Search

Background: Genetic biomarkers of lung cancer (LC) susceptibility may provide a basis for treatment and prevention. This study analyzed an association between SNPs (single nucleotide polymorphisms) in the complementary region of the 3′-UTR (3′ untranslated region) of microRNAs of the gene RIPK1 (receptor-interacting serine/threonine-protein kinase 1) and LC among an adult Han Chinese population aged younger than 60 years. Also explored the effect of regulation of the RIPK1 gene via rs17548629 and microRNA-1197 on the occurrence of LC. Methods: RIPK1 variants (rs17548629, rs77736895) were determined in a population of 571 adults (younger than 60 years) with LC, and 609 gender- and age-matched healthy individuals. Bioinformatics methods predicted the microRNAs bound to rs17548629. Dual luciferase reporter assay was performed to confirm the presence of both rs17548629 and the predicted microRNA. Results: A mutation (T) of rs17548629 was associated with an increased risk for LC in this population under the codominant and recessive genetic models. The risk of lung adenocarcinoma in rs17548629 mutant carriers was 1.769-fold higher than that of the wildtype. In vitro, the luciferase activity of co-transfected mutant psiCHECK2-RIPK1 and microRNA-1197 mimics was less than that of the group transfected with microRNA-1197 mimics only. Factorial analysis indicated interactions between microRNA-1197 mimics and genotypes of rs17548629. Conclusion: A mutation (T) of rs17548629 may increase the risk of LC/lung adenocarcinoma in adult Han populations younger than 60 years. When carrying the T allele, rs17548629 may be the target of hsa-miR-1197. This mutation may affect transcriptional level of the RIPK1, thereby promoting the occurrence of LC. [ABSTRACT FROM AUTHOR]

Background: Chronic obstructive pulmonary disease (COPD) is a common respiratory disease, whose pathogenetic complexity was strongly associated with aging/smoking and poorly understood. Methods: Here we performed single-cell RNA sequencing (scRNA-seq) analysis of 66,610 cells from COPD and age-stratified control lung tissues of donors with different smoking histories to prioritize cell types most perturbed in COPD lungs in aging/smoking dependent or independent manner. By performing an array of advanced bioinformatic analyses, such as gene set enrichment analysis, trajectory analysis, cell–cell interactions analysis, regulatory potential analysis, weighted correlation network analysis, functional interaction analysis, and gene set variation analysis, we integrated cell-type-level alterations into a system-level malfunction and provided a more clarified COPD pathological model containing specific mechanisms by which aging and smoking facilitate COPD development. Finally, we integrated the publicly available scRNA-seq data of 9 individuals, resulting in a total of 110,931 cells, and replicated the analyses to enhance the credibility of our findings. Results: Our study pointed to enrichment of COPD molecular alteration in monocytes, which further induced a previously unrecognized pro-inflammatory effect on alveolar epithelial cells. In addition, aged monocytes and club cells facilitated COPD development via maintaining an autoimmune airway niche. Unexpectedly, macrophages, whose defect to resolve inflammation was long-recognized in COPD pathogenesis, primarily induced an imbalance of sphingolipids rheostat in a smoking-dependent way. These findings were validated in a meta-analysis including other public single-cell transcriptomic data. Conclusions: In sum, our study provided a clarified view of COPD pathogenesis and demonstrated the potential of targeting monocytes in COPD diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Background: Chronic obstructive pulmonary disease (COPD) is a common respiratory disease, whose pathogenetic complexity was strongly associated with aging/smoking and poorly understood. Methods: Here we performed single-cell RNA sequencing (scRNA-seq) analysis of 66,610 cells from COPD and age-stratified control lung tissues of donors with different smoking histories to prioritize cell types most perturbed in COPD lungs in aging/smoking dependent or independent manner. By performing an array of advanced bioinformatic analyses, such as gene set enrichment analysis, trajectory analysis, cell–cell interactions analysis, regulatory potential analysis, weighted correlation network analysis, functional interaction analysis, and gene set variation analysis, we integrated cell-type-level alterations into a system-level malfunction and provided a more clarified COPD pathological model containing specific mechanisms by which aging and smoking facilitate COPD development. Finally, we integrated the publicly available scRNA-seq data of 9 individuals, resulting in a total of 110,931 cells, and replicated the analyses to enhance the credibility of our findings. Results: Our study pointed to enrichment of COPD molecular alteration in monocytes, which further induced a previously unrecognized pro-inflammatory effect on alveolar epithelial cells. In addition, aged monocytes and club cells facilitated COPD development via maintaining an autoimmune airway niche. Unexpectedly, macrophages, whose defect to resolve inflammation was long-recognized in COPD pathogenesis, primarily induced an imbalance of sphingolipids rheostat in a smoking-dependent way. These findings were validated in a meta-analysis including other public single-cell transcriptomic data. Conclusions: In sum, our study provided a clarified view of COPD pathogenesis and demonstrated the potential of targeting monocytes in COPD diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Background: RNA regulation by RNA-binding proteins (RBPs) involve extremely complicated mechanisms. MOV10 and MOV10L1 are two homologous RNA helicases implicated in distinct intracellular pathways. MOV10L1 participates specifically in Piwi-interacting RNA (piRNA) biogenesis and protects mouse male fertility. In contrast, the functional complexity of MOV10 remains incompletely understood, and its role in the mammalian germline is unknown. Here, we report a study of the biological and molecular functions of the RNA helicase MOV10 in mammalian male germ cells. Results: MOV10 is a nucleocytoplasmic protein mainly expressed in spermatogonia. Knockdown and transplantation experiments show that MOV10 deficiency has a negative effect on spermatogonial progenitor cells (SPCs), limiting proliferation and in vivo repopulation capacity. This effect is concurrent with a global disturbance of RNA homeostasis and downregulation of factors critical for SPC proliferation and/or self-renewal. Unexpectedly, microRNA (miRNA) biogenesis is impaired due partially to decrease of miRNA primary transcript levels and/or retention of miRNA via splicing control. Genome-wide analysis of RNA targetome reveals that MOV10 binds preferentially to mRNAs with long 3′-UTR and also interacts with various non-coding RNA species including those in the nucleus. Intriguingly, nuclear MOV10 associates with an array of splicing factors, particularly with SRSF1, and its intronic binding sites tend to reside in proximity to splice sites. Conclusions: These data expand the landscape of MOV10 function and highlight a previously unidentified role initiated from the nucleus, suggesting that MOV10 is a versatile RBP involved in a broader RNA regulatory network. [ABSTRACT FROM AUTHOR]