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Humans heavily rely on dozens of domesticated plant species that have been further improved through intensive breeding. To evaluate how breeding changed the tomato fruit metabolome, we have generated and analyzed a dataset encompassing genomes, transcriptomes, and metabolomes from hundreds of tomato genotypes. The combined results illustrate how breeding globally altered fruit metabolite content. Selection for alleles of genes associated with larger fruits altered metabolite profiles as a consequence of linkage with nearby genes. Selection of five major loci reduced the accumulation of anti-nutritional steroidal glycoalkaloids in ripened fruits, rendering the fruit more edible. Breeding for pink tomatoes modified the content of over 100 metabolites. The introgression of resistance genes from wild relatives in cultivars also resulted in major and unexpected metabolic changes. The study reveals a multi-omics view of the metabolic breeding history of tomato, as well as provides insights into metabolome-assisted breeding and plant biology.
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Frutas/genética , Metaboloma , Metabolómica/métodos , Fitomejoramiento/métodos , Solanum lycopersicum/genética , Flavonoides/genética , Flavonoides/metabolismo , Frutas/crecimiento & desarrollo , Frutas/metabolismo , Selección ArtificialRESUMEN
The structural and functional diversity of plant metabolites is largely created via chemical modification of a basic backbone. However, metabolite modifications in plants have still not been thoroughly investigated by metabolomics approaches. In this study, a widely targeted metabolite modificomics (WTMM) strategy was developed based on ultra-high performance liquid chromatography-quadrupole-linear ion trap (UHPLC-Q-Trap) and UHPLC-Q-Exactive-Orbitrap (UHPLC-QE-Orbitrap), which greatly improved the detection sensitivity and the efficiency of identification of modified metabolites. A metabolite modificomics study was carried out using tomato as a model, and over 34,000 signals with MS2 information were obtained from approximately 232 neutral loss transitions. Unbiased metabolite profiling was also performed by utilizing high-resolution mass spectrometry data to annotate a total of 2,118 metabolites with 125 modification types; of these, 165 modified metabolites were identified in this study. Next, the WTMM database was used to assess diseased tomato tissues and 29 biomarkers were analyzed. In summary, the WTMM strategy is not only capable of large-scale detection and quantitative analysis of plant-modified metabolites in plants, but also can be used for plant biomarker development.
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Solanum lycopersicum , Espectrometría de Masas/métodos , Cromatografía Líquida de Alta Presión/métodos , Metabolómica/métodosRESUMEN
Pummelo (Citrus maxima or Citrus grandis) is a basic species and an important type for breeding in Citrus. Pummelo is used not only for fresh consumption but also for medicinal purposes. However, the molecular basis of medicinal traits is unclear. Here, compared with wild citrus species/Citrus-related genera, the content of 43 bioactive metabolites and their derivatives increased in the pummelo. Furthermore, we assembled the genome sequence of a variety for medicinal purposes with a long history, Citrus maxima 'Huazhouyou-tomentosa' (HZY-T), at the chromosome level with a genome size of 349.07 Mb. Comparative genomics showed that the expanded gene family in the pummelo genome was enriched in flavonoids-, terpenoid-, and phenylpropanoid biosynthesis. Using the metabolome and transcriptome of six developmental stages of HZY-T and Citrus maxima 'Huazhouyou-smooth' (HZY-S) fruit peel, we generated the regulatory networks of bioactive metabolites and their derivatives. We identified a novel MYB transcription factor, CmtMYB108, as an important regulator of flavone pathways. Both mutations and expression of CmtMYB108, which targets the genes PAL (phenylalanine ammonia-lyase) and FNS (flavone synthase), displayed differential expression between Citrus-related genera, wild citrus species and pummelo species. This study provides insights into the evolution-associated changes in bioactive metabolism during the origin process of pummelo.
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Citrus , Flavonas , Multiómica , Fitomejoramiento , Citrus/genética , Flavonas/metabolismo , Flavonoides/genética , Flavonoides/metabolismoRESUMEN
Steroidal glycoalkaloids (SGAs) constitute a characteristic class of antinutritional metabolites that are found in certain Solanum species. Despite the considerable studies on SGA biosynthesis, the mechanisms of crosstalk between hormone signaling pathways that regulate SGA content still remain to be elucidated. Here, we performed a metabolic genome-wide association study (mGWAS) based on the levels of SGA metabolites and identified SlERF.H6 as a negative regulator of bitter-SGA biosynthesis. SlERF.H6 repressed the expression of SGA biosynthetic glycoalkaloid metabolism (GAME) genes and caused a subsequent decrease in the abundance of bitter SGAs. Furthermore, SlERF.H6 were shown to act downstream of GAME9, a regulator of SGA biosynthesis in tomato. We also uncovered the interplay between ethylene and gibberellin (GA) signaling in regulating SGA biosynthesis. SlERF.H6, acting as a downstream component in ethylene signaling, modulated GA content by inhibiting SlGA2ox12 expression. Increasing levels of endogenous GA12 and GA53 in SlERF.H6-OE could inhibit of GA on SGA biosynthesis. Additionally, 1-aminocyclopropane-1-carboxylic acid (ACC) treatment decreased the stability of SlERF.H6, weakening its inhibition on GAME genes and SlGA2ox12, and caused bitter-SGA accumulation. Our findings reveal a key role of SlERF.H6 in the regulation of SGA biosynthesis through the coordinated ethylene-gibberellin signaling.
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Solanum lycopersicum , Solanum lycopersicum/genética , Giberelinas , Estudio de Asociación del Genoma Completo , Etilenos/metabolismo , Regulación de la Expresión Génica de las PlantasRESUMEN
Steroidal alkaloids (SAs) and steroidal glycoalkaloids (SGAs) are common constituents of plant species belonging to the Solanaceae family. However, the molecular mechanism regulating the formation of SAs and SGAs remains unknown. Here, genome-wide association mapping was used to elucidate SA and SGA regulation in tomatoes: a SlGAME5-like glycosyltransferase (Solyc10g085240) and the transcription factor SlDOG1 (Solyc10g085210) were significantly associated with steroidal alkaloid composition. In this study, it was found that rSlGAME5-like can catalyze a variety of substrates for glycosidation and can catalyze SA and flavonol pathways to form O-glucoside and O-galactoside in vitro. The overexpression of SlGAME5-like promoted α-tomatine, hydroxytomatine, and flavonol glycoside accumulation in tomatoes. Furthermore, assessments of natural variation combined with functional analyses identified SlDOG1 as a major determinant of tomato SGA content, which also promoted SA and SGA accumulation via the regulation of GAME gene expression. This study provides new insights into the regulatory mechanisms underlying SGA production in tomatoes.
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Alcaloides , Solanaceae , Solanum lycopersicum , Estudio de Asociación del Genoma Completo , Alcaloides/química , Solanaceae/genética , Glicósidos/químicaRESUMEN
Specialized plant metabolism is a rich resource of compounds for drug discovery. The acylated flavonoid glycoside melitidin is being developed as an anti-cholesterol statin drug candidate, but its biosynthetic route in plants has not yet been fully characterized. Here, we describe the gene discovery and functional characterization of a new flavonoid gene cluster (UDP-glucuronosyltransferases (CgUGTs), 1,2 rhamnosyltransferase (Cg1,2RhaT), acyltransferases (CgATs)) that is responsible for melitidin biosynthesis in pummelo (Citrus grandis (L.) Osbeck). Population variation analysis indicated that the tailoring of acyltransferases, specific for bitter substrates, mainly determine the natural abundance of melitidin. Moreover, 3-hydroxy-3-methylglutaryl-CoA reductase enzyme inhibition assays showed that the product from this metabolic gene cluster, melitidin, may be an effective anti-cholesterol statin drug candidate. Co-expression of these clustered genes in Nicotiana benthamiana resulted in the formation of melitidin, demonstrating the potential for metabolic engineering of melitidin in a heterologous plant system. This study establishes a biosynthetic pathway for melitidin, which provides genetic resources for the breeding and genetic improvement of pummelo aimed at fortifying the content of biologically active metabolites.
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Citrus , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Vías Biosintéticas/genética , Fitomejoramiento , Flavonoides/metabolismo , Citrus/genética , Aciltransferasas/metabolismoAsunto(s)
Cocos , Genoma de Planta , Cocos/clasificación , Cocos/genética , Anotación de Secuencia MolecularRESUMEN
Trichomes are storage compartments for specialized metabolites in many plant species. In trichome, plant primary metabolism is significantly changed, providing substrates for downstream secondary metabolism. However, little is known of how plants coordinate trichome formation and primary metabolism regulation. In this report, tomato (Solanum lycopersicum) trichome regulator SlMIXTA-like is indicated as a metabolic regulation gene by mGWAS analysis. Overexpression of SlMIXTA-like in tomato fruit enhances trichome formation. In addition, SlMIXTA-like can directly bind to the promoter region of gene encoding 3-deoxy-7-phosphoheptulonate synthase (SlDAHPS) to activate its expression. Induction of SlDAHPS expression enhances shikimate pathway activities and provides substrates for downstream secondary metabolism. Our data provide direct evidence that trichome regulator can directly manipulate primary metabolism, in which way plants can coordinate metabolic regulation and the formation of storage compartments for specialized metabolites. The newly identified SlMIXTA-like can be used for future metabolic engineering.
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Frutas , Regulación de la Expresión Génica de las Plantas , Solanum lycopersicum , Tricomas , Frutas/metabolismo , Regulación de la Expresión Génica de las Plantas/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Unión Proteica , Ácido Shikímico/metabolismo , Tricomas/genéticaRESUMEN
Phenolamides (PAs) are specialized (secondary) metabolites mainly synthesized by BAHD N-acyltransferases. Here, we report metabolic profiling coupled with association and linkage mapping of 11 PAs in rice (Oryza sativa). We identified 22 loci affecting PAs in leaves and 16 loci affecting PAs in seeds. We identified eight BAHD N-acyltransferases located on five chromosomes with diverse specificities, including four aromatic amine N-acyltransferases. We show that genetic variation in PAs is determined, at least in part, by allelic variation in the tissue specificity of expression of the BAHD genes responsible for their biosynthesis. Tryptamine hydroxycinnamoyl transferase 1/2 (Os-THT1/2) and tryptamine benzoyl transferase 1/2 (Os-TBT1/2) were found to be bifunctional tryptamine/tyramine N-acyltransferases. The specificity of Os-THT1 and Os-TBT1 for agmatine involved four tandem arginine residues, which have not been identified as specificity determinants for other plant BAHD transferases, illustrating the versatility of plant BAHD transferases in acquiring new acyl acceptor specificities. With phylogenetic analysis, we identified both divergent and convergent evolution of N-acyltransferases in plants, and we suggest that the BAHD family of tryptamine/tyramine N-acyltransferases evolved conservatively in monocots, especially in Gramineae. Our work demonstrates that omics-assisted gene-to-metabolite analysis provides a useful tool for bulk gene identification and crop genetic improvement.
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Aciltransferasas/metabolismo , Aminas/metabolismo , Oryza/enzimología , Oryza/metabolismo , Proteínas de Plantas/metabolismo , Aciltransferasas/genética , Regulación de la Expresión Génica de las Plantas/genética , Regulación de la Expresión Génica de las Plantas/fisiología , Oryza/genética , Filogenia , Proteínas de Plantas/clasificación , Proteínas de Plantas/genética , Plantas Modificadas Genéticamente/enzimología , Plantas Modificadas Genéticamente/genética , Plantas Modificadas Genéticamente/metabolismoRESUMEN
BACKGROUND: Flavonoids constitute a diverse class of secondary metabolites which exhibit potent bioactivities for human health and have been indicated to play an important role in plant development and defense. However, accumulation and variation of flavonoid content in diverse maize lines and the genes responsible for their biosynthesis in this important crop remain largely unknown. In this study, we combine genetic mapping, metabolite profiling and gene regulatory network analysis to further enhance understanding of the maize flavonoid pathway. RESULTS: We repeatedly detected 25 QTL corresponding to 23 distinct flavonoids across different environments or populations. In addition, a total of 39 genes were revealed both by an expression based network analysis and genetic mapping. Finally, the function of three candidate genes, including two UDP-glycosyltransferases (UGT) and an oxygenase which belongs to the flavone synthase super family, was revealed via preliminary molecular functional characterization. CONCLUSION: We explored the genetic influences on the flavonoid biosynthesis based on integrating the genomic, transcriptomic and metabolomic information which provided a rich source of potential candidate genes. The integrated genomics based genetic mapping strategy is highly efficient for defining the complexity of functional genetic variants and their respective regulatory networks as well as in helping to select candidate genes and allelic variance before embarking on laborious transgenic validations.
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Flavonoides/biosíntesis , Proteínas de Plantas/genética , Zea mays/genética , Zea mays/metabolismo , Vías Biosintéticas , Mapeo Cromosómico , Genómica , Proteínas de Plantas/metabolismo , Sitios de Carácter CuantitativoRESUMEN
Phosphorus is an essential macronutrient for plant growth and development. However, the network that affects phosphate (Pi) accumulation in crops is not well established. It is reported here that OsCSLF6, a member of the cellulose synthase-like family (CSLF), which is found only in grasses, is involved in Pi accumulation. The oscslf6 mutants (oscslf6-1 and oscslf6-2) display Pi toxic symptoms and increased Pi accumulation in both roots and shoots under the Pi-sufficient condition, which correlate with the induced expression of Pi transporters in the knockout mutants. Consistent with the over-accumulation of Pi, a significant decrease in primary root length, adventitious root length, and adventitious root number were observed in the oscslf6 mutants when compared with the wild type (WT) under Pi-sufficient conditions. In addition, the sucrose (Suc) level was increased in the oscslf6 mutants and the expression of sucrose synthases (OsSUS4/5) and sucrose transporters (OsSUT1/2/4/OsSweet14) genes were also induced in the shoots of oscslf6 mutants, suggesting that OsCSLF6 may play a role in affecting Pi accumulation by affecting the level of carbon metabolism.
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Carbono/metabolismo , Glucosiltransferasas/fisiología , Oryza/metabolismo , Fosfatos/metabolismo , Proteínas de Plantas/fisiología , Pared Celular/metabolismo , Técnicas de Inactivación de Genes , Glucosiltransferasas/genética , Glucosiltransferasas/metabolismo , Mutación , Oryza/enzimología , Oryza/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Brotes de la Planta/genética , Brotes de la Planta/metabolismoRESUMEN
The diversity of anthocyanins is largely due to the action of glycosyltransferases, which add sugar moieties to anthocyanidins. Although a number of glycosyltransferases have been identified to glycosylate anthocyanidin in plants, the enzyme that catalyzes malvidin galactosylation remains unclear. In this study, we identified three rice varieties with different leaf color patterns, different anthocyanin accumulation patterns, and different expression patterns of anthocyanin biosynthesis genes (ABGs) to explore uridine diphosphate (UDP)-glycosyltransferases (UGTs) responsible for biosynthesis of galactosylated malvidin. Based on correlation analysis of transcriptome data, nine candidate UGT genes coexpressed with 12 ABGs were identified (r values range from 0.27 to 1.00). Further analysis showed that the expression levels of one candidate gene, OsUGT88C3, were highly correlated with the contents of malvidin 3-O-galactoside, and recombinant OsUGT88C3 catalyzed production of malvidin 3-O-galactoside using UDP-galactose and malvidin as substrates. OsUGT88C3 was closely related to UGTs with flavone and flavonol glycosylation activities in phylogeny. Its plant secondary product glycosyltransferase (PSPG) motif ended with glutamine. Haplotype analysis suggested that the malvidin galactosylation function of OsUGT88C3 was conserved among most of the rice germplasms. OsUGT88C3 was highly expressed in the leaf, pistil, and embryo, and its protein was located in the endoplasmic reticulum and nucleus. Our findings indicate that OsUGT88C3 is responsible for the biosynthesis of malvidin 3-O-galactoside in rice and provide insight into the biosynthesis of anthocyanin in plants.
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Plants orchestrate drought responses at metabolic level but the genetic basis remains elusive in rice. In this study, 233 drought-responsive metabolites (DRMs) were quantified in a large rice population comprised of 510 diverse accessions at the reproductive stage. Large metabolic variations in drought responses were detected, and little correlation of metabolic levels between drought and normal conditions were observed. Interestingly, most of these DRMs could predict drought resistance in high accuracy. Genome-wide association study revealed 2522 significant association signals for 233 DRMs, and 98% (2471/2522) of the signals were co-localized with the association loci for drought-related phenotypic traits in the same population or the linkage-mapped QTLs for drought resistance in other populations. Totally, 10 candidate genes were efficiently identified for nine DRMs, seven of which harbored cis-eQTLs under drought condition. Based on comparative GWAS of common DRMs in rice and maize, representing irrigated and upland crops, we have identified three pairs of homologous genes associated with three DRMs between the two crops. Among the homologous genes, a transferase gene responsible for metabolic variation of N-feruloylputrescine was confirmed to confer enhanced drought resistance in rice. Our study provides not only genetic architecture of metabolic responses to drought stress in rice but also metabolic data resources to reveal the common and specific metabolite-mediated drought responses in different crops.
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Volatile accumulation during tomato ripening greatly affects the fruit flavor. In this study, four accessions from each of the three tomato subgroups (BIG, S. lycopersicum, CER, S. lycopersicumvar. Cerasiforme, and PIM, S. pimpinellifolium) were subjected to a sensory evaluation. The CER subgroup had the highest fruit-flavor score. Using a Headspace solid-phase microextraction/gas chromatography-mass spectrometer (HP-SPME/GC-MS), a volatile database containing 94 volatiles was created. Pentanal accumulated in green fruits and 1-pentanol in red fruits. 1-Octen-3-ol was discovered to underlie the bitterness of green tomatoes, and it was most abundant in PIM green fruits. Phenylethyl alcohol affected the acidity and sweetness of red tomatoes, and it was most abundant in CER red fruits. Branched-chain volatiles were most abundant in PIM and BIG red fruits, while apocarotenoids were most abundant in CER red fruits. These findings suggest that domestication and improvement have influenced volatile content, and apocarotenoids and branched-chain volatiles synergistically mediated aromatic flavors in red fruits. This study provides a metabolic basis for analyses of the molecular mechanisms of fruit-flavor formation.
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Among plant metabolites, phenolamides, which are conjugates of hydroxycinnamic acid derivatives and polyamines, play important roles in plant adaptation to abiotic and biotic stresses. However, the molecular mechanisms underlying phenolamide metabolism and regulation as well as the effects of domestication and breeding on phenolamide diversity in tomato remain largely unclear. In this study, we performed a metabolite-based genome-wide association study and identified two biosynthetic gene clusters (BGC7 and BGC11) containing 12 genes involved in phenolamide metabolism, including four biosynthesis genes (two 4CL genes, one C3H gene, and one CPA gene), seven decoration genes (five AT genes and two UGT genes), and one transport protein gene (DTX29). Using gene co-expression network analysis we further discovered that SlMYB13 positively regulates the expression of two gene clusters, thereby promoting phenolamide accumulation. Genetic and physiological analyses showed that BGC7, BGC11 and SlMYB13 enhance drought tolerance by enhancing scavenging of reactive oxygen species and increasing abscisic acid content in tomato. Natural variation analysis suggested that BGC7, BGC11 and SlMYB13 were negatively selected during tomato domestication and improvement, leading to reduced phenolamide content and drought tolerance of cultivated tomato. Collectively, our study discovers a key mechanism of phenolamide biosynthesis and regulation in tomato and reveals that crop domestication and improvement shapes metabolic diversity to affect plant environmental adaptation.
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Resistencia a la Sequía , Solanum lycopersicum , Solanum lycopersicum/genética , Estudio de Asociación del Genoma Completo , Domesticación , Fitomejoramiento , Estrés Fisiológico/genética , Familia de Multigenes , Sequías , Regulación de la Expresión Génica de las Plantas/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismoRESUMEN
Tomato (Solanum lycopersicum) is the most valuable fruit and horticultural crop species worldwide. Compared with the fruits of their progenitors, those of modern tomato cultivars are, however, often described as having unsatisfactory taste or lacking flavor. The flavor of a tomato fruit arises from a complex mix of tastes and volatile metabolites, including sugars, acids, amino acids, and various volatiles. However, considerable differences in fruit flavor occur among tomato varieties, resulting in mixed consumer experiences. While tomato breeding has traditionally been driven by the desire for continual increases in yield and the introduction of traits that provide a long shelf-life, consumers are prepared to pay a reasonable premium for taste. Therefore, it is necessary to characterize preferences of tomato flavor and to define its underlying genetic basis. Here, we review recent conceptual and technological advances that have rendered this more feasible, including multi-omics-based QTL and association analyses, along with the use of trained testing panels, and machine learning approaches. This review proposes how the comprehensive datasets compiled to date could allow a precise rational design of tomato germplasm resources with improved organoleptic quality for the future.
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Areca catechu L., of the Arecaceae family, is widely distributed in tropical Asia. In A. catechu, the extracts and compounds, including flavonoids, have various pharmacological activities. Although there are many studies of flavonoids, the molecular mechanism of their biosynthesis and regulation remains unclear in A. catechu. In this study, 331 metabolites were identified from the root, stem, and leaf of A. catechu using untargeted metabolomics, including 107 flavonoids, 71 lipids, 44 amino acids and derivatives, and 33 alkaloids. The transcriptome analysis identified 6119 differentially expressed genes, and some were enriched in the flavonoid pathway. To analyze the biosynthetic mechanism of the metabolic differences in A. catechu tissues, 36 genes were identified through combined transcriptomic and metabolomic analysis, in which glycosyltransferase genes Acat_15g017010 and Acat_16g013670 were annotated as being involved in the glycosylation of kaempferol and chrysin by their expression and in vitro activities. Flavonoid biosynthesis could be regulated by the transcription factors, AcMYB5 and AcMYB194. This study laid a foundation for further research on the flavonoid biosynthetic pathway of A. catechu.
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Catequina , Transcriptoma , Areca/química , Flavonoides/metabolismo , Catequina/metabolismo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica de las PlantasRESUMEN
Coconut flesh is widely consumed in the market for its good flavor. However, a comprehensive and dynamic assessment of the nutrients in coconut flesh and their molecular regulatory mechanisms is lacking. In this study, the metabolite accumulation and gene expression of three representative coconut cultivars belonging to two subspecies were investigated using ultra performance liquid chromatography/tandem mass spectrometry. A total of 6101 features were detected, of which 52, 8, and 158 were identified as amino acids and derivatives, polyamines, and lipids, respectively. The analysis of the metabolite pathway showed that glutathione and α-linolenate were the main differential metabolites. Transcriptome data revealed significant differences in the expression of five glutathione structural genes and thirteen polyamine-regulated genes, consistent with trends in metabolite accumulation. Weighted correlation network and co-expression analyses showed that a novel gene WRKY28 was implicated in the regulation of lipid synthesis. These results broaden our understanding of coconut nutrition metabolism and provide new insights into the molecular basis of coconut nutrition metabolism.
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Melatonin is a functionally conserved broad-spectrum physiological regulator found in most biological organisms in nature. Enrichment of tomato fruit with melatonin not only enhances its agronomic traits but also provides extra health benefits. In this study, we elucidate the full melatonin biosynthesis pathway in tomato fruit by identifying biosynthesis-related genes that encode caffeic acid O-methyltransferase 2 (SlCOMT2) and N-acetyl-5-hydroxytryptamine-methyltransferases 5/7 (SlASMT5/7). We further reveal that red light supplementation significantly enhances the melatonin content in tomato fruit. This induction relies on the "serotonin-N-acetylserotonin-melatonin" biosynthesis route via the SlphyB2-SlPIF4-SlCOMT2 module. Based on the regulatory mechanism, we design a gene-editing strategy to target the binding motif of SlPIF4 in the promoter of SlCOMT2, which significantly enhances the production of melatonin in tomato fruit. Our study provides a good example of how the understanding of plant metabolic pathways responding to environmental factors can guide the engineering of health-promoting foods.
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Melatonina , Solanum lycopersicum , Solanum lycopersicum/genética , Melatonina/genética , Ingeniería , Agricultura , Frutas/genéticaRESUMEN
DNA methylation is an important epigenetic marker, yet its diversity and consequences in tomato breeding at the population level are largely unknown. We performed whole-genome bisulfite sequencing (WGBS), RNA sequencing, and metabolic profiling on a population comprising wild tomatoes, landraces, and cultivars. A total of 8,375 differentially methylated regions (DMRs) were identified, with methylation levels progressively decreasing from domestication to improvement. We found that over 20% of DMRs overlapped with selective sweeps. Moreover, more than 80% of DMRs in tomato were not significantly associated with single-nucleotide polymorphisms (SNPs), and DMRs had strong linkages with adjacent SNPs. We additionally profiled 339 metabolites from 364 diverse accessions and further performed a metabolic association study based on SNPs and DMRs. We detected 971 and 711 large-effect loci via SNP and DMR markers, respectively. Combined with multi-omics, we identified 13 candidate genes and updated the polyphenol biosynthetic pathway. Our results showed that DNA methylation variants could complement SNP profiling of metabolite diversity. Our study thus provides a DNA methylome map across diverse accessions and suggests that DNA methylation variation can be the genetic basis of metabolic diversity in plants.