RNA sequencing identifies novel non-coding RNA and exon-specific effects associated with cigarette smoking

Parker, Margaret M.; Chase, Robert; Lamb, Andrew; Reyes, Alejandro; Saferali, Aabida; Yun, Jeong H.; Himes, Blanca E.; Silverman, Edwin K.; Hersh, Craig P.; Castaldi, Peter J.

doi:10.1186/s12920-017-0295-9

Cited by 53 publications

(59 citation statements)

References 60 publications

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“…However, many lncRNAs and their biological functions involved in COPD are still unclear. RNA sequencing is a useful technology with an advantage in discovering novel tissue-and disease-specific ncRNAs, whereas microarray and qRT-PCR can only measure the expression levels of known ncRNAs 10 , 16 . To date, RNA sequencing has been widely used in transcriptome profiles analyses 17 .…”

Section: Introductionmentioning

confidence: 99%

Long non-coding RNA expression patterns in lung tissues of chronic cigarette smoke induced COPD mouse model

Zhang

Sun

et al. 2018

Sci Rep

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Long non-coding RNAs (lncRNAs) have critical regulatory roles in protein-coding gene expression. Aberrant expression profiles of lncRNAs have been observed in various human diseases. In this study, we investigated transcriptome profiles in lung tissues of chronic cigarette smoke (CS)-induced COPD mouse model. We found that 109 lncRNAs and 260 mRNAs were significantly differential expressed in lungs of chronic CS-induced COPD mouse model compared with control animals. GO and KEGG analyses indicated that differentially expressed lncRNAs associated protein-coding genes were mainly involved in protein processing of endoplasmic reticulum pathway, and taurine and hypotaurine metabolism pathway. The combination of high throughput data analysis and the results of qRT-PCR validation in lungs of chronic CS-induced COPD mouse model, 16HBE cells with CSE treatment and PBMC from patients with COPD revealed that NR_102714 and its associated protein-coding gene UCHL1 might be involved in the development of COPD both in mouse and human. In conclusion, our study demonstrated that aberrant expression profiles of lncRNAs and mRNAs existed in lungs of chronic CS-induced COPD mouse model. From animal models perspective, these results might provide further clues to investigate biological functions of lncRNAs and their potential target protein-coding genes in the pathogenesis of COPD.

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Section: Introductionmentioning

confidence: 99%

Long non-coding RNA expression patterns in lung tissues of chronic cigarette smoke induced COPD mouse model

Zhang

Sun

et al. 2018

Sci Rep

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“…Our analysis assesses only the genetic component of gene expression. We also investigated whether these genes were differentially expressed in COPD patients, in 464 blood samples from the COPDGene study [ 54 ], and 151 lung tissue samples [ 55 ] (Additional file 1 : Supplementary Methods and Table S5-S8). These genes were not differentially expressed, with the exception of LILRA3 , which was nominally significant with %LAA-950 ( P = 0.03).…”

Section: Discussionmentioning

confidence: 99%

Integrative genomics identifies new genes associated with severe COPD and emphysema

et al. 2018

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BackgroundGenome-wide association studies have identified several genetic risk loci for severe chronic obstructive pulmonary disease (COPD) and emphysema. However, these studies do not fully explain disease heritability and in most cases, fail to implicate specific genes. Integrative methods that combine gene expression data with GWAS can provide more power in discovering disease-associated genes and give mechanistic insight into regulated genes.MethodsWe applied a recently described method that imputes gene expression using reference transcriptome data to genome-wide association studies for two phenotypes (severe COPD and quantitative emphysema) and blood and lung tissue gene expression datasets. We further tested the potential causality of individual genes using multi-variant colocalization.ResultsWe identified seven genes significantly associated with severe COPD, and five genes significantly associated with quantitative emphysema in whole blood or lung. We validated results in independent transcriptome databases and confirmed colocalization signals for PSMA4, EGLN2, WNT3, DCBLD1, and LILRA3. Three of these genes were not located within previously reported GWAS loci for either phenotype. We also identified genetically driven pathways, including those related to immune regulation.ConclusionsAn integrative analysis of GWAS and gene expression identified novel associations with severe COPD and quantitative emphysema, and also suggested disease-associated genes in known COPD susceptibility loci.Trial registrationNCT00608764, Registry: ClinicalTrials.gov, Date of Enrollment of First Participant: November 2007, Date Registered: January 28, 2008 (retrospectively registered); NCT00292552, Registry: ClinicalTrials.gov, Date of Enrollment of First Participant: December 2005, Date Registered: February 14, 2006 (retrospectively registered).Electronic supplementary materialThe online version of this article (10.1186/s12931-018-0744-9) contains supplementary material, which is available to authorized users.

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“…The protocol for RNASeq data generation has been previously described (21). Total RNA was extracted from PAXgene Blood RNA tubes using the Qiagen PreAnalytiX PAXgene Blood miRNA Kit (Qiagen, Valencia, CA).…”

Section: Methodsmentioning

confidence: 99%

Analysis of genetically driven alternative splicing identifies FBXO38 as a novel COPD susceptibility gene

Saferali

Yun

Parker

et al. 2019

Preprint

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While many disease-associated single nucleotide polymorphisms (SNPs) are associated with gene expression (expression quantitative trait loci, eQTLs), a large proportion of complex disease genome-wide association study (GWAS) variants are of unknown function. Some of these SNPs may contribute to disease by regulating gene splicing. Here, we investigate whether SNPs that are associated with alternative splicing (splice QTL or sQTL) can identify novel functions for existing GWAS variants or suggest new associated variants in chronic obstructive pulmonary disease (COPD).RNA sequencing was performed on whole blood from 376 subjects from the COPDGene Study. Using linear models, we identified 561,060 unique sQTL SNPs associated with 30,333 splice sites corresponding to 6,419 unique genes. Similarly, 708,928 unique eQTL SNPs involving 15,913 genes were detected at 10% FDR. While there is overlap between sQTLs and eQTLs, 60% of sQTLs are not eQTLs. Co-localization analysis revealed that 7 out of 21 loci associated with COPD (p<1×10−6) in a published GWAS have at least one shared causal variant between the GWAS and sQTL studies. Among the genes identified to have splice sites associated with top GWAS SNPs was FBXO38, in which a novel exon was discovered to be protective against COPD. Importantly, the sQTL in this locus was validated by qPCR in both blood and lung tissue, demonstrating that splice variants relevant to lung tissue can be identified in blood. Other identified genes included CDK11A and SULT1A2.Overall, these data indicate that analysis of alternative splicing can provide novel insights into disease mechanisms. In particular, we demonstrated that SNPs in a known COPD GWAS locus on chromosome 5q32 influence alternative splicing in the gene FBXO38.Author SummaryWhile it is known that chronic obstructive pulmonary disease (COPD) is caused in part by genetic factors, few studies have identified specific causative genes. Genetic variants that alter the expression levels of genes have explained part of the genetic component of COPD, however, there are additional genetic variants with unknown function. In some genes the protein coding sequence can be altered by a mechanism known as RNA splicing. We hypothesized that some genetic variants that are associated with risk of COPD contribute to the disease by altering RNA splicing. In this study, we identified genetic variants that are associated both with COPD risk and RNA splicing. In particular, we found that a COPD associated variant of previously unknown function may contribute to the inclusion of a new exon in the FBXO38 gene. These finding are significant because they indicate that analysis of RNA splicing can help identify genes that contribute to disease.

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RNA sequencing identifies novel non-coding RNA and exon-specific effects associated with cigarette smoking

Cited by 53 publications

References 60 publications

Long non-coding RNA expression patterns in lung tissues of chronic cigarette smoke induced COPD mouse model

Long non-coding RNA expression patterns in lung tissues of chronic cigarette smoke induced COPD mouse model

Integrative genomics identifies new genes associated with severe COPD and emphysema

Analysis of genetically driven alternative splicing identifies FBXO38 as a novel COPD susceptibility gene

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