Silicosis is a fatal occupational lung disease which currently has no effective clinical cure. Recent studies examining the underlying mechanism of silicosis have primarily examined experimental models, which may not perfectly reflect the nature of human silicosis progression. A comprehensive profiling of the molecular changes in human silicosis lungs is urgently needed. Here, we conducted RNA sequencing (RNA-seq) on the lung tissues of 10 silicosis patients and 7 non-diseased donors. A total of 2,605 differentially expressed genes (DEGs) and critical pathway changes were identified in human silicosis lungs. Further, the DEGs in silicosis were compared with those in idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary diseases (COPD), to extend current knowledge about the disease mechanisms and develop potential drugs. This analysis revealed both common and specific regulations in silicosis, along with several critical genes (e.g., MUC5AC and FGF10), which are potential drug targets for silicosis treatment. Drugs including Plerixafor and Retinoic acid were predicted as potential candidates in treating silicosis. Overall, this study provides the first transcriptomic fingerprint of human silicosis lungs. The comparative transcriptome analyses comprehensively characterize pathological regulations resulting from silicosis, and provide valuable cues for silicosis treatment.

SUBMITTER: Pang J

PROVIDER: S-EPMC8210851 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundPichia pastoris (Komagataella phaffii) is a model organism widely used for the recombinant expression of eukaryotic proteins, and it can metabolize methanol as its sole carbon and energy source. Methanol is oxidized to formaldehyde by alcohol oxidase (AOX). In the dissimilation pathway, formaldehyde is oxidized to CO2 by formaldehyde dehydrogenase (FLD), S-hydroxymethyl glutathione hydrolase (FGH) and formate dehydrogenase (FDH).ResultsThe transcriptome and metabolome of P. pastoris were determined under methanol cultivation when its dissimilation pathway cut off. Firstly, Δfld and Δfgh were significantly different compared to the wild type (GS115), with a 60.98% and 23.66% reduction in biomass, respectively. The differential metabolites between GS115 and Δfld were mainly enriched in ABC transporters, amino acid biosynthesis, and protein digestion and absorption. Secondly, comparative transcriptome between knockout and wild type strains showed that oxidative phosphorylation, glycolysis and the TCA cycle were downregulated, while alcohol metabolism, proteasomes, autophagy and peroxisomes were upregulated. Interestingly, the down-regulation of the oxidative phosphorylation pathway was positively correlated with the gene order of dissimilation pathway knockdown. In addition, there were significant differences in amino acid metabolism and glutathione redox cycling that raised our concerns about formaldehyde sorption in cells.ConclusionsThis is the first time that integrity of dissimilation pathway analysis based on transcriptomics and metabolomics was carried out in Pichia pastoris. The blockage of dissimilation pathway significantly down-regulates the level of oxidative phosphorylation and weakens the methanol assimilation pathway to the point where deficiencies in energy supply and carbon fixation result in inefficient biomass accumulation and genetic replication. In addition, transcriptional upregulation of the proteasome and autophagy may be a stress response to resolve formaldehyde-induced DNA-protein crosslinking.

Project description:Labyrinthulomycetes are a group of ubiquitous and diverse unicellular Stramenopiles and have long been known for their vital role in ocean carbon cycling. However, their ecological function from the perspective of organic matter degradation remains poorly understood. This study reports high-quality genomes of two newly isolated Labyrinthulomycetes strains, namely, Botryochytrium sp. strain S-28 and Oblongichytrium sp. strain S-429, and provides molecular analysis of their ecological functions using comparative genomics and a biochemical assay. Our results suggest that Labyrinthulomycetes may occupy multiple ecological niches in marine ecosystems because of the significant differences in gene function among different genera. Certain strains could degrade wheat bran independently by secreting cellulase. The key glycoside hydrolase families (GH1, GH5, and GH9) related to cellulase and the functional domains of carbohydrate-active enzymes (CAZymes) were more enriched in their genomes. This group can actively participate in marine biochemical cycles as decomposers. In contrast, other strains that could not produce cellulase may thrive as "leftover scavengers" and act as a source of nutrients to the higher-trophic-level plankton. In addition, our findings emphasize the dual roles of endoglucanase, acting as both exo- and endoglucanases, in the process of cellulose degradation. Using genomic, biochemical, and phylogenetic analyses, our study provides a broader insight into the nutritional patterns and ecological functions of Labyrinthulomycetes. IMPORTANCE Unicellular heterotrophic eukaryotes are an important component of marine ecosystems. However, their ecological functions and modes of nutrition remain largely unknown. Our current understanding of marine microbial ecology is incomplete without integrating these heterotrophic microeukaryotes into the food web models. This study focuses on the unicellular fungus-like protists Labyrinthulomycetes and provides two high-quality genomes of cellulase-producing Labyrinthulomycetes. Our study uncovers the basis of their cellulase production by deciphering the results of genomic, biochemical, and phylogenetic analyses. This study instigates a further investigation of the molecular mechanism of organic matter utilization by Labyrinthulomycetes in the world's oceans.

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Comparative Transcriptome Analyses Reveal a Transcriptional Landscape of Human Silicosis Lungs and Provide Potential Strategies for Silicosis Treatment.

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