Causal effects of genetically determined metabolites on cancers included lung, breast, ovarian cancer, and glioma: a Mendelian randomization study.

Background: Previous studies have shown that metabolites play important roles in phenotypic regulation, but the causal link between metabolites and tumors has not been examined adequately. Herein, we investigate the causality between metabolites and various cancers through a Mendelian randomization (MR) study. Methods: We carried out a two-sample MR analysis based on genetic instrumental variables as proxies for 486 selected human serum metabolites to evaluate the causal effects of genetically determined metabotypes (GDMs) on cancers. Summary data from various cancer types obtained from large consortia. Inverse variance weighted (IVW), MR-Egger and weighted-median methods were implemented to infer the causal effects, moreover, we particularly explored the presentence of horizontal pleiotropy through MR-Egger regression and MR-PRESSO Global test. Metabolic pathways analysis and subgroup analyses were further explored using available data. Statistical analyses were all performed in R. Results: In MR analysis, 202 significant causative relationship features were identified. 7-alpha-hydroxy-3-oxo-4-cholestenoate (ORIVW =1.45; 95% CI: 1.06-1.97; PIVW =0.018), gamma-glutamylisoleucine (ORIVW =1.40; 95% CI: 1.16-1.69; PIVW =0.0004), 1-oleoylglycerophosphocholine (ORIVW =1.22; 95% CI: 1.1-1.35; PIVW =0.0001), gamma-glutamylleucine (ORIVW =4.74; 95% CI: 1.18-18.93; PIVW =0.027) were the most dangerous metabolites for lung cancer, ovarian cancer, breast cancer, and glioma, respectively; while pseudouridine (ORIVW =0.50; 95% CI: 0.30-0.83; PIVW =0.007), 2-methylbutyroylcarnitine (ORIVW =0.77; 95% CI: 0.68-0.86; PIVW =2.9×10-6), 2-methylbutyroylcarnitine (ORIVW =0.77; 95% CI: 0.70-0.85; PIVW =3.4×10-7), glycylvaline (ORIVW =0.13; 95% CI: 0.02-0.75; PIVW =0.021) were associated with lower risk of lung cancer, ovarian cancer, breast cancer, and glioma, respectively. Interestingly, 2-methylbutyroylcarnitine was also associated with decreased risk of lung cancer (ORIVW =0.59; 0.50-0.70; P IVW =1.98×10-9) expect ovarian cancer and breast cancer. In subgroup analysis, 2-methylbutyroylcarnitine was associated with decreased risk of estrogen receptor (ER) positive breast cancer (ORIVW =0.72; 0.64-0.80; PIVW =3.55×10-9), lung adenocarcinoma (LAC) (ORIVW =0.60; 0.48-0.70; PIVW =1.14×10-5). Metabolic pathways analysis identified 4 significant pathways. Conclusions: Our study integrated metabolomics and genomics to explore the risk factors involved in the development of cancers. It is worth exploring whether metabolites with causality can be used as biomarkers to distinguish patients at high risk of cancer in clinical practice. More detailed studies are needed to clarify the mechanistic pathways.

RNA sequencing of Brassica napus reveals cellular redox control of Sclerotinia infection.

Brassica napus is one of the world's most valuable oilseeds and is under constant pressure by the necrotrophic fungal pathogen, Sclerotinia sclerotiorum, the causal agent of white stem rot. Despite our growing understanding of host pathogen interactions at the molecular level, we have yet to fully understand the biological processes and underlying gene regulatory networks responsible for determining disease outcomes. Using global RNA sequencing, we profiled gene activity at the first point of infection on the leaf surface 24 hours after pathogen exposure in susceptible (B. napus cv. Westar) and tolerant (B. napus cv. Zhongyou 821) plants. We identified a family of ethylene response factors that may contribute to host tolerance to S. sclerotiorum by activating genes associated with fungal recognition, subcellular organization, and redox homeostasis. Physiological investigation of redox homeostasis was further studied by quantifying cellular levels of the glutathione and ascorbate redox pathway and the cycling enzymes associated with host tolerance to S. sclerotiorum. Functional characterization of an Arabidopsis redox mutant challenged with the fungus provides compelling evidence into the role of the ascorbate-glutathione redox hub in the maintenance and enhancement of plant tolerance against fungal pathogens.

Vitamin C deficiency improves somatic embryo development through distinct gene regulatory networks in Arabidopsis.

Changes in the endogenous ascorbate redox status through genetic manipulation of cellular ascorbate levels were shown to accelerate cell proliferation during the induction phase and improve maturation of somatic embryos in Arabidopsis. Mutants defective in ascorbate biosynthesis such as vtc2-5 contained ~70 % less cellular ascorbate compared with their wild-type (WT; Columbia-0) counterparts. Depletion of cellular ascorbate accelerated cell division processes and cellular reorganization and improved the number and quality of mature somatic embryos grown in culture by 6-fold compared with WT tissues. To gain insight into the molecular mechanisms underlying somatic embryogenesis (SE), we profiled dynamic changes in the transcriptome and analysed dominant patterns of gene activity in the WT and vtc2-5 lines across the somatic embryo culturing process. Our results provide insight into the gene regulatory networks controlling SE in Arabidopsis based on the association of transcription factors with DNA sequence motifs enriched in biological processes of large co-expressed gene sets. These data provide the first detailed account of temporal changes in the somatic embryo transcriptome starting with the zygotic embryo, through tissue dedifferentiation, and ending with the mature somatic embryo, and impart insight into possible mechanisms for the improved culture of somatic embryos in the vtc2-5 mutant line.