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Integrative Multi-Omics in Biomedical Research

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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Cellular Biochemistry".

Deadline for manuscript submissions: closed (15 May 2021) | Viewed by 43288

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Special Issue Editors

Prof. Christopher Gerner

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Guest Editor

Department of Analytical Chemistry, University of Vienna, 1090 Vienna, Austria
Interests: clinical proteomics; lipidomics; metabolomics; chronic inflammation; cancer research; mechanisms of drug action; drug resistance

Dr. Michelle Hill

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Guest Editor

Faculty of Medicine, The University of Queensland, Herston, Brisbane, QLD 4102, Australia
Interests: membrane lipids; cell biology; subcellular omics; integrative biology; clinical proteomics; clinical lipidomics; liquid biopsy; extracellular vesicles; clinical diagnostics

Special Issue Information

Dear Colleagues,

Postgenomic methods, typically based on mass spectrometry, comprise the analysis of metabolites, lipids, and proteins and are an essential complement to genomics and transcriptomics. Multidimensional omics is becoming established to provide accurate and comprehensive state descriptions and to support the understanding of molecular mechanisms in complex systems. In this Special Issue, we invite you to share laboratory and computational method innovations that enable the concurrent and integrative analysis of multiple omics data sets. We would also like to showcase novel findings as a result of application of multi-omics to address questions in biology and pathology. Both original research and review papers are welcome.

We look forward to reading your contributions to this rapidly advancing interdisciplinary field.

Assoc. Prof. Michelle Hill
Prof. Christopher Gerner
Guest Editors

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Keywords

mass spectrometry
bioinformatics
integrative biology
systems biology
biomarker discovery

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Published Papers (10 papers)

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Editorial

Jump to: Research, Review

2 pages, 153 KiB

Open AccessEditorial

Integrative Multi-Omics in Biomedical Research

by Michelle M. Hill and Christopher Gerner

Biomolecules 2021, 11(10), 1527; https://doi.org/10.3390/biom11101527 - 16 Oct 2021

Cited by 1 | Viewed by 1787

Abstract

Genome technologies have revolutionized biomedicine, but the complexity of biological systems cannot be explained by genomics alone [...] Full article

(This article belongs to the Special Issue Integrative Multi-Omics in Biomedical Research)

Research

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15 pages, 2716 KiB

Open AccessArticle

Epithelial Cell Line Derived from Endometriotic Lesion Mimics Macrophage Nervous Mechanism of Pain Generation on Proteome and Metabolome Levels

by Benjamin Neuditschko, Marlene Leibetseder, Julia Brunmair, Gerhard Hagn, Lukas Skos, Marlene C. Gerner, Samuel M. Meier-Menches, Iveta Yotova and Christopher Gerner

Biomolecules 2021, 11(8), 1230; https://doi.org/10.3390/biom11081230 - 17 Aug 2021

Cited by 5 | Viewed by 4708

Abstract

Endometriosis is a benign disease affecting one in ten women of reproductive age worldwide. Although the pain level is not correlated to the extent of the disease, it is still one of the cardinal symptoms strongly affecting the patients’ quality of life. Yet, a molecular mechanism of this pathology, including the formation of pain, remains to be defined. Recent studies have indicated a close interaction between newly generated nerve cells and macrophages, leading to neurogenic inflammation in the pelvic area. In this context, the responsiveness of an endometriotic cell culture model was characterized upon inflammatory stimulation by employing a multi-omics approach, including proteomics, metabolomics and eicosanoid analysis. Differential proteomic profiling of the 12-Z endometriotic cell line treated with TNFα and IL1β unexpectedly showed that the inflammatory stimulation was able to induce a protein signature associated with neuroangiogenesis, specifically including neuropilins (NRP1/2). Untargeted metabolomic profiling in the same setup further revealed that the endometriotic cells were capable of the autonomous production of 7,8-dihydrobiopterin (BH2), 7,8-dihydroneopterin, normetanephrine and epinephrine. These metabolites are related to the development of neuropathic pain and the former three were found up-regulated upon inflammatory stimulation. Additionally, 12-Z cells were found to secrete the mono-oxygenated oxylipin 16-HETE, a known inhibitor of neutrophil aggregation and adhesion. Thus, inflammatory stimulation of endometriotic 12-Z cells led to specific protein and metabolite expression changes suggesting a direct involvement of these epithelial-like cells in endometriosis pain development. Full article

(This article belongs to the Special Issue Integrative Multi-Omics in Biomedical Research)

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23 pages, 4808 KiB

Open AccessArticle

Omics Technologies to Decipher Regulatory Networks in Granulocytic Cell Differentiation

by Svetlana Novikova, Olga Tikhonova, Leonid Kurbatov, Tatiana Farafonova, Igor Vakhrushev, Alexey Lupatov, Konstantin Yarygin and Victor Zgoda

Biomolecules 2021, 11(6), 907; https://doi.org/10.3390/biom11060907 - 18 Jun 2021

Cited by 9 | Viewed by 2944

Abstract

Induced granulocytic differentiation of human leukemic cells under all-trans-retinoid acid (ATRA) treatment underlies differentiation therapy of acute myeloid leukemia. Knowing the regulation of this process it is possible to identify potential targets for antileukemic drugs and develop novel approaches to differentiation therapy. In this study, we have performed transcriptomic and proteomic profiling to reveal up- and down-regulated transcripts and proteins during time-course experiments. Using data on differentially expressed transcripts and proteins we have applied upstream regulator search and obtained transcriptome- and proteome-based regulatory networks of induced granulocytic differentiation that cover both up-regulated (HIC1, NFKBIA, and CASP9) and down-regulated (PARP1, VDR, and RXRA) elements. To verify the designed network we measured HIC1 and PARP1 protein abundance during granulocytic differentiation by selected reaction monitoring (SRM) using stable isotopically labeled peptide standards. We also revealed that transcription factor CEBPB and LYN kinase were involved in differentiation onset, and evaluated their protein levels by SRM technique. Obtained results indicate that the omics data reflect involvement of the DNA repair system and the MAPK kinase cascade as well as show the balance between the processes of the cell survival and apoptosis in a p53-independent manner. The differentially expressed transcripts and proteins, predicted transcriptional factors, and key molecules such as HIC1, CEBPB, LYN, and PARP1 may be considered as potential targets for differentiation therapy of acute myeloid leukemia. Full article

(This article belongs to the Special Issue Integrative Multi-Omics in Biomedical Research)

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19 pages, 5042 KiB

Open AccessArticle

LPS Tolerance Inhibits Cellular Respiration and Induces Global Changes in the Macrophage Secretome

by Joseph Gillen, Thunnicha Ondee, Devikala Gurusamy, Jiraphorn Issara-Amphorn, Nathan P. Manes, Sung Hwan Yoon, Asada Leelahavanichkul and Aleksandra Nita-Lazar

Biomolecules 2021, 11(2), 164; https://doi.org/10.3390/biom11020164 - 27 Jan 2021

Cited by 32 | Viewed by 4405

Abstract

Inflammatory response plays an essential role in the resolution of infections. However, inflammation can be detrimental to an organism and cause irreparable damage. For example, during sepsis, a cytokine storm can lead to multiple organ failures and often results in death. One of the strongest triggers of the inflammatory response is bacterial lipopolysaccharides (LPS), acting mostly through Toll-like receptor 4 (TLR4). Paradoxically, while exposure to LPS triggers a robust inflammatory response, repeated or prolonged exposure to LPS can induce a state of endotoxin tolerance, a phenomenon where macrophages and monocytes do not respond to new endotoxin challenges, and it is often associated with secondary infections and negative outcomes. The cellular mechanisms regulating this phenomenon remain elusive. We used metabolic measurements to confirm differences in the cellular metabolism of naïve macrophages and that of macrophages responding to LPS stimulation or those in the LPS-tolerant state. In parallel, we performed an unbiased secretome survey using quantitative mass spectrometry during the induction of LPS tolerance, creating the first comprehensive secretome profile of endotoxin-tolerant cells. The secretome changes confirmed that LPS-tolerant macrophages have significantly decreased cellular metabolism and that the proteins secreted by LPS-tolerant macrophages have a strong association with cell survival, protein metabolism, and the metabolism of reactive oxygen species. Full article

(This article belongs to the Special Issue Integrative Multi-Omics in Biomedical Research)

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13 pages, 2611 KiB

Open AccessArticle

Eicosanoid Content in Fetal Calf Serum Accounts for Reproducibility Challenges in Cell Culture

by Laura Niederstaetter, Benjamin Neuditschko, Julia Brunmair, Lukas Janker, Andrea Bileck, Giorgia Del Favero and Christopher Gerner

Biomolecules 2021, 11(1), 113; https://doi.org/10.3390/biom11010113 - 15 Jan 2021

Cited by 13 | Viewed by 3812

Abstract

Reproducibility issues regarding in vitro cell culture experiments are related to genetic fluctuations and batch-wise variations of biological materials such as fetal calf serum (FCS). Genome sequencing may control the former, while the latter may remain unrecognized. Using a U937 macrophage model for cell differentiation and inflammation, we investigated whether the formation of effector molecules was dependent on the FCS batch used for cultivation. High resolution mass spectrometry (HRMS) was used to identify FCS constituents and to explore their effects on cultured cells evaluating secreted cytokines, eicosanoids, and other inflammatory mediators. Remarkably, the FCS eicosanoid composition showed more batch-dependent variations than the protein composition. Efficient uptake of fatty acids from the medium by U937 macrophages and inflammation-induced release thereof was evidenced using C13-labelled arachidonic acid, highlighting rapid lipid metabolism. For functional testing, FCS batch-dependent nanomolar concentration differences of two selected eicosanoids, 5-HETE and 15-HETE, were balanced out by spiking. Culturing U937 cells at these defined conditions indeed resulted in significant proteome alterations indicating HETE-induced PPARγ activation, independently corroborated by HETE-induced formation of peroxisomes observed by high-resolution microscopy. In conclusion, the present data demonstrate that FCS-contained eicosanoids, subject to substantial batch-wise variation, may modulate cellular effector functions in cell culture experiments. Full article

(This article belongs to the Special Issue Integrative Multi-Omics in Biomedical Research)

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16 pages, 3032 KiB

Open AccessArticle

From Prevention to Disease Perturbations: A Multi-Omic Assessment of Exercise and Myocardial Infarctions

by Melanie T. Odenkirk, Kelly G. Stratton, Lisa M. Bramer, Bobbie-Jo M. Webb-Robertson, Kent J. Bloodsworth, Matthew E. Monroe, Kristin E. Burnum-Johnson and Erin S. Baker

Biomolecules 2021, 11(1), 40; https://doi.org/10.3390/biom11010040 - 30 Dec 2020

Cited by 7 | Viewed by 4949

Abstract

While a molecular assessment of the perturbations and injury arising from diseases is essential in their diagnosis and treatment, understanding changes due to preventative strategies is also imperative. Currently, complex diseases such as cardiovascular disease (CVD), the leading cause of death worldwide, suffer from a limited understanding of how the molecular mechanisms taking place following preventive measures (e.g., exercise) differ from changes occurring due to the injuries caused from the disease (e.g., myocardial infarction (MI)). Therefore, this manuscript assesses lipidomic changes before and one hour after exercise treadmill testing (ETT) and before and one hour after a planned myocardial infarction (PMI) in two separate patient cohorts. Strikingly, unique lipidomic perturbations were observed for these events, as could be expected from their vastly different stresses on the body. The lipidomic results were then combined with previously published metabolomic characterizations of the same patients. This integration provides complementary insights into the exercise and PMI events, thereby giving a more holistic understanding of the molecular changes associated with each. Full article

(This article belongs to the Special Issue Integrative Multi-Omics in Biomedical Research)

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17 pages, 2276 KiB

Open AccessFeature PaperArticle

Chronic High-Fat Diet Induces Early Barrett’s Esophagus in Mice through Lipidome Remodeling

by Jeffrey Molendijk, Thi-My-Tam Nguyen, Ian Brown, Ahmed Mohamed, Yenkai Lim, Johanna Barclay, Mark P. Hodson, Thomas P. Hennessy, Lutz Krause, Mark Morrison and Michelle M. Hill

Biomolecules 2020, 10(5), 776; https://doi.org/10.3390/biom10050776 - 16 May 2020

Cited by 10 | Viewed by 4044

Abstract

Esophageal adenocarcinoma (EAC) incidence has been rapidly increasing, potentially associated with the prevalence of the risk factors gastroesophageal reflux disease (GERD), obesity, high-fat diet (HFD), and the precursor condition Barrett’s esophagus (BE). EAC development occurs over several years, with stepwise changes of the squamous esophageal epithelium, through cardiac metaplasia, to BE, and then EAC. To establish the roles of GERD and HFD in initiating BE, we developed a dietary intervention model in C57/BL6 mice using experimental HFD and GERD (0.2% deoxycholic acid, DCA, in drinking water), and then analyzed the gastroesophageal junction tissue lipidome and microbiome to reveal potential mechanisms. Chronic (9 months) HFD alone induced esophageal inflammation and metaplasia, the first steps in BE/EAC pathogenesis. While 0.2% deoxycholic acid (DCA) alone had no effect on esophageal morphology, it synergized with HFD to increase inflammation severity and metaplasia length, potentially via increased microbiome diversity. Furthermore, we identify a tissue lipid signature for inflammation and metaplasia, which is characterized by elevated very-long-chain ceramides and reduced lysophospholipids. In summary, we report a non-transgenic mouse model, and a tissue lipid signature for early BE. Validation of the lipid signature in human patient cohorts could pave the way for specific dietary strategies to reduce the risk of BE in high-risk individuals. Full article

(This article belongs to the Special Issue Integrative Multi-Omics in Biomedical Research)

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18 pages, 3528 KiB

Open AccessArticle

Identification and Validation of VEGFR2 Kinase as a Target of Voacangine by a Systematic Combination of DARTS and MSI

by Yonghyo Kim, Yutaka Sugihara, Tae Young Kim, Sung Min Cho, Jin Young Kim, Ju Yeon Lee, Jong Shin Yoo, Doona Song, Gyoonhee Han, Melinda Rezeli, Charlotte Welinder, Roger Appelqvist, György Marko-Varga and Ho Jeong Kwon

Biomolecules 2020, 10(4), 508; https://doi.org/10.3390/biom10040508 - 27 Mar 2020

Cited by 14 | Viewed by 5091

Abstract

Although natural products are an important source of drugs and drug leads, identification and validation of their target proteins have proven difficult. Here, we report the development of a systematic strategy for target identification and validation employing drug affinity responsive target stability (DARTS) and mass spectrometry imaging (MSI) without modifying or labeling natural compounds. Through a validation step using curcumin, which targets aminopeptidase N (APN), we successfully standardized the systematic strategy. Using label-free voacangine, an antiangiogenic alkaloid molecule as the model natural compound, DARTS analysis revealed vascular endothelial growth factor receptor 2 (VEGFR2) as a target protein. Voacangine inhibits VEGFR2 kinase activity and its downstream signaling by binding to the kinase domain of VEGFR2, as was revealed by docking simulation. Through cell culture assays, voacangine was found to inhibit the growth of glioblastoma cells expressing high levels of VEGFR2. Specific localization of voacangine to tumor compartments in a glioblastoma xenograft mouse was revealed by MSI analysis. The overlap of histological images with the MSI signals for voacangine was intense in the tumor regions and showed colocalization of voacangine and VEGFR2 in the tumor tissues by immunofluorescence analysis of VEGFR2. The strategy employing DARTS and MSI to identify and validate the targets of a natural compound as demonstrated for voacangine in this study is expected to streamline the general approach of drug discovery and validation using other biomolecules including natural products. Full article

(This article belongs to the Special Issue Integrative Multi-Omics in Biomedical Research)

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Review

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15 pages, 2949 KiB

Open AccessReview

A Customizable Analysis Flow in Integrative Multi-Omics

by Samuel M. Lancaster, Akshay Sanghi, Si Wu and Michael P. Snyder

Biomolecules 2020, 10(12), 1606; https://doi.org/10.3390/biom10121606 - 27 Nov 2020

Cited by 18 | Viewed by 6053

Abstract

The number of researchers using multi-omics is growing. Though still expensive, every year it is cheaper to perform multi-omic studies, often exponentially so. In addition to its increasing accessibility, multi-omics reveals a view of systems biology to an unprecedented depth. Thus, multi-omics can be used to answer a broad range of biological questions in finer resolution than previous methods. We used six omic measurements—four nucleic acid (i.e., genomic, epigenomic, transcriptomics, and metagenomic) and two mass spectrometry (proteomics and metabolomics) based—to highlight an analysis workflow on this type of data, which is often vast. This workflow is not exhaustive of all the omic measurements or analysis methods, but it will provide an experienced or even a novice multi-omic researcher with the tools necessary to analyze their data. This review begins with analyzing a single ome and study design, and then synthesizes best practices in data integration techniques that include machine learning. Furthermore, we delineate methods to validate findings from multi-omic integration. Ultimately, multi-omic integration offers a window into the complexity of molecular interactions and a comprehensive view of systems biology. Full article

(This article belongs to the Special Issue Integrative Multi-Omics in Biomedical Research)

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23 pages, 998 KiB

Open AccessReview

Interrogating Host Antiviral Environments Driven by Nuclear DNA Sensing: A Multiomic Perspective

by Timothy R. Howard and Ileana M. Cristea

Biomolecules 2020, 10(12), 1591; https://doi.org/10.3390/biom10121591 - 24 Nov 2020

Cited by 8 | Viewed by 3860

Abstract

Nuclear DNA sensors are critical components of the mammalian innate immune system, recognizing the presence of pathogens and initiating immune signaling. These proteins act in the nuclei of infected cells by binding to foreign DNA, such as the viral genomes of nuclear-replicating DNA viruses herpes simplex virus type 1 (HSV-1) and human cytomegalovirus (HCMV). Upon binding to pathogenic DNA, the nuclear DNA sensors were shown to initiate antiviral cytokines, as well as to suppress viral gene expression. These host defense responses involve complex signaling processes that, through protein–protein interactions (PPIs) and post-translational modifications (PTMs), drive extensive remodeling of the cellular transcriptome, proteome, and secretome to generate an antiviral environment. As such, a holistic understanding of these changes is required to understand the mechanisms through which nuclear DNA sensors act. The advent of omics techniques has revolutionized the speed and scale at which biological research is conducted and has been used to make great strides in uncovering the molecular underpinnings of DNA sensing. Here, we review the contribution of proteomics approaches to characterizing nuclear DNA sensors via the discovery of functional PPIs and PTMs, as well as proteome and secretome changes that define a host antiviral environment. We also highlight the value of and future need for integrative multiomic efforts to gain a systems-level understanding of DNA sensors and their influence on epigenetic and transcriptomic alterations during infection. Full article

(This article belongs to the Special Issue Integrative Multi-Omics in Biomedical Research)

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