An integrated host-microbiome response to atrazine exposure mediates toxicity in Drosophila

The gut microbiome produces vitamins, nutrients, and neurotransmitters, and helps to modulate the host immune system—and also plays a major role in the metabolism of many exogenous compounds, including drugs and chemical toxicants. However, the extent to which specific microbial species or communities modulate hazard upon exposure to chemicals remains largely opaque. Focusing on the effects of collateral dietary exposure to the widely used herbicide atrazine, we applied integrated omics and phenotypic screening to assess the role of the gut microbiome in modulating host resilience in Drosophila melanogaster. Transcriptional and metabolic responses to these compounds are sex-specific and depend strongly on the presence of the commensal microbiome. Sequencing the genomes of all abundant microbes in the fly gut revealed an enzymatic pathway responsible for atrazine detoxification unique to Acetobacter tropicalis. We find that Acetobacter tropicalis alone, in gnotobiotic animals, is sufficient to rescue increased atrazine toxicity to wild-type, conventionally reared levels. This work points toward the derivation of biotic strategies to improve host resilience to environmental chemical exposures, and illustrates the power of integrative omics to identify pathways responsible for adverse health outcomes.

Applying Proteomics and Integrative “Omics” Strategies to Decipher the Chronic Kidney Disease-Related Atherosclerosis

Patients with chronic kidney disease (CKD) are at increased risk of atherosclerosis and premature mortality, mainly due to cardiovascular events. However, well-known risk factors, which promote “classical” atherosclerosis are alone insufficient to explain the high prevalence of atherosclerosis-related to CKD (CKD-A). The complexity of the molecular mechanisms underlying the acceleration of CKD-A is still to be defied. To obtain a holistic picture of these changes, comprehensive proteomic approaches have been developed including global protein profiling followed by functional bioinformatics analyses of dysregulated pathways. Furthermore, proteomics surveys in combination with other “omics” techniques, i.e., transcriptomics and metabolomics as well as physiological assays provide a solid ground for interpretation of observed phenomena in the context of disease pathology. This review discusses the comprehensive application of various “omics” approaches, with emphasis on proteomics, to tackle the molecular mechanisms underlying CKD-A progression. We summarize here the recent findings derived from global proteomic approaches and underline the potential of utilizing integrative systems biology, to gain a deeper insight into the pathogenesis of CKD-A and other disorders.

Common and mutation specific phenotypes of KRAS and BRAF mutations in colorectal cancer cells revealed by integrative -omics analysis

Background Genes in the Ras pathway have somatic mutations in at least 60 % of colorectal cancers. Despite activating the same pathway, the BRAF V600E mutation and the prevalent mutations in codon 12 and 13 of KRAS have all been linked to different clinical outcomes, but the molecular mechanisms behind these differences largely remain to be clarified. Methods To characterize the similarities and differences between common activating KRAS mutations and between KRAS and BRAF mutations, we used genome editing to engineer KRAS G12C/D/V and G13D mutations in colorectal cancer cells that had their mutant BRAF V600E allele removed and subjected them to transcriptome sequencing, global proteomics and metabolomics analyses. Results By intersecting differentially expressed genes, proteins and metabolites, we uncovered (i) two-fold more regulated genes and proteins when comparing KRAS to BRAF mutant cells to those lacking Ras pathway mutation, (ii) five differentially expressed proteins in KRAS mutants compared to cells lacking Ras pathway mutation (IFI16, S100A10, CD44, GLRX and AHNAK2) and 6 (CRABP2, FLNA, NXN, LCP1, S100A10 and S100A2) compared to BRAF mutant cells, (iii) 19 proteins expressed differentially in a KRAS mutation specific manner versus BRAF V600E cells, (iv) regulation of the Integrin Linked Kinase pathway by KRAS but not BRAF mutation, (v) regulation of amino acid metabolism, particularly of the tyrosine, histidine, arginine and proline pathways, the urea cycle and purine metabolism by Ras pathway mutations, (vi) increased free carnitine in KRAS and BRAF mutant RKO cells. Conclusions This comprehensive integrative -omics analysis confirms known and adds novel genes, proteins and metabolic pathways regulated by mutant KRAS and BRAF signaling in colorectal cancer. The results from the new model systems presented here can inform future development of diagnostic and therapeutic approaches targeting tumors with KRAS and BRAF mutations.