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Metabolomics-Edited Transcriptomics Analysis (META)

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The Handbook of Metabolomics

Part of the book series: Methods in Pharmacology and Toxicology ((MIPT))

Abstract

The study of the metabolome or systems biochemical functions in response to external agents such as drugs or toxicants is made possible by recent advances in NMR and mass spectrometry. By coupling the analytical technologies with the stable isotope tracer approach, it is also practical to map changes in metabolic networks with atomic resolution such that metabolic perturbations can be discerned at the enzyme reaction level. This information readily lends its use in guiding transcriptomic analysis for metabolic regulations at the transcriptional level—an approach called “Metabolomics-Edited Transcriptomic Analysis” or META. Two example studies are given to illustrate the use of uniformly 13C-labeled glucose tracer, 13C-isotopomer-based metabolomic analysis, and META for reconstructing metabolic pathways and for discerning their regulatory pathways. The first example describes a hypothetical investigation on the role of a “master” metabolic switch (AMP-activated protein kinase or AMPK) in regulating nucleic acid, lipid, and protein-related metabolism. NMR and GC-MS are complementarily used to obtain quantitative changes in metabolite and 13C-isotopomer profiles in a model cancer cell in response to AMPK activation (induced by AICAR, an adenosine analogue) or AMPK inactivation via siRNA knockdown. Expected findings from META that are consistent with known AMPK-mediated regulations include downregulation or phosphorylation of key proteins involved in the synthesis of fatty acids, phospholipids, and proteins. Scenarios for uncovering metabolic regulations previously unknown or contradictory to known AMPK actions are also given. The second example illustrates a real-world investigation on defining the multitargeted action of selenite in human lung adenocarcinoma A549 cells. The META approach revealed AMPK-mediated downregulation of fatty acid and protein synthesis, in addition to negative regulation of glycolysis, pentose phosphate pathway, Krebs cycle, glutathione synthesis, and nucleotide synthesis, as well as positive regulation of Gln metabolism. The complexity of the selenite action including the induction of opposing regulatory events was resolvable with the integrated metabolomics and transcriptomics approach, which is also generally applicable to any living system including the human body.

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Abbreviations

ACC:

Acetyl CoA carboxylase

ACLY:

ATP citrate lyase

aG3P:

α-Glycerol-3-phosphate

AICAR:

5-Aminoimidazole-4-carboxamide ribonucleoside

aKG:

α-Ketoglutarate

AMPK:

AMP-activated protein kinase

AXP:

Adenine nucleotides

ChREBP:

Carbohydrate-response-element-binding protein

CT:

Choline transporter

CXP:

Cytosine nucleotides

DAG:

Diacylglycerol

DAGK:

Diacylglycerol kinase

DHAP:

Dihydroxyacetone phosphate

eEF2:

Eukaryotic elongation factor 2

eIF4E-BP:

Eukaryotic initiation factor 4E binding protein

FAS:

Fatty acid synthase

FBPase:

Fructose bisphosphatase

G6Pase:

Glucose-6-phosphatase

G6PDH:

Glucose-6-phosphate dehydrogenase

GAP:

Glyceraldehyde-3-phosphate

GCL:

Glutamyl-cysteinyl ligase

GDH:

Glutamate dehydrogenase

Glnase IP:

Glutaminase interacting protein

GLU4:

Glucose transporter 4

GPAT:

Glycerol phosphate acyl transferase

GPC:

Glycerophosphorylcholine

GPDH:

Glycerol-3-phosphate dehydrogenase

GS:

Glycogen synthase

GSH:

Reduced glutathione

GSSG:

Oxidized glutathione

GXP:

Guanine nucleotides

HMGR:

3-Hydroxy-3-methylglutaryl-coenzyme A reductase

HSQC:

Heteronuclear single quantum coherence spectroscopy

iPFK2:

Inducible phosphofructokinase 2

KD:

Knockdown

LDH:

Lactate dehydrogenase

LysoPlase:

Lysophospholipase

MCT1:

Monocarboxylic acid transporter 1

MDH:

Malate dehydrogenase

ME:

Malic enzyme

META:

Metabolomics-edited transcriptomic analysis

METPA:

Metabolomics-edited transcriptomics and proteomics analysis

mTOR:

Mammalian target of rapamycin

N transporter:

Neutral amino acid transporter

OAA:

Oxaloacetate

PABP:

Poly(A)-binding protein

PC:

Phosphatidylcholines

PCase:

Pyruvate carboxylase

P-choline:

Phosphorylcholine

PDH:

Pyruvate dehydrogenase

PDK:

1,3-Phosphoinositide-dependent protein kinase

PE:

Phosphatidylethanolamines

PEP:

Phosphoenolpyruvate

PEPCK:

Phosphoenolpyruvate carboxykinase

PFK:

6-Phosphofructo-2-kinase

PI3K:

Phosphoinositide-3 kinase

PK:

Pyruvate kinase

PKB:

Protein kinase B

PKC:

Protein kinase C

PL:

Phospholipids

PLase:

Phospholipase

PPP:

Pentose phosphate pathway

S6K:

S6 protein kinase

SDH:

Succinate dehydrogenase

SREBP:

Steroid-regulated-element binding protein

TCA:

Trichloroacetic acid

TOCSY:

Total correlation spectroscopy

TOP:

5′-Tract of oligopyrimidine

TPI:

Triosephosphate isomerase

TSC2:

Tuberous sclerosis component 2

[U-13C]-Glc:

13C labeled glucose

UXP:

Uracil nucleotides

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Acknowledgments

This work was supported in part by the National Cancer Institute grant # 1 R01 CA101199-01, NIH Grant Number RR018733 from the National Center for Research Resources, National Science Foundation EPSCoR grant # EPS-0447479, Kentucky Challenge for Excellence, and the Brown Foundation. We thank Dr. Laura Bandura and Ms. Vennila Arumugum for A549 cell culturing, sample processing, and extraction.

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  1. Department of Chemistry, Center for Regulatory and Environmental Analytical Metabolomics (CREAM), and James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA

    Teresa Whei-Mei Fan

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Correspondence to Teresa Whei-Mei Fan .

Editor information

Editors and Affiliations

  1. Department of Chemistry, University of Louisville, Louisville, Kentucky, USA

    Teresa Whei-Mei Fan

  2. Structural Biology Program, University of Louisville, Louisville, Kentucky, USA

    Andrew N. Lane

  3. Department of Chemistry, University of Louisville, Louisville, Kentucky, USA

    Richard M. Higashi

Glossary

META

Metabolomics-edited transcriptomics analysis

Systems biology

Holistic and integrated analysis of biological processes as a system, not as individual parts

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© 2012 Springer Science+Business Media New York

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Fan, T.WM. (2012). Metabolomics-Edited Transcriptomics Analysis (META). In: Fan, TM., Lane, A., Higashi, R. (eds) The Handbook of Metabolomics. Methods in Pharmacology and Toxicology. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-61779-618-0_14

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  • DOI: https://doi.org/10.1007/978-1-61779-618-0_14

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  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-61779-617-3

  • Online ISBN: 978-1-61779-618-0

  • eBook Packages: Springer Protocols

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