CYP51A1-mediated alkaliptosis resistance is a targetable vulnerability in pancreatic cancer
Ontology highlight
ABSTRACT: Alkaliptosis, a pH-dependent form of regulated cell death characterized by impaired lysosomal function and lethal alkalinization, holds promise as a target for cancer therapy. Here, we utilize mass spectrometry-based drug target, transcriptomic screens, and lipid metabolomics to explore the metabolic mechanisms underlying alkaliptosis. We reveal CYP51A1, a gene involved in cholesterol synthesis, as a key suppressor of alkaliptosis in pancreatic cancer cells. Inducing alkaliptosis leads to a decrease in endoplasmic reticulum cholesterol levels, subsequently activating SREBF2, a transcription factor responsible for controlling the expression of genes involved in cholesterol biosynthesis. Specifically, SREBF2-driven upregulation of CYP51A1 prevents cholesterol accumulation within lysosomes, leading to TMEM175-dependent lysosomal proton efflux, ultimately resulting in the inhibition of alkaliptosis. PDAC-SW1990 cell line analysis is reported in the current study MTBLS9288. PDAC-PANC1 cell line analysis is reported in MTBLS9283.
INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - positive - reverse phase
PROVIDER: MTBLS9288 | MetaboLights | 2025-02-28
REPOSITORIES: MetaboLights
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| sw1990_12h_1_N.mzML | Mzml | |||
| sw1990_12h_1_P.mzML | Mzml | |||
| sw1990_12h_2_N.mzML | Mzml | |||
| sw1990_12h_2_P.mzML | Mzml | |||
| sw1990_12h_3_N.mzML | Mzml |
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Project description:<p>Alkaliptosis, a pH-dependent form of regulated cell death characterized by impaired lysosomal function and lethal alkalinization, holds promise as a target for cancer therapy. Here, we utilize mass spectrometry-based drug target, transcriptomic screens and lipid metabolomics to explore the metabolic mechanisms underlying alkaliptosis. We reveal CYP51A1, a gene involved in cholesterol synthesis, as a key suppressor of alkaliptosis in pancreatic cancer cells. Inducing alkaliptosis leads to a decrease in endoplasmic reticulum cholesterol levels, subsequently activating SREBF2, a transcription factor responsible for controlling the expression of genes involved in cholesterol biosynthesis. Specifically, SREBF2-driven upregulation of CYP51A1 prevents cholesterol accumulation within lysosomes, leading to TMEM175-dependent lysosomal proton efflux, ultimately resulting in the inhibition of alkaliptosis. In animal models, including xenografts, orthotopic and patient-derived models, the genetic or pharmacological inhibition of CYP51A1 enhances the effectiveness of JTC801 in suppressing pancreatic tumors. These findings demonstrate the key role of the CYP51A1-dependent lysosomal pathway in inhibiting alkaliptosis and highlight its potential as a targetable vulnerability in pancreatic cancer.</p><p><br></p><p><strong>PDAC-PANC1 cell line analysis</strong> is reported in the current study <a href='https://www.ebi.ac.uk/metabolights/MTBLS9283' rel='noopener noreferrer' target='_blank'><strong>MTBLS9283</strong></a>.</p><p><strong>PDAC-SW1990 cell line analysis</strong> is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS9288' rel='noopener noreferrer' target='_blank'><strong>MTBLS9288</strong></a>.</p>
2025-02-28 | MTBLS9283 | MetaboLights
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2020-07-16 | MSV000085765 | GNPS
Project description:<p>Here we present LipidCreator, a software that fully supports targeted lipidomics assay development. LipidCreator offers a comprehensive framework to compute MS/MS fragment masses for over 60 lipid classes. LipidCreator provides all functionalities needed to define fragments, manage stable isotope labeling, optimize collision energy and generate in silico spectral libraries. We validate LipidCreator assays computationally and analytically and prove that it is capable to generate large targeted experiments to analyze blood and to dissect lipid-signaling pathways such as in human platelets.</p><p><br></p><p>In MTBLS1334, 55 lipid mediator standards were used to study the lipid fragmentation on the Agilent QTof 6545 MS platform (Agilent Technologies, Waldbronn, Germany), build optimal collision energy models and create an in-silico spectral library for use with LipidCreator. Lipid fragment masses of mediators were validated with the Metlin database (https://metlin.scripps.edu/).</p><p><br></p><p>Studies linked to this manuscript include;</p><p><a href='https://www.ebi.ac.uk/metabolights/mtbls1333' rel='noopener noreferrer' target='_blank'>MTBLS1333; LipidCreator: Collision Energy Optimization and Fragment Intensity Prediction for Lipid Mediators - Thermo QExactive HF</a></p><p><a href='https://www.ebi.ac.uk/metabolights/mtbls1334' rel='noopener noreferrer' target='_blank'>MTBLS1334; LipidCreator: Collision Energy Optimization and Fragment Intensity Prediction for Lipid Mediators - Agilent QTof</a></p><p><a href='https://www.ebi.ac.uk/metabolights/mtbls1369' rel='noopener noreferrer' target='_blank'>MTBLS1369; LipidCreator: Platelet isolation and stimulation - Targeted Phospho- and Glycerolipid Profiling</a></p><p><a href='https://www.ebi.ac.uk/metabolights/mtbls1375' rel='noopener noreferrer' target='_blank'>MTBLS1375; LipidCreator: Targeted lipidomics analysis of Human Plasma samples and comparison with NIST SRM 1950 standard</a></p><p><a href='https://www.ebi.ac.uk/metabolights/mtbls1376' rel='noopener noreferrer' target='_blank'>MTBLS1376; LipidCreator: Targeted lipidomics analysis of S. cerevisiae to determine true and false identification</a></p><p><a href='https://www.ebi.ac.uk/metabolights/mtbls1381' rel='noopener noreferrer' target='_blank'>MTBLS1381; LipidCreator: Platelet isolation and stimulation - Targeted Lipid Mediator Profiling</a></p><p><a href='https://www.ebi.ac.uk/metabolights/mtbls1382' rel='noopener noreferrer' target='_blank'>MTBLS1382; LipidCreator: Platelet isolation and stimulation - DIA Lipid Mediator Validation</a></p>
2020-07-14 | MSV000085747 | GNPS
Project description:<p>Here we present LipidCreator, a software that fully supports targeted lipidomics assay development. LipidCreator offers a comprehensive framework to compute MS/MS fragment masses for over 60 lipid classes. LipidCreator provides all functionalities needed to define fragments, manage stable isotope labeling, optimize collision energy and generate in silico spectral libraries. We validate LipidCreator assays computationally and analytically and prove that it is capable to generate large targeted experiments to analyze blood and to dissect lipid-signaling pathways such as in human platelets.</p><p><br></p><p>In MTBLS1382, to validate lipid mediator species identified with the Qtrap instrument (<a href='https://www.ebi.ac.uk/metabolights/MTBLS1381' rel='noopener noreferrer' target='_blank'>https://www.ebi.ac.uk/metabolights/MTBLS1381</a>), the Thermo QEx HF was used to perform high resolution MS full scan (HR-FS) and data independent acquisition (DIA) analyses between 200-400 m/z with a 20 m/z step size. DIA method preparation and data analysis were performed with Skyline. We used LipidCreator as an external tool in Skyline to generate a collision-energy specific transition list for the mediators 12-HETE, 13-HODE, 15-HETE, arachidonic acid (AA),<strong> </strong>docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) and thromboxane B2 (TXB2) and their deuterated counterparts 12-HETE-d8, 13-HODE-d4, 15-HETE-d8, AA-d8, DHA-d5, EPA-d5 and TXB2-d4, at a normalized collision energy NCE=21. We also used LipidCreator's relative fragment intensity prediction model to generate a custom spectral library for the light and heavy mediators. We transfered both the transition list and the spectral library directly from LipidCreator to Skyline and exported the dot product values after manual fragment peaks review.</p><p><br></p><p>Studies linked to this manuscript include;</p><p><a href='https://www.ebi.ac.uk/metabolights/MTBLS1333' rel='noopener noreferrer' target='_blank'>MTBLS1333; LipidCreator: Collision Energy Optimization and Fragment Intensity Prediction for Lipid Mediators - Thermo QExactive HF</a></p><p><a href='https://www.ebi.ac.uk/metabolights/MTBLS1334' rel='noopener noreferrer' target='_blank'>MTBLS1334; LipidCreator: Collision Energy Optimization and Fragment Intensity Prediction for Lipid Mediators - Agilent QTof</a></p><p><a href='https://www.ebi.ac.uk/metabolights/MTBLS1369' rel='noopener noreferrer' target='_blank'>MTBLS1369; LipidCreator: Platelet isolation and stimulation - Targeted Phospho- and Glycerolipid Profiling</a></p><p><a href='https://www.ebi.ac.uk/metabolights/MTBLS1375' rel='noopener noreferrer' target='_blank'>MTBLS1375; LipidCreator: Targeted lipidomics analysis of Human Plasma samples and comparison with NIST SRM 1950 standard</a></p><p><a href='https://www.ebi.ac.uk/metabolights/MTBLS1376' rel='noopener noreferrer' target='_blank'>MTBLS1376; LipidCreator: Targeted lipidomics analysis of S. cerevisiae to determine true and false identification</a></p><p><a href='https://www.ebi.ac.uk/metabolights/MTBLS1381' rel='noopener noreferrer' target='_blank'>MTBLS1381; LipidCreator: Platelet isolation and stimulation - Targeted Lipid Mediator Profiling</a></p><p><a href='https://www.ebi.ac.uk/metabolights/MTBLS1382' rel='noopener noreferrer' target='_blank'>MTBLS1382; LipidCreator: Platelet isolation and stimulation - DIA Lipid Mediator Validation</a></p>
2020-06-26 | MSV000085632 | GNPS
Project description:<p>Here we present LipidCreator, a software that fully supports targeted lipidomics assay development. LipidCreator offers a comprehensive framework to compute MS/MS fragment masses for over 60 lipid classes. LipidCreator provides all functionalities needed to define fragments, manage stable isotope labeling, optimize collision energy and generate in silico spectral libraries. We validate LipidCreator assays computationally and analytically and prove that it is capable to generate large targeted experiments to analyze blood and to dissect lipid-signaling pathways such as in human platelets.</p><p><br></p><p>In MTBLS1381, to validate the performance and accuracy of the transition lists provided by LipidCreator and their applicabability on other MS platforms, we used the transition lists for targeted profiling of lipid mediators in human platelet material. Platelets were stimulated with 0.01 U/ml thrombin, 1 U/ml thrombin, 1 µg/ml CRP or 5 µg/ml CRP for 5 min. The MS profiling of unstimulated and stimulated platelet material (pellet and supernatant) was performed after HPLC separation on an AB Sciex QTrap 6500 (Applied Biosystems, Darmstadt, Germany) in negative mode. Samples were measured in triplicates, interspersed with blank and standard runs.</p><p><br></p><p>Studies linked to this manuscript include;</p><p><a href='https://www.ebi.ac.uk/metabolights/MTBLS1333' rel='noopener noreferrer' target='_blank'>MTBLS1333; LipidCreator: Collision Energy Optimization and Fragment Intensity Prediction for Lipid Mediators - Thermo QExactive HF</a></p><p><a href='https://www.ebi.ac.uk/metabolights/MTBLS1334' rel='noopener noreferrer' target='_blank'>MTBLS1334; LipidCreator: Collision Energy Optimization and Fragment Intensity Prediction for Lipid Mediators - Agilent QTof</a></p><p><a href='https://www.ebi.ac.uk/metabolights/MTBLS1369' rel='noopener noreferrer' target='_blank'>MTBLS1369; LipidCreator: Platelet isolation and stimulation - Targeted Phospho- and Glycerolipid Profiling</a></p><p><a href='https://www.ebi.ac.uk/metabolights/MTBLS1375' rel='noopener noreferrer' target='_blank'>MTBLS1375; LipidCreator: Targeted lipidomics analysis of Human Plasma samples and comparison with NIST SRM 1950 standard</a></p><p><a href='https://www.ebi.ac.uk/metabolights/MTBLS1376' rel='noopener noreferrer' target='_blank'>MTBLS1376; LipidCreator: Targeted lipidomics analysis of S. cerevisiae to determine true and false identification</a></p><p><a href='https://www.ebi.ac.uk/metabolights/MTBLS1381' rel='noopener noreferrer' target='_blank'>MTBLS1381; LipidCreator: Platelet isolation and stimulation - Targeted Lipid Mediator Profiling</a></p><p><a href='https://www.ebi.ac.uk/metabolights/MTBLS1382' rel='noopener noreferrer' target='_blank'>MTBLS1382; LipidCreator: Platelet isolation and stimulation - DIA Lipid Mediator Validation</a></p>
2020-07-14 | MSV000085743 | GNPS
Project description:<p>Here we present LipidCreator, a software that fully supports targeted lipidomics assay development. LipidCreator offers a comprehensive framework to compute MS/MS fragment masses for over 60 lipid classes. LipidCreator provides all functionalities needed to define fragments, manage stable isotope labeling, optimize collision energy and generate in silico spectral libraries. We validate LipidCreator assays computationally and analytically and prove that it is capable to generate large targeted experiments to analyze blood and to dissect lipid-signaling pathways such as in human platelets.</p><p><br></p><p>In MTBLS1376, to validate the performance and accuracy of the transition lists provided by LipidCreator, we validated our theoretical calculations and the transition lists computed by LipidCreator experimentally, monitoring true and false targets on the model organism Saccharomyces <em>cerevisiae</em>. The lipidome of the yeast S. <em>cerevisiae</em> is well described and has been thoroughly investigated before. It has a limited number of fatty acyls and double bonds, and certain fatty acyls and lipid classes do not occur in it, which is important for our consecutive false identification calculations. Therefore, the yeast matrix from the theoretical calculation, 21 target lipids and 21 decoy lipids from commercially available lipid standards that are known to not be present in the yeast lipidome were selected. Based on our previous results, none of the lipid species was redundant among all three sets.</p><p><br></p><p>Studies linked to this manuscript include;</p><p><a href='https://www.ebi.ac.uk/metabolights/MTBLS1333' rel='noopener noreferrer' target='_blank'>MTBLS1333; LipidCreator: Collision Energy Optimization and Fragment Intensity Prediction for Lipid Mediators - Thermo QExactive HF</a></p><p><a href='https://www.ebi.ac.uk/metabolights/MTBLS1334' rel='noopener noreferrer' target='_blank'>MTBLS1334; LipidCreator: Collision Energy Optimization and Fragment Intensity Prediction for Lipid Mediators - Agilent QTof</a></p><p><a href='https://www.ebi.ac.uk/metabolights/MTBLS1369' rel='noopener noreferrer' target='_blank'>MTBLS1369; LipidCreator: Platelet isolation and stimulation - Targeted Phospho- and Glycerolipid Profiling</a></p><p><a href='https://www.ebi.ac.uk/metabolights/MTBLS1375' rel='noopener noreferrer' target='_blank'>MTBLS1375; LipidCreator: Targeted lipidomics analysis of Human Plasma samples and comparison with NIST SRM 1950 standard</a></p><p><a href='https://www.ebi.ac.uk/metabolights/MTBLS1376' rel='noopener noreferrer' target='_blank'>MTBLS1376; LipidCreator: Targeted lipidomics analysis of S. cerevisiae to determine true and false identification</a></p><p><a href='https://www.ebi.ac.uk/metabolights/MTBLS1381' rel='noopener noreferrer' target='_blank'>MTBLS1381; LipidCreator: Platelet isolation and stimulation - Targeted Lipid Mediator Profiling</a></p><p><a href='https://www.ebi.ac.uk/metabolights/MTBLS1382' rel='noopener noreferrer' target='_blank'>MTBLS1382; LipidCreator: Platelet isolation and stimulation - DIA Lipid Mediator Validation</a></p>
2020-07-31 | MSV000085865 | GNPS
Project description:<p><strong>Background:</strong> Cell line specific, genome-scale metabolic models enable rigorous and systematic in silico investigation of cellular metabolism. Such models have recently become available for Chinese hamster ovary (CHO) too. However, a key ingredient, namely an experimentally validated biomass function that summarizes the cellular composition, was so far missing in all genome-scale metabolic models of CHO cell lines. Here, we close this gap by providing extensive experimental data on the biomass composition of 13 parental and producer CHO cell lines under various conditions.</p><p><strong>Results:</strong> We report protein, lipid, DNA, RNA and carbohydrate content, cell dry mass, and protein and lipid composition. Furthermore, we present meticulous data on exchange rates between cells and environment and provide detailed experimental protocols on how to determine all of the above. The biomass composition is converted into cell line and condition specific biomass functions for usage in cell line specific, genome-scale metabolic models of CHO. Finally, flux-balance analysis (FBA) is used to demonstrate consistency between in silico predictions and experimental analysis.</p><p><strong>Conclusions:</strong> Our study reveals a strong variability of the total protein content and cell dry mass across cell lines. Yet, the relative amino acid composition is independent of the cell lines and conditions and thus needs not be explicitly measured for each new cell line. In contrast, the lipid composition is strongly influenced by the growth media and needs to be determined for each case. These cell line specific variations in the biomass composition have a small impact on growth rate predictions with FBA, as inaccuracies in the predictions are typically dominated by inaccuracies in the exchange rate spectra. Cell specific biomass variations become only important if the experimental errors in the exchange rate spectra drop below twenty percent.</p><p><br></p><p><strong>Links:</strong></p><p>All data and code for data processing are available at <a href='http://dx.doi.org/10.17632/g3wz7spyc9.1' rel='noopener noreferrer' target='_blank'>Data Mendeley</a>.</p><p>Cell line specific metabolic models were deposited in <a href='https://www.ebi.ac.uk/biomodels/(Chelliah et al, 2014)' rel='noopener noreferrer' target='_blank'>BioModels</a>, identifiers are listed in the study sample table.</p>
2020-07-13 | MTBLS1210 | MetaboLights
Project description:<h4><strong>Summary</strong></h4><p>Primary cilia are key sensory organelles whose dysfunction leads to ciliopathy disorders such as Bardet-Biedl syndrome (BBS). Retinal degeneration is common in ciliopathies, since the outer segments (OSs) of photoreceptors are highly specialized primary cilia. BBS1, encoded by the most commonly mutated BBS-associated gene, is part of the BBSome protein complex. Using a new bbs1 zebrafish mutant, we show that retinal development and photoreceptor differentiation are unaffected by Bbs1-loss, supported by an initially unaffected transcriptome. Quantitative proteomics and lipidomics on isolated OSs show that Bbs1 is required for BBSome-entry into OSs and that Bbs1-loss leads to accumulation of membrane-associated proteins in OSs, with enrichment in proteins involved in lipid homeostasis. Disruption of the tightly regulated OS lipid composition with increased OS cholesterol content are paralleled by early functional visual deficits, which precede progressive OS morphological anomalies. Our findings identify a new role for Bbs1/BBSome in OS lipid homeostasis and suggest a new pathomechanism underlying retinal degeneration in BBS.</p><p><br></p><p><strong>Data availability</strong>:</p><p>The <strong>proteomic </strong>data generated in this study have been deposited in <strong>PRIDE </strong>repository under accession code <a href='https://www.ebi.ac.uk/pride/archive/projects/PXD026646' rel='noopener noreferrer' target='_blank'><strong>PXD026646</strong></a><strong> </strong>for the <strong>OS proteome</strong> and <a href='https://www.ebi.ac.uk/pride/archive/projects/PXD030522' rel='noopener noreferrer' target='_blank'><strong>PXD030522</strong></a><strong> </strong>for the <strong>whole eye lysate proteome </strong>[<a href='https://www.ebi.ac.uk/pride' rel='noopener noreferrer' target='_blank'>https://www.ebi.ac.uk/pride</a>].</p><p>The <strong>RNAseq </strong>data generated in this study have been deposited in the <strong>SRA </strong>repository under the BioProject accession number <strong>PRJNA789116</strong> [<a href='https://www.ncbi.nlm.nih.gov/sra/?term=PRJNA789116' rel='noopener noreferrer' target='_blank'>https://www.ncbi.nlm.nih.gov/sra/?term=PRJNA789116</a>].</p>
2022-02-18 | MTBLS4013 | MetaboLights
Project description:<p>The biogeography of tropical Andean plants and the effects of altitudinal barriers as evolutionary constraints have been the focus of great debate. Although genetic markers have provided evidence for the geographic isolation of Andean-endemic groups, even highly variable molecular markers commonly used to assess biogeography do not have the resolving power needed for a fine geographic discrimination in some Andean taxa. We present a metabolomics approach based on ultrahigh-performance liquid chromatography-mass spectrometry combined with multivariate statistical methods and machine learning algorithms of multiple species and populations of Espeletiinae (Asteraceae) to provide metabolomic evidence for biogeographic segregation in this Andean-endemic subtribe. Our approach allows the discrimination of Espeletiinae taxa at different geographic scales with characteristic metabolic fingerprints related to their country of origin on a global scale, to their páramo massifs on a regional scale and to their páramo complexes on a local scale, revealing inter- and intraspecific metabolic variations. Our results, together with previous studies, suggest that Andean geography and Pleistocene glacial cycles not only shaped the evolutionary history of Espeletiinae but also its metabolic fingerprints, demonstrating the potential of metabolomics for understanding biogeographic patterns in recently diversified plant groups where genetic divergence is still at an early stage.</p><p><br></p><p><strong>Interspecific chemical variability assay</strong> protocols and data are reported in the current study <a href='https://www.ebi.ac.uk/metabolights/MTBLS944' rel='noopener noreferrer' target='_blank'><strong>MTBLS944</strong></a>.</p><p><strong>Intraspecific chemical variability assay</strong> protocols and data are reported in study <a href='https://www.ebi.ac.uk/metabolights/MTBLS943' rel='noopener noreferrer' target='_blank'><strong>MTBLS943</strong></a>.</p>
2020-08-01 | MSV000085886 | GNPS
Project description:<p>The biogeography of tropical Andean plants and the effects of altitudinal barriers as evolutionary constraints have been the focus of great debate. Although genetic markers have provided evidence for the geographic isolation of Andean-endemic groups, even highly variable molecular markers commonly used to assess biogeography do not have the resolving power needed for a fine geographic discrimination in some Andean taxa. We present a metabolomics approach based on ultrahigh-performance liquid chromatography-mass spectrometry combined with multivariate statistical methods and machine learning algorithms of multiple species and populations of Espeletiinae (Asteraceae) to provide metabolomic evidence for biogeographic segregation in this Andean-endemic subtribe. Our approach allows the discrimination of Espeletiinae taxa at different geographic scales with characteristic metabolic fingerprints related to their country of origin on a global scale, to their páramo massifs on a regional scale and to their páramo complexes on a local scale, revealing inter- and intraspecific metabolic variations. Our results, together with previous studies, suggest that Andean geography and Pleistocene glacial cycles not only shaped the evolutionary history of Espeletiinae but also its metabolic fingerprints, demonstrating the potential of metabolomics for understanding biogeographic patterns in recently diversified plant groups where genetic divergence is still at an early stage.</p><p><br></p><p><strong>Intraspecific chemical variability assay</strong> protocols and data are reported in the current study <a href='https://www.ebi.ac.uk/metabolights/MTBLS943' rel='noopener noreferrer' target='_blank'><strong>MTBLS943</strong></a>.</p><p>I<strong>nterspecific chemical variability assay</strong> protocols and data are reported in study <a href='https://www.ebi.ac.uk/metabolights/MTBLS944' rel='noopener noreferrer' target='_blank'><strong>MTBLS944</strong></a>.</p>
2020-08-01 | MSV000085869 | GNPS