Studies on mammalian ribosomal protein S7

http://www.ester.ee/record=b1163838~S1*es

Natural antisense transcript of natriuretic peptide precursor A (NPPA): structural organization and modulation of NPPA expression

<p>Abstract</p> <p>Background</p> <p>Mammalian transcriptome contains a large proportion of diverse and structurally complex noncoding RNAs. One class of such RNAs, natural antisense transcripts (NATs), are derived from the opposite strand of many protein-coding genes. Although the exact structure and functional relevance of most of the NATs is unknown, their emerging role as gene expression regulators raises the hypothesis that NATs might contribute to development of complex human disorders. The goal of our study was to investigate the involvement of NATs in regulation of candidate genes for blood pressure.</p> <p>Results</p> <p>First we analysed blood pressure candidate genes for the presence of natural antisense transcripts. <it>In silico </it>analysis revealed that seven genes (<it>ADD3</it>, <it>NPPA</it>, <it>ATP1A1</it>, <it>NPR2</it>, <it>CYP17A1</it>, <it>ACSM3</it>, <it>SLC14A2</it>) have an antisense partner transcribed from the opposite strand. We characterized <it>NPPA </it>and its antisense transcript (<it>NPPA-AS</it>) in more detail. We found that <it>NPPA-AS </it>is expressed in a number of human tissues as a collection of alternatively spliced isoforms and that <it>NPPA-AS </it>and <it>NPPA </it>can form RNA duplexes <it>in vivo</it>. We also demonstrated that a specific <it>NPPA-AS </it>isoform is capable of down-regulating the intron-retained <it>NPPA </it>mRNA variant. We studied the evolutionary conservation of <it>NPPA-AS </it>and were able to detect the presence of <it>Nppa-as </it>transcript in mouse.</p> <p>Conclusion</p> <p>Our results demonstrate functional interaction of <it>NPPA-AS </it>with <it>NPPA </it>at the RNA level and suggest that antisense transcription might be an important post-transcriptional mechanism modulating <it>NPPA </it>expression.</p

Genome-wide analysis of nuclear magnetic resonance metabolites revealed parent-of-origin effect on triglycerides in medium very low-density lipoprotein in PTPRD gene

The aim of the study was to explore the parent-of-origin effects (POEs) on a range of human nuclear magnetic resonance metabolites. Materials & methods: We search for POEs in 14,815 unrelated individuals from Estonian and Finnish cohorts using POE method for the genotype data imputed with 1000 G reference panel and 82 nuclear magnetic resonance metabolites. Results: Meta-analysis revealed the evidence of POE for the variant rs1412727 in PTPRD gene for the metabolite: triglycerides in medium very low-density lipoprotein. No POEs were detected for genetic variants that were previously known to have main effect on circulating metabolites. Conclusion: We demonstrated possibility to detect POEs for human metabolites, but the POEs are weak, and therefore it is hard to detect those using currently available sample sizes.Peer reviewe

Cis-epistasis at the LPA locus and risk of cardiovascular diseases

AIMS Coronary artery disease (CAD) has a strong genetic predisposition. However, despite substantial discoveries made by genome-wide association studies (GWAS), a large proportion of heritability awaits identification. Non-additive genetic-effects might be responsible for part of the unaccounted genetic variance. Here we attempted a proof-of-concept study to identify non-additive genetic effects, namely epistatic interactions, associated with CAD. METHODS AND RESULTS We tested for epistatic interactions in ten CAD case-control studies and UK Biobank with focus on 8,068 SNPs at 56 loci with known associations with CAD risk. We identified a SNP pair located in cis at the LPA locus, rs1800769 and rs9458001, to be jointly associated with risk for CAD (odds ratio OR=1.37, p = 1.07 $\times$ 10-11), peripheral arterial disease (OR = 1.22, p = 2.32 $\times$ 10-4), aortic stenosis (OR = 1.47, p = 6.95 $\times$ 10-7), hepatic lipoprotein(a) (Lp(a)) transcript levels (beta = 0.39, p = 1.41 $\times$ 10-8), and Lp(a) serum levels (beta = 0.58, p = 8.7 $\times$ 10-32), while individual SNPs displayed no association. Further exploration of the LPA locus revealed a strong dependency of these associations on a rare variant, rs140570886, that was previously associated with Lp(a) levels. We confirmed increased CAD risk for heterozygous (relative OR = 1.46, p = 9.97 $\times$ 10-32) and individuals homozygous for the minor allele (relative OR = 1.77, p = 0.09) of rs140570886. Using forward model selection, we also show that epistatic interactions between rs140570886, rs9458001, and rs1800769 modulate the effects of the rs140570886 risk allele. CONCLUSIONS These results demonstrate the feasibility of a large-scale knowledge-based epistasis scan and provide rare evidence of an epistatic interaction in a complex human disease. We were directed to a variant (rs140570886) influencing risk through additive genetic as well as epistatic effects. In summary, this study provides deeper insights into the genetic architecture of a locus important for cardiovascular diseases. TRANSLATIONAL PERSPECTIVE Genetic variants identified by GWAS studies explain about a quarter of the heritability of coronary artery disease by additive genetic effects. Our study demonstrates that non-additive effects contribute to the genetic architecture of the disease as well and identifies complex interaction patterns at the LPA locus, which affect LPA expression, Lp(a) plasma levels and risk of atherosclerosis. This proof-of-concept study encourages systematic searches for epistatic interactions in further studies to shed new light on the aetiology of the disease

C-reactive protein upregulates the whole blood expression of CD59 - an integrative analysis

Elevated C-reactive protein (CRP) concentrations in the blood are associated with acute and chronic infections and inflammation. Nevertheless, the functional role of increased CRP in multiple bacterial and viral infections as well as in chronic inflammatory diseases remains unclear. Here, we studied the relationship between CRP and gene expression levels in the blood in 491 individuals from the Estonian Biobank cohort, to elucidate the role of CRP in these inflammatory mechanisms. As a result, we identified a set of 1,614 genes associated with changes in CRP levels with a high proportion of interferon-stimulated genes. Further, we performed likelihood-based causality model selection and Mendelian randomization analysis to discover causal links between CRP and the expression of CRP-associated genes. Strikingly, our computational analysis and cell culture stimulation assays revealed increased CRP levels to drive the expression of complement regulatory protein CD59, suggesting CRP to have a critical role in protecting blood cells from the adverse effects of the immune defence system. Our results show the benefit of integrative analysis approaches in hypothesis-free uncovering of causal relationships between traits.</p

Comparative Evolution of S7 Intron 1 and Ribosomal Internal Transcribed Spacer in Coilia nasus (Clupeiformes: Engraulidae)

Coilia nasus is widely distributed in the Yangtze River, the coastal waters of China, Korea and the Ariake Sound of Japan. Several ecotypes exist and this provides a useful model for the study of comparative diversity between molecular markers. Here we analyze and compare the nucleotide sequences between single-copy ribosomal protein S7 gene intron 1 (rpS7) and multiple-copy ribosomal internal transcribed spacer 1 (ITS1) in this species to compare the phylogenetic signal of the two nuclear genes. Nucleotide substitutions among the two gene sequences and partial sequence of mitochondrial cytochrome c oxidase subunit I (COI) gene were also analyzed. A total of 115 clones for rpS7 and 122 clones for ITS1 were obtained from 37 specimens. The nucleotide sequence length is 741 to 743 bp for rpS7 and 334 to 348 bp for ITS1. Intra- and inter-specimen variation in rpS7 results from nucleotide substitution, while such variation in ITS1 is mainly due to different numbers of short base repeats. The content of G + C is lower in rpS7 (43.5%) than in ITS1 (68.2%). Our results indicate that the proportion of the sequence variable sites is higher in rpS7 (61) than in ITS1 (23); the informative parsimony of rpS7 is evidently higher than that of ITS1 (26 vs. 2); the overall ratio between transitions and transversions in ITS1 is slightly lower than in rpS7, but remarkably lower than in COI. These results suggest that rpS7 is more suitable than ITS1 as a marker for genetic divergence of this group. Furthermore, gene flow is observed between the different geographic populations of C. nasus from the phylogeny of this species based on rpS7, showing that rpS7 has more evolutionary characteristics for understanding the processes of genomic evolution at the intraspecific level

Family Size and Turnover Rates among Several Classes of Small Non–Protein-Coding RNA Genes in Caenorhabditis Nematodes

It is important to understand the forces that shape the size and evolutionary histories of gene families. Here, we investigated the evolution of non–protein-coding RNA genes in the genomes of Caenorhabditis nematodes. We specifically focused on nested arrangements, that is, cases in which an RNA gene is entirely contained in an intron of another gene. Comparing these arrangements between species simplifies the inference of orthology and, therefore, of evolutionary fates of nested genes. Two distinct patterns are evident in the data. Genes encoding small nuclear RNAs (snRNAs) and transfer RNAs form large families, which have persisted since before the common ancestor of Metazoa. Yet, individual genes die relatively rapidly, with few orthologs having survived since the divergence of Caenorhabditis elegans and Caenorhabditis briggsae. In contrast, genes encoding small nucleolar RNAs (snoRNAs) are either single-copy or form small families. Individual snoRNAs turn over at a relatively slow rate—most C. elegans genes have clearly identifiable orthologs in C. briggsae. We also found that in Drosophila, genes from larger snRNA families die at a faster rate than their counterparts from single-gene families. These results suggest that a relationship between family size and the rate of gene turnover may be a general feature of genome evolution

MicroRNA profiling associated with non-small cell lung cancer: next generation sequencing detection, experimental validation, and prognostic value

[EN] Background: The average five-year survival for non-small cell lung cancer (NSCLC) patients is approximately 15%. Emerging evidence indicates that microRNAs (miRNAs) constitute a new class of gene regulators in humans that may play an important role in tumorigenesis. Hence, there is growing interest in studying their role as possible new biomarkers whose expression is aberrant in cancer. Therefore, in this study we identified dysregulated miRNAs by next generation sequencing (NGS) and analyzed their prognostic value. Methods: Sequencing by oligo ligation detection technology was used to identify dysregulated miRNAs in a training cohort comprising paired tumor/normal tissue samples (N = 32). We validated 22 randomly selected differentially-expressed miRNAs by quantitative real time PCR in tumor and adjacent normal tissue samples (N = 178). Kaplan-Meier survival analysis and Cox regression were used in multivariate analysis to identify independent prognostic biomarkers. Results: NGS analysis revealed that 39 miRNAs were dysregulated in NSCLC: 28 were upregulated and 11 were downregulated. Twenty-two miRNAs were validated in an independent cohort. Interestingly, the group of patients with high expression of both miRNAs (miR-21(high) and miR-188(high)) showed shorter relapse-free survival (RFS) and overall survival (OS) times. Multivariate analysis confirmed that this combined signature is an independent prognostic marker for RFS and OS (p = 0.001 and p < 0.0001, respectively). Conclusions: NGS technology can specifically identify dysregulated miRNA profiles in resectable NSCLC samples. MiR-21 or miR-188 overexpression correlated with a negative prognosis, and their combined signature may represent a new independent prognostic biomarker for RFS and OS.This work was supported by the RD12/0036/0025 and RD06/0020/1024 PI12-02838, ISCIII, grants from the Fondo Europeo de Desarrollo Regional (FEDER), by funds from the Proyecto de Investigacion Fundamental Orientada a la Transmision de Conocimiento a la Empresa (TRACE; TRA09-0132) and Beca Roche Oncohematologia.Gallach-Garcia, S.; Jantus-Lewintre, E.; Calabuig-Fariñas, S.; Montaner, D.; Alonso, S.; Sirera Pérez, R.; Blasco, A.... (2017). MicroRNA profiling associated with non-small cell lung cancer: next generation sequencing detection, experimental validation, and prognostic value. Oncotarget. 8(34):56143-56157. https://doi.org/10.18632/oncotarget.18603S561435615783

Methylation Markers of Early-Stage Non-Small Cell Lung Cancer

Despite of intense research in early cancer detection, there is a lack of biomarkers for the reliable detection of malignant tumors, including non-small cell lung cancer (NSCLC). DNA methylation changes are common and relatively stable in various types of cancers, and may be used as diagnostic or prognostic biomarkers.We performed DNA methylation profiling of samples from 48 patients with stage I NSCLC and 18 matching cancer-free lung samples using microarrays that cover the promoter regions of more than 14,500 genes. We correlated DNA methylation changes with gene expression levels and performed survival analysis.We observed hypermethylation of 496 CpGs in 379 genes and hypomethylation of 373 CpGs in 335 genes in NSCLC. Compared to adenocarcinoma samples, squamous cell carcinoma samples had 263 CpGs in 223 hypermethylated genes and 513 CpGs in 436 hypomethylated genes. 378 of 869 (43.5%) CpG sites discriminating the NSCLC and control samples showed an inverse correlation between CpG site methylation and gene expression levels. As a result of a survival analysis, we found 10 CpGs in 10 genes, in which the methylation level differs in different survival groups.We have identified a set of genes with altered methylation in NSCLC and found that a minority of them showed an inverse correlation with gene expression levels. We also found a set of genes that associated with the survival of the patients. These newly-identified marker candidates for the molecular screening of NSCLC will need further analysis in order to determine their clinical utility