Dataset Information

Network, Transcriptomic and Genomic Features Differentiate Genes Relevant for Drug Response.

ABSTRACT: Understanding the mechanisms underlying drug therapeutic action and toxicity is crucial for the prevention and management of drug adverse reactions, and paves the way for a more efficient and rational drug design. The characterization of drug targets, drug metabolism proteins, and proteins associated to side effects according to their expression patterns, their tolerance to genomic variation and their role in cellular networks, is a necessary step in this direction. In this contribution, we hypothesize that different classes of proteins involved in the therapeutic effect of drugs and in their adverse effects have distinctive transcriptomics, genomics and network features. We explored the properties of these proteins within global and organ-specific interactomes, using multi-scale network features, evaluated their gene expression profiles in different organs and tissues, and assessed their tolerance to loss-of-function variants leveraging data from 60K subjects. We found that drug targets that mediate side effects are more central in cellular networks, more intolerant to loss-of-function variation, and show a wider breadth of tissue expression than targets not mediating side effects. In contrast, drug metabolizing enzymes and transporters are less central in the interactome, more tolerant to deleterious variants, and are more constrained in their tissue expression pattern. Our findings highlight distinctive features of proteins related to drug action, which could be applied to prioritize drugs with fewer probabilities of causing side effects.

SUBMITTER: Pinero J

PROVIDER: S-EPMC6168038 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Network, Transcriptomic and Genomic Features Differentiate Genes Relevant for Drug Response.

Piñero Janet J Gonzalez-Perez Abel A Guney Emre E Aguirre-Plans Joaquim J Sanz Ferran F Oliva Baldo B Furlong Laura I LI

Frontiers in genetics 20180925

Understanding the mechanisms underlying drug therapeutic action and toxicity is crucial for the prevention and management of drug adverse reactions, and paves the way for a more efficient and rational drug design. The characterization of drug targets, drug metabolism proteins, and proteins associated to side effects according to their expression patterns, their tolerance to genomic variation and their role in cellular networks, is a necessary step in this direction. In this contribution, we hypo ...[more]

PMID: 30319692

Similar Datasets

Project description:Polyunsaturated fatty acids (PUFAs) are a set of important nutrients that mainly include arachidonic acid (ARA4), docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and α-linolenic acid (ALA). Recently, fish-derived PUFAs have been associated with cardiovascular health, fetal development, and improvement of brain functions. Studies have shown that fish muscular tissues are rich in PUFAs, which are influenced by various factors, including genetic variations, regulatory profiles, and methylation status of desaturase genes during fatty acid desaturation and elongation processes. However, the genetic mechanism and the pathways involved in fatty acid metabolism in fishes remain unclear. The overall aim of this study was to assess differences in gene expression responses among fishes with different fatty acid levels. To achieve this goal, we conducted genome-wide association analysis (GWAS) using a 250K SNP array in a population of 203 samples of common carp (Cyprinus carpio) and identified nine SNPs and 15 genes associated with muscular PUFA content. Then, RNA-Seq and whole genome bisulfite sequencing (WGBS) of different groups with high and low EPA, DHA, ARA4, and ALA contents in muscle, liver and brain tissues were conducted, resulting in 6,750 differentially expressed genes and 5,631 genes with differentially methylated promoters. Gene ontology and KEGG pathway enrichment analyses of RNA-Seq and WGBS results identified enriched pathways for fatty acid metabolism, which included the adipocytokine signaling pathway, ARA4 and linoleic acid metabolism pathway, and insulin signaling pathway. Integrated analysis indicated significant correlations between gene expression and methylation status among groups with high and low PUFA contents in muscular tissues. Taken together, these multi-level results uncovered candidate genes and pathways that are associated with fatty acid metabolism and paved the way for further genomic selection and carp breeding for PUFA traits.

Project description:Alexandrium minutum is a typical marine toxic dinoflagellate responsible for producing paralytic shellfish poisoning (PSP) toxins. Until now, we know little about the genomic information of A. minutum, so a transcriptome study was conducted to clarify the physiological adaptations related to nutritional deficiency. Here, we performed RNA-Seq analysis to assess the gene expression patterns of A. minutum under N and P deficient conditions for 0 (control), 6, and 72 h. Main differences between the control and experimental groups were observed in hydrolase activity and fatty acid, lipid, protein, and P metabolism. Activities of photosystem I (PSI) and PSII were significantly down-regulated, and the endocytosis pathway (clathrin-dependent endocytosis) was significantly enriched under N and P stress compared with the control, indicating that A. minutum shifts its trophy pattern under N and P stress. We also identified several unigenes related to the process of sexual reproduction, including sex determination, sperm-egg recognition, sex differentiation, mating, and fertilization. Approximately 50% of the successfully annotated unigenes were differentially expressed between the short-term stimulated sample (6 h) and control (R). However, the expression level of most unigenes returned to normal levels after 72 h, indicating that N and P stress plays a limited role in the induction of sexual reproduction. Furthermore, the quantitative real-time PCR (qRT-PCR) results of the five representative sex-related unigenes were consistent with sequencing data, which confirmed the authenticity of transcriptomic analysis. Also, qRT-PCR analysis showed that the long and short form transcripts of the saxitoxin biosynthesis gene (sxtA) were down-regulated under the nutrient deficient condition compared with the control, indicating that N and P stress regulates sxtA expression. Overall, transcriptome analysis of A. minutum revealed that N and P deficiency induced responses associated with stress response, photosynthetic efficiency, toxin biosynthesis, and sexual reproduction. Our data indicate that algae change their trophic modes (to facultative mixotrophy) and related physiological reactions under stress conditions; this possibly represents an ecological adaption strategy in the algal life cycle.

Project description:AimsAlzheimer's disease (AD) is one of the leading causes of death in elderly people. Its pathogenesis is greatly associated with the abnormality of immune system. However, only a few immune-relevant AD drug target genes have been discovered up to now, and it is speculated that there are still many potential drug target genes of AD (at least immune-relevant genes) to be discovered. Thus, this study was designed to identify novel AD drug target genes and explore their biological properties.MethodsA combinatorial approach was adopted for the first time to discover AD drug targets by collectively considering ontology inference and network analysis. Moreover, a novel strategy limiting the distance of reasoning and in turn reducing noise interference was further proposed to improve inference performance. Potential AD drug target genes were discovered by integrating information of multiple popular databases (TTD, DrugBank, PharmGKB, AlzGene, and BioGRID). Then, the enrichment analyses of the identified drug targets genes based on nine well-known pathway-related databases were conducted to explore the function of the identified potential drug target genes.ResultsEighteen potential drug target genes were finally identified, and 13 of them had been reported to be closely associated with AD. Enrichment analyses of these identified drug target genes, based on nine pathway-related databases, revealed that the enriched terms were primarily focus on immune-relevant biological processes. Four of those identified drug target genes are involved in the classical complement pathway and process of antigen presenting.ConclusionThe well-reproducible results showed the good performance of the combinatorial approach, and the remaining five new targets could be a good starting point for our understanding of the pathogenesis and drug discovery of AD. Moreover, this study supported validity of the combinatorial approach integrating ontology inference with network analysis in the discovery of novel drug target for neurological diseases.

Project description:Global increases in the use of carbapenems have resulted in several strains of Gram-negative bacteria acquiring carbapenem resistance, thereby limiting treatment options. Klebsiella pneumoniae is a common carbapenem-resistant pathogenic bacterium that is widely studied to identify novel antibiotic resistance mechanisms and drug targets. Antibiotic-resistant clinical isolates generally harbor many genetic alterations, and the identification of responsible mutations would provide insights into the molecular mechanisms of antibiotic resistance. We propose a method to prioritize mutated genes responsible for antibiotic resistance on the basis of expression changes in their local subnetworks, hypothesizing that mutated genes that show significant expression changes among the corresponding functionally associated genes are more likely to be involved in the carbapenem resistance. For network-based gene prioritization, we developed KlebNet (www.inetbio.org/klebnet), a genome-scale cofunctional network of K. pneumoniae genes. Using KlebNet, we reconstructed the functional modules for carbapenem resistance and virulence and identified the functional association between antibiotic resistance and virulence. Using complementation assays with the top candidate genes, we were able to validate a novel gene that negatively regulated carbapenem resistance and four novel genes that positively regulated virulence in Galleria mellonella larvae. Therefore, our study demonstrated the feasibility of network-based identification of genes required for antibiotic resistance and virulence of human-pathogenic bacteria.IMPORTANCEKlebsiella pneumoniae is a major bacterial pathogen that causes pneumonia and urinary tract infections in human. K. pneumoniae infections are treated with carbapenem, but carbapenem-resistant K. pneumoniae has been spreading worldwide. We are able to identify antimicrobial-resistant genes among mutated genes of the antibiotic-resistant clinical isolates. However, they usually harbor many mutated genes, including those that cause weak or neutral functional effects. Therefore, we need to prioritize the mutated genes to identify the more likely candidates for the follow-up functional analysis. For this study, we present a functional network of K. pneumoniae genes and propose a network-based method of prioritizing the mutated genes of the resistant clinical isolates. We also reconstructed the network-based functional modules for carbapenem resistance and virulence and retrieved the functional association between antibiotic resistance and virulence. This study demonstrated the feasibility of network-based analysis of clinical genomics data for the study of K. pneumoniae infection.

Dataset Information

Network, Transcriptomic and Genomic Features Differentiate Genes Relevant for Drug Response.

Publications

Network, Transcriptomic and Genomic Features Differentiate Genes Relevant for Drug Response.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets