Dataset Information

Determination of Abundant Metabolite Matrix Adducts Illuminates the Dark Metabolome of MALDI-Mass Spectrometry Imaging Datasets

ABSTRACT: Spatial metabolomics using mass spectrometry imaging (MSI) is a powerful tool to map hundreds to thousands of metabolites in biological systems. One major challenge in MSI is the annotation of m/z values, which is substantially complicated by background ions introduced throughout the chemicals and equipment used during experimental procedures. Among many factors, the formation of adducts with sodium or potassium ions, or in case of matrix-assisted laser desorption ionization (MALDI)-MSI, the presence of abundant matrix clusters strongly increases total m/z peak counts. Currently, there is a limitation to identify the chemistry of the many unknown peaks to interpret their biological function. We took advantage of the co-localization of adducts with their parent ions and the accuracy of high mass resolution to estimate adduct abundance in 20 datasets from different vendors of mass spectrometers. Metabolites ranging from lipids to amines and amino acids form matrix adducts with the commonly used 2,5-dihydroxybenzoic acid (DHB) matrix like [M + (DHB-H₂O) + H]⁺ and [M + DHB + Na]⁺. Current data analyses neglect those matrix adducts and overestimate total metabolite numbers, thereby expanding the number of unidentified peaks. Our study demonstrates that MALDI-MSI data are strongly influenced by adduct formation across different sample types and vendor platforms and reveals a major influence of so far unrecognized metabolite-matrix adducts on total peak counts (up to one third). We developed a software package, mass2adduct, for the community for an automated putative assignment and quantification of metabolite-matrix adducts enabling users to ultimately focus on the biologically relevant portion of the MSI data.

INSTRUMENT(S): MS Imaging -

SUBMITTER: Manuel Liebeke

PROVIDER: MTBLS954 | MetaboLights | 2021-06-15

REPOSITORIES: MetaboLights

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Determination of Abundant Metabolite Matrix Adducts Illuminates the Dark Metabolome of MALDI-Mass Spectrometry Imaging Datasets.

Janda Moritz M Seah Brandon K B BKB Jakob Dennis D Beckmann Janine J Geier Benedikt B Liebeke Manuel M

Analytical chemistry 20210607 24

Spatial metabolomics using mass spectrometry imaging (MSI) is a powerful tool to map hundreds to thousands of metabolites in biological systems. One major challenge in MSI is the annotation of <i>m</i>/<i>z</i> values, which is substantially complicated by background ions introduced throughout the chemicals and equipment used during experimental procedures. Among many factors, the formation of adducts with sodium or potassium ions, or in case of matrix-assisted laser desorption ionization (MALDI ...[more]

PMID: 34097397

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Project description:Changes in chromatin organization are associated with resistance to anti-cancer drugs, such as platinum-based chemotherapy used as the primary treatment of ovarian cancer. We have examined the genomic distribution of chromatin accessibility changes, and relationship to gene expression changes, occurring during acquisition of resistance in vivo of high grade serous ovarian cancer (HGSOC) patients and whether this associates with genomic DNA damage distribution. Using matched chemo-sensitive and chemo-resistant ovarian cell lines isolated from HGSOC patients before and following acquisition of clinical resistance to platinum-based chemotherapy, we have examined the relationship between chromatin accessibility by ATAC-seq, platinum-DNA adduct distribution by Pt-Exo-seq and gene expression by RNA-seq. We have correlated chromatin changes between the lines at gene promoters, CpG islands, enhancer sequences and other genomic regions with changes in gene expression and platinum-DNA adduct distribution. We observe chromatin conformation differences following acquisition of platinum-resistance, with the HGSOC resistant lines clustering together, separately from their respective sensitive counterparts. Resistant lines show altered chromatin accessibility at intergenic regions, but less so at gene promoters. Super-enhancers, as defined by clusters of cis-regulatory elements, at these intergenic regions show chromatin changes that are associated with altered expression of linked genes, with enrichment for genes involved in the Fanconi anemia/BRCA DNA damage response pathway. Genome-wide distribution of platinum adducts associates with the chromatin changes and distinguish sensitive from resistant lines. Regions incurring fewer platinum-adducts showed a significant reduction in accessibility the resistant HGSOC cell line PEO4 compared to the sensitive PEO1 counterpart. Surprisingly, regions showing increased damage in PEO4 had an even greater reduction in accessibility. In the resistant line, we observe fewer adducts around gene promoters and more adducts at intergenic regions. In cell lines derived from patients following acquisition of clinical resistance to platinum-based chemotherapy, chromatin changes at super-enhancers correlate with gene expression changes in DNA repair pathways known to influence platinum sensitivity. Although cisplatin is a relatively non-specific DNA damaging agent, there are consistent differences in distribution of adducts between the matched sensitive and resistant ovarian cell lines, which is independent of the overall level of adducts formed.

Dataset Information

Determination of Abundant Metabolite Matrix Adducts Illuminates the Dark Metabolome of MALDI-Mass Spectrometry Imaging Datasets

Publications

Determination of Abundant Metabolite Matrix Adducts Illuminates the Dark Metabolome of MALDI-Mass Spectrometry Imaging Datasets.

Similar Datasets

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