Genome-wide post-transcriptional dysregulation by microRNAs in human asthma as revealed by Frac-seq
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE85216 | GEO | 2018/04/11
SECONDARY ACCESSION(S): PRJNA336564
REPOSITORIES: GEO
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Project description:MicroRNAs are small noncoding RNAs that inhibit gene expression posttranscriptionally, implicated in virtually all biological processes. Although the effect of individual microRNAs is generally studied, the genome-wide role of multiple microRNAs is less investigated. We assessed paired genome-wide expression of microRNAs with total (cytoplasmic) and translational (polyribosome-bound) mRNA levels employing subcellular fractionation and RNA sequencing (Frac-seq) in human primary bronchoepithelium from healthy controls and severe asthmatics. Severe asthma is a chronic inflammatory disease of the airways characterized by poor response to therapy. We found genes (i.e., isoforms of a gene) and mRNA isoforms differentially expressed in asthma, with novel inflammatory and structural pathophysiological mechanisms related to bronchoepithelium disclosed solely by polyribosome-bound mRNAs (e.g., IL1A and LTB genes or ITGA6 and ITGA2 alternatively spliced isoforms). Gene expression (i.e., isoforms of a gene) and mRNA expression analysis revealed different molecular candidates and biological pathways, with differentially expressed polyribosome-bound and total mRNAs also showing little overlap. We reveal a hub of six dysregulated microRNAs accounting for ∼90% of all microRNA targeting, displaying preference for polyribosome-bound mRNAs. Transfection of this hub in bronchial epithelial cells from healthy donors mimicked asthma characteristics. Our work demonstrates extensive posttranscriptional gene dysregulation in human asthma, in which microRNAs play a central role, illustrating the feasibility and importance of assessing posttranscriptional gene expression when investigating human disease.
| S-EPMC6013048 | biostudies-literature
Project description:Genome-wide post-transcriptional dysregulation by microRNAs in human asthma as revealed by Frac-seq
| PRJNA336564 | ENA
Project description:Transcription and translation correlate poorly, as mRNA undergoes multiple regulatory steps such as alternative splicing and microRNA regulation that determine its translationability into protein. Measures of transcriptional mRNA levels may therefore misrepresent cellular activation. To test this hypothesis employing human physiological mRNA levels, we analyzed cytoplasmic and polyribosome-bound mRNA expression (Frac-seq) combined with microRNA profiling by small RNA-seq in bronchoepithelial cells from healthy and severe asthma (SA) donors, SA being a chronic inflammatory airways disease, poorly understood at the molecular level. We found 275 genes bound to polyribosomes differentially between healthy and severe asthma, of which only 11.64% overlapped with differentially expressed cytoplasmic mRNAs (226 genes). We found 335 alternatively spliced mRNA isoforms differentially bound to polyribosomes of which only ~8% were revealed by cytoplasmic mRNA analysis. Approximately two thirds of differentially expressed isoforms could not be found at the gene level in both cytoplasmic and polyribosome bound fractions, demonstrating the disruption of splicing in asthma. Only the analysis of differentially expressed isoforms bound to polyribosomes revealed disease-related pathways overlooked in total mRNA. We detected a network of 21 microRNAs differentially expressed, with 8 microRNAs accounting for more than 80% targeting observed in both cytoplasmic and polyribosome bound mRNA isoforms. Importantly, microRNAs target distinct cytoplasmic and polyribosome bound mRNAs. Hence this work, integrating deep-sequencing, subcellular fractionation and microRNA profiling, demonstrates the disruption of post-transcriptional regulatory processes as the main disease causing molecular mechanism in asthma, something that cannot be dissected employing more classic transcriptomics approaches alone.
2018-04-11 | GSE85214 | GEO
Project description:Transcription and translation correlate poorly, as mRNA undergoes multiple regulatory steps such as alternative splicing and microRNA regulation that determine its translationability into protein. Measures of transcriptional mRNA levels may therefore misrepresent cellular activation. To test this hypothesis employing human physiological mRNA levels, we analyzed cytoplasmic and polyribosome-bound mRNA expression (Frac-seq) combined with microRNA profiling by small RNA-seq in bronchoepithelial cells from healthy and severe asthma (SA) donors, SA being a chronic inflammatory airways disease, poorly understood at the molecular level. We found 275 genes bound to polyribosomes differentially between healthy and severe asthma, of which only 11.64% overlapped with differentially expressed cytoplasmic mRNAs (226 genes). We found 335 alternatively spliced mRNA isoforms differentially bound to polyribosomes of which only ~8% were revealed by cytoplasmic mRNA analysis. Approximately two thirds of differentially expressed isoforms could not be found at the gene level in both cytoplasmic and polyribosome bound fractions, demonstrating the disruption of splicing in asthma. Only the analysis of differentially expressed isoforms bound to polyribosomes revealed disease-related pathways overlooked in total mRNA. We detected a network of 21 microRNAs differentially expressed, with 8 microRNAs accounting for more than 80% targeting observed in both cytoplasmic and polyribosome bound mRNA isoforms. Importantly, microRNAs target distinct cytoplasmic and polyribosome bound mRNAs. Hence this work, integrating deep-sequencing, subcellular fractionation and microRNA profiling, demonstrates the disruption of post-transcriptional regulatory processes as the main disease causing molecular mechanism in asthma, something that cannot be dissected employing more classic transcriptomics approaches alone.
2018-04-11 | GSE85215 | GEO
Project description:Post-transcriptional regulation of gene expression plays important roles in diverse cellular processes such as development, metabolism and cancer progression. Whereas many classical studies explored the mechanistics and physiological impact on specific mRNA substrates, the recent development of genome-wide analysis tools enables the study of post-transcriptional gene regulation on a global scale. Importantly, these studies revealed distinct programs of RNA regulation, suggesting a complex and versatile post-transcriptional regulatory network. This network is controlled by specific RNA-binding proteins and/or non-coding RNAs, which bind to specific sequence or structural elements in the RNAs and thereby regulate subsets of mRNAs that partly encode functionally related proteins. It will be a future challenge to link the spectra of targets for RNA-binding proteins to post-transcriptional regulatory programs and to reveal its physiological implications.
| S-EPMC2771128 | biostudies-other
Project description:Previously, we identified a subpopulation of schizophrenia (SCZ) showing increased levels of plasma pentosidine, a marker of glycation and oxidative stress. However, its causative genetic factors remain largely unknown. Recently, it has been suggested that dysregulated posttranslational modification by copy number variable microRNAs (CNV-miRNAs) may contribute to the etiology of SCZ. Here, an integrative genome-wide CNV-miRNA analysis was performed to investigate the etiology of SCZ with accumulated plasma pentosidine (PEN-SCZ). The number of CNV-miRNAs and the gene ontology (GO) in the context of miRNAs within CNVs were compared between PEN-SCZ and non-PEN-SCZ groups. Gene set enrichment analysis of miRNA target genes was further performed to evaluate the pathways affected in PEN-SCZ. We show that miRNAs were significantly enriched within CNVs in the PEN-SCZ versus non-PEN-SCZ groups (p = 0.032). Of note, as per GO analysis, the dysregulated neurodevelopmental events in the two groups may have different origins. Additionally, gene set enrichment analysis of miRNA target genes revealed that miRNAs involved in glycation/oxidative stress and synaptic neurotransmission, especially glutamate/GABA receptor signaling, were possibly affected in PEN-SCZ. To the best of our knowledge, this is the first genome-wide CNV-miRNA study suggesting the role of CNV-miRNAs in the etiology of PEN-SCZ, through effects on genes related to glycation/oxidative stress and synaptic function. Our findings provide supportive evidence that glycation/oxidative stress possibly caused by genetic defects related to the posttranscriptional modification may lead to synaptic dysfunction. Therefore, targeting miRNAs may be one of the promising approaches for the treatment of PEN-SCZ.
| S-EPMC8163801 | biostudies-literature
Project description:Low socioeconomic status (SES) is one of the most robust social factors associated with disease morbidity, including more severe asthma in childhood. However, our understanding of the biological processes that explain this link is limited. This study tested whether the social environment could get "under the skin" to alter genomic activity in children with asthma.Two group design of children with physician diagnosed asthma who came from low or high SES families.Genome-wide transcriptional profiles from T lymphocytes of children with asthma.Children with asthma from a low SES background showed overexpression of genes regulating inflammatory processes, including those involved in chemokine activity, stress responses and wound responses, compared with children with asthma from a high SES background. Bioinformatic analysis suggested that decreased activity of cyclic AMP response element binding protein and nuclear factor Y and increased nuclear factor kappaB transcriptional signalling mediated these effects. These pathways are known to regulate catecholamine and inflammatory signalling in immune cells.This study provides the first evidence in a sample of paediatric patients diagnosed with asthma that the larger social environment can affect processes at the genomic level. Specifically, gene transcription control pathways that regulate inflammation and catecholamine signalling were found to vary by SES in children with asthma. Because these pathways are the primary targets of many asthma medications, these findings suggest that the larger social environment may alter molecular mechanisms that have implications for the efficacy of asthma therapeutics.
| S-EPMC2717793 | biostudies-literature
Project description:MicroRNA-mediated post-transcriptional regulation has been reported on ROS production and scavenging systems. Although microRNAs first appeared highly conserved among plant species, several aspects of biogenesis, function and evolution of microRNAs were shown to differ. High throughput transcriptome and degradome analyses enable to identify small RNAs and their mRNA targets. A non-photosynthetic tissue particularly prone to redox reactions, laticifers from Hevea brasiliensis, revealed species-specific post-transcriptional regulations. This paper sets out to identify the 407 genes of the thirty main redox-related gene families harboured by the Hevea genome. There are 161 redox-related genes expressed in latex. Thirteen of these redox-related genes were targeted by 11 microRNAs. To our knowledge, this is the first report on a mutation in the miR398 binding site of the cytosolic CuZnSOD. A working model was proposed for transcriptional and post-transcriptional regulation with respect to the predicted subcellular localization of deduced proteins.
| S-EPMC6450977 | biostudies-literature
Project description:ObjectivesThere is evidence to suggest that asthma pathogenesis is affected by both genetic and epigenetic variation independently, and there is some evidence to suggest that genetic-epigenetic interactions affect risk of asthma. However, little research has been done to identify such interactions on a genome-wide scale. The aim of this studies was to identify genes with genetic-epigenetic interactions associated with asthma.MethodsUsing asthma case-control data, we applied a novel nonparametric gene-centric approach to test for interactions between multiple SNPs and CpG sites simultaneously in the vicinities of 18,178 genes across the genome.ResultsTwelve genes, PF4, ATF3, TPRA1, HOPX, SCARNA18, STC1, OR10K1, UPK1B, LOC101928523, LHX6, CHMP4B, and LANCL1, exhibited statistically significant SNP-CpG interactions (false discovery rate = 0.05). Of these, three have previously been implicated in asthma risk (PF4, ATF3, and TPRA1). Follow-up analysis revealed statistically significant pairwise SNP-CpG interactions for several of these genes, including SCARNA18, LHX6, and LOC101928523 (p = 1.33E-04, 8.21E-04, 1.11E-03, respectively).ConclusionsJoint effects of genetic and epigenetic variation may play an important role in asthma pathogenesis. Statistical methods that simultaneously account for multiple variations across chromosomal regions may be needed to detect these types of effects on a genome-wide scale.
| S-EPMC7365350 | biostudies-literature
Project description:Post-transcriptional control of gene expression has central importance during development and adulthood and in physiology in general. However, little is known about the extent of post-transcriptional control of gene expression in the brain. Most post-transcriptional regulatory effectors (e.g., miRNAs) destabilize target mRNAs by shortening their polyA tails. Hence, the fraction of a given mRNA that it is fully polyadenylated should correlate with its stability and serves as a good measure of post-transcriptional control. Here, we compared RNA-seq datasets from fly brains that were generated either from total (rRNA-depleted) or polyA-selected RNA. By doing this comparison we were able to compute a coefficient that measures the extent of post-transcriptional control for each brain-expressed mRNA. In agreement with current knowledge, we found that mRNAs encoding ribosomal proteins, metabolic enzymes, and housekeeping genes are among the transcripts with least post-transcriptional control, whereas mRNAs that are known to be highly unstable, like circadian mRNAs and mRNAs expressing synaptic proteins and proteins with neuronal functions, are under strong post-transcriptional control. Surprisingly, the latter group included many specific groups of genes relevant to brain function and behavior. In order to determine the importance of miRNAs in this regulation, we profiled miRNAs from fly brains using oligonucleotide microarrays. Surprisingly, we did not find a strong correlation between the expression levels of miRNAs in the brain and the stability of their target mRNAs; however, genes identified as highly regulated post-transcriptionally were strongly enriched for miRNA targets. This demonstrates a central role of miRNAs for modulating the levels and turnover of brain-specific mRNAs in the fly.
| S-EPMC3856366 | biostudies-literature