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Gene-Metabolite Network Analysis Revealed Tissue-Specific Accumulation of Therapeutic Metabolites in Mallotus japonicus.

ABSTRACT: Mallotus japonicus is a valuable traditional medicinal plant in East Asia for applications as a gastrointestinal drug. However, the molecular components involved in the biosynthesis of bioactive metabolites have not yet been explored, primarily due to a lack of omics resources. In this study, we established metabolome and transcriptome resources for M. japonicus to capture the diverse metabolite constituents and active transcripts involved in its biosynthesis and regulation. A combination of untargeted metabolite profiling with data-dependent metabolite fragmentation and metabolite annotation through manual curation and feature-based molecular networking established an overall metabospace of M. japonicus represented by 2129 metabolite features. M. japonicus de novo transcriptome assembly showed 96.9% transcriptome completeness, representing 226,250 active transcripts across seven tissues. We identified specialized metabolites biosynthesis in a tissue-specific manner, with a strong correlation between transcripts expression and metabolite accumulations in M. japonicus. The correlation- and network-based integration of metabolome and transcriptome datasets identified candidate genes involved in the biosynthesis of key specialized metabolites of M. japonicus. We further used phylogenetic analysis to identify 13 C-glycosyltransferases and 11 methyltransferases coding candidate genes involved in the biosynthesis of medicinally important bergenin. This study provides comprehensive, high-quality multi-omics resources to further investigate biological properties of specialized metabolites biosynthesis in M. japonicus.

SUBMITTER: Rai M

PROVIDER: S-EPMC8396295 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The HTT CAG expansion mutation causes Huntington's Disease and is associated with a wide range of cellular consequences, including altered metabolism. The mutant allele is expressed widely, in all tissues, but the striatum and cortex are especially vulnerable to its effects. To more fully understand this tissue-specificity, early in the disease process, we asked whether the metabolic impact of the mutant CAG expanded allele in heterozygous B6.HdhQ111/+ mice would be common across tissues, or whether tissues would have tissue-specific responses and whether such changes may be affected by diet. Specifically, we cross-sectionally examined steady state metabolite concentrations from a range of tissues (plasma, brown adipose tissue, cerebellum, striatum, liver, white adipose tissue), using an established liquid chromatography-mass spectrometry pipeline, from cohorts of 8 month old mutant and wild-type littermate mice that were fed one of two different high-fat diets. The differential response to diet highlighted a proportion of metabolites in all tissues, ranging from 3% (7/219) in the striatum to 12% (25/212) in white adipose tissue. By contrast, the mutant CAG-expanded allele primarily affected brain metabolites, with 14% (30/219) of metabolites significantly altered, compared to wild-type, in striatum and 11% (25/224) in the cerebellum. In general, diet and the CAG-expanded allele both elicited metabolite changes that were predominantly tissue-specific and non-overlapping, with evidence for mutation-by-diet interaction in peripheral tissues most affected by diet. Machine-learning approaches highlighted the accumulation of diverse lipid species as the most genotype-predictive metabolite changes in the striatum. Validation experiments in cell culture demonstrated that lipid accumulation was also a defining feature of mutant HdhQ111 striatal progenitor cells. Thus, metabolite-level responses to the CAG expansion mutation in vivo were tissue specific and most evident in brain, where the striatum featured signature accumulation of a set of lipids including sphingomyelin, phosphatidylcholine, cholesterol ester and triglyceride species. Importantly, in the presence of the CAG mutation, metabolite changes were unmasked in peripheral tissues by an interaction with dietary fat, implying that the design of studies to discover metabolic changes in HD mutation carriers should include metabolic perturbations.

Project description:BackgroundSesame (Sesamum indicum L.) leaves, flowers, especially seeds are used in traditional medicine to prevent or cure various diseases. Its seed's market is expanding. However, the other tissues are still underexploited due to the lack of information related to metabolites distribution and variability in the plant. Herein, the metabolite profiles of five sesame tissues (leaves, fresh seeds, white and purple flowers, and fresh carpels) have been investigated using ultra-high-performance liquid chromatography-mass spectrometry (UPLC-MS/MS)-based widely targeted metabolomics analysis platform.ResultsIn total, 776 metabolites belonging to diverse classes were qualitatively and quantitatively identified. The different tissues exhibited obvious differences in metabolites composition. The majority of flavonoids predominantly accumulated in flowers. Amino acids and derivatives, and lipids were identified predominantly in fresh seeds followed by flowers. Many metabolites, including quinones, coumarins, tannins, vitamins, terpenoids and some bioactive phenolic acids (acteoside, isoacteoside, verbascoside, plantamajoside, etc.) accumulated mostly in leaves. Lignans were principally detected in seeds. 238 key significantly differential metabolites were filtered out. KEGG annotation and enrichment analyses of the differential metabolites revealed that flavonoid biosynthesis, amino acids biosynthesis, and phenylpropanoid biosynthesis were the main differently regulated pathways. In addition to the tissue-specific accumulation of metabolites, we noticed a cooperative relationship between leaves, fresh carpels, and developing seeds in terms of metabolites transfer. Delphinidin-3-O-(6"-O-p-coumaroyl)glucoside and most of the flavonols were up-regulated in the purple flowers indicating they might be responsible for the purple coloration.ConclusionThis study revealed that the metabolic processes in the sesame tissues are differently regulated. It offers valuable resources for investigating gene-metabolites interactions in sesame tissues and examining metabolic transports during seed development in sesame. Furthermore, our findings provide crucial knowledge that will facilitate sesame biomass valorization.

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Gene-Metabolite Network Analysis Revealed Tissue-Specific Accumulation of Therapeutic Metabolites in Mallotus japonicus.

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